Molecular Neurobiology最新文献

Parkinson's disease (PD) is the second most common neurodegenerative disorder, and its pathogenesis is closely associated with oxidative stress, mitochondrial dysfunction, and iron-dependent cell death. In our previous study, we showed that 3-n-butylphthalide (NBP) alleviates behavioral deficits in a PD mouse model. However, the underlying mechanisms remain unclear. Here, we found that NBP treatment significantly attenuated ferroptosis induced by Erastin or RSL3 in SH-SY5Y cells, as evidenced by improved cell viability, reduced reactive oxygen species (ROS) production, decreased mitochondrial oxidative stress, and lower levels of lipid peroxidation. Molecular docking analysis revealed that NBP interacts with ACSL4 at residues PRO-404, TYR-425, VAL-447, ILE-526, and LYS-649. A cellular thermal shift assay combined with site-directed mutagenesis indicated that PRO-404 and ILE-526 are critical for the interaction between ACSL4 and NBP. Furthermore, pulse-chase experiments showed that NBP enhances ACSL4 protein stability. Notably, ACSL4 overexpression abrogated the protective effects of NBP in Erastin- or RSL3-treated cells. Collectively, our data indicate that NBP protects SH-SY5Y cells from ferroptosis, likely through the suppression of ACSL4-mediated lipid peroxidation. These results highlight the therapeutic potential of NBP for treating ferroptosis-related neurodegenerative diseases such as PD.

Blood pressure (BP) regulation involves complex interactions between peripheral organs and the brain. As a key area gating BP regulation, how the hypothalamic paraventricular nucleus (PVN) modulates salt‑sensitive hypertension remains unclear. Here, we found that Sik1, a member of the AMP-activated protein kinase family, was upregulated in PVN neurons of mice following a high-salt diet (HSD). When Sik1 was ablated, Sik1 knockout mice exhibited an increase in BP upon HSD feeding. Furthermore, specific deletion of the Sik1 gene in the nervous system by Nestin-Cre (Nestin-Cre;Sik1^-/-) resulted in elevated BP after high salt intake. Notably, AAV-Cre-mediated selective ablation of Sik1 in the PVN neurons was sufficient to cause BP elevation following an HSD. In combination with western blot and immunofluorescence detection, single-nucleus RNA sequencing combined with KEGG pathway analysis showed that Sik1 is predominantly expressed in arginine vasopressin (AVP)-positive neurons of the PVN, and in the absence of Sik1, the cellular NF-κB pathway in these neurons is downregulated by HSD. In addition, Sik1 deficiency led to microglial activation within the PVN under HSD conditions. These results suggest that Sik1 in AVP-positive neurons of PVN attenuates HSD-induced blood pressure elevation, possibly via modulation by the NF-κB signaling pathway. Our findings uncover a previously unrecognized role of neuronal Sik1 in salt‑sensitive hypertension pathophysiology, advancing our understanding of neurogenic blood pressure regulation.

Methamphetamine (METH) abuse has emerged as a significant public health concern due to its widespread use and persistent adverse effects on brain function. Accumulating evidence indicates that chronic METH exposure disrupts dopaminergic neurotransmission and induces neurotoxic processes that overlap with key pathological features of Parkinson's disease (PD). This review critically examines clinical, epidemiological, and experimental studies exploring the association between METH use and increased vulnerability to PD-related neurodegeneration. Particular emphasis is placed on findings from animal models and cellular studies demonstrating dopamine depletion, motor impairments, mitochondrial dysfunction, and sustained neuroinflammatory responses following METH exposure. The review highlights oxidative stress and neuroinflammation as central mechanisms linking METH-induced neurotoxicity to PD pathology. Emerging evidence suggests that METH-driven activation of the NFĸB promotes the release of proinflammatory cytokines, thereby exacerbating neuronal injury, while concurrent impairment of Nrf2 signaling compromises antioxidant defense and cellular resilience. Dysregulation and crosstalk between the NFĸB and Nrf2 pathways appear to play a critical role in sustaining chronic inflammation, redox imbalance, and progressive dopaminergic neuronal loss. By integrating molecular, cellular, and translational evidence, this review provides mechanistic insights into the contribution of Nrf2 and NFĸB signaling pathways to METH-associated neuroinflammation and PD-related pathology. Furthermore, it discusses the therapeutic potential of targeting these pathways and underscores the need for longitudinal studies to clarify causality. Finally, the review addresses broader public health implications, emphasizing the importance of preventive strategies, awareness programs, and future research aimed at mitigating the long-term consequences of methamphetamine abuse.

High-altitude retinopathy (HAR) arises under acute hypobaric hypoxia (AHH), yet the temporal coupling of oxidative stress, apoptosis and cytokine signaling in the retina remains unclear. We exposed healthy male C57BL/6 mice to a hypobaric chamber (≈5,000 m) for 2-72 h, with normoxic controls at 1,500 m (n = 3 eyes/group). Haematoxylin-eosin sections quantified total and laminar thickness; at 24 h, bulk RNA-seq profiled transcripts. Reactive oxygen species (ROS) were assayed by dihydroethidium, and Western blotting/immunofluorescence evaluated Bax, Bcl-2/Bcl-xL, cleaved caspase-3, cytochrome c, poly(ADP-ribose) polymerase-1, tumour necrosis factor-α, phosphorylated Janus kinase-1 (p-JAK1), phosphorylated signal transducer and activator of transcription-3 (p-STAT3), leukemia inhibitory factor (LIF) and LIF receptor (LIFR). Total retinal thickness increased from 173.10 ± 0.36 μm (control) to 227.99 ± 0.33 μm at 24 h and 234.61 ± 0.39 μm at 72 h, with concordant GCL/INL/ONL thickening. RNA-seq showed enrichment of hypoxia/oxidative-stress, apoptotic, and JAK-STAT pathways with Lif/Lifr up-regulation. ROS rose from 12 h and peaked at 72 h (p < 0.05). Pro-apoptotic indices (Bax/Bcl-2, Bax/Bcl-xL, cleaved caspase-3/total) and cytochrome c, PARP-1, and TNF-α increased with exposure. p-JAK1 rose from 12 to 72 h, whereas p-STAT3 peaked at 48 h and remained elevated at 72 h. LIF/LIFR protein accumulated from 2-72 h (48 h apex). These time-resolved data reveal progressive oedema with sustained oxidative burden and a LIF-JAK1-STAT3 activation peak, suggesting a therapeutic window in AHH-induced retinal injury.

Physiological aging involves a progressive deterioration of homeostatic mechanisms that cause obesity and defective glucose homeostasis, which develop age-related diseases increasing mortality risk and reducing lifespan. The brainstem is involved in glucose and metabolic homeostasis by integrating peripheral signals such as insulin and leptin. Here, we evaluated the brainstem response to intracerebroventricular administration of insulin or leptin and the relationship with physiological levels of key molecules implicated in their signal transduction pathway and inflammation in 3-, 6-, and 12-month-old mice which progressively increase adiposity and develop signs of insulin resistance. The initial steps of insulin and leptin signaling pathways decline with age, as well as the protein kinase B (Akt) phosphorylation response. Both hormones decrease the phosphorylation of AMP-activated protein kinase (AMPK) but, while the response to insulin increases with age, the response to leptin decreases in older animals. This insulin and leptin resistance is accompanied by changes in basal protein expression or phosphorylation of insulin and leptin receptors and insulin receptor substrates-1 (IRS-1), as well as the imbalance between basal levels of Akt-phosphorylated and non-phosphorylated protein, without changes in other serine kinases and/or inflammatory pathways such as glycogen-synthase-kinase-3 (GSK3), mammalian targets of rapamycin (mTOR), kinase-p70S6 (p70), protein kinase-C-ε (PKCε), p38 mitogen-activated protein kinase (p38), or c-Janus N-terminal kinase (JNK). High levels of proinflammatory cytokines and glial cell activation suggest the development of neuroinflammation in the brainstem with age, which could mediate the age-associated insulin and leptin resistance and the impairment in glucose and metabolic homeostasis commonly observed in the aging process.

Memory plays a crucial role in human cognitive processes and daily functioning. While memory has a genetic basis, identifying the specific genetic factors influencing memory performance has proven challenging. This challenge arises because memory is a complex trait, whose genetic architecture likely comprises an accumulation of many low-effect size common variants. Thus, study sample sizes are easily insufficient, leading to underpowered genetic association analyses. This limitation is especially pronounced in studies that prioritize deep phenotyping over broader recruitment, resulting in smaller cohorts. Given these limitations, important biological signals may remain undetected when relying solely on conventional genome-wide significance thresholds. However, even variants that fall below these thresholds can yield meaningful insights when analyzed in a broader biological context. Therefore, we propose that relevant biological information can still be extracted by employing a less stringent p-value threshold paired with elaborate variant mapping and functional annotation to identify candidate variants, genes, and biological pathways associated with memory performance. We present three independent genome-wide association studies within the Human Connectome Project on a (i) Penn-Word verbal episodic memory test (n = 1131), a (ii) Picture Sequence visual episodic memory test (n = 1133), and a (iii) List Sorting verbal working memory test (n = 1134). Subsequent variant mapping, functional annotation, and pathway identification were performed using FUMA, Cytoscape, KEGG, Reactome, and WikiPathways. At the pathway level, but not single variant or gene level, we observed substantial overlap in results across the three memory tests, and between our results and previously reported findings. Several identified genes and pathways were previously associated with memory-related disorders, and processes related to cognition, neurodevelopment, and neurological dysfunction. We interpret the common pathways as reflecting shared biological mechanisms underlying memory. Our findings underscore the potential of our proposed approach, which we provide as an openly accessible pipeline, for exploring other complex polygenic traits.

Brain organoids have revolutionized neuroscience by providing unique in vitro models for studying human brain development and disease. This study presents a comprehensive bibliometric analysis of brain organoid research from 2015 to 2025, integrating VOSviewer and CiteSpace, while using Scimago Graphica to enhance the visualization. Our journal analysis reveals Stem Cell Reports and Cell Stem Cell as stable high-impact venues, with Stem Cell Reports and Nature Communications showing the fastest growth. Geographically, the USA and European nations maintain dominance in both productivity and citation impact. We systematically mapped the field's evolution across three phases: the technological germination period (2001-2014), rapid expansion from foundation to application (2015-2020), and recent developments including refinement and ethical considerations (2020-2025). Our analysis reveals key factors contributing to the field's recent cooling trend, including standardization challenges, diversification trends, and emerging ethical concerns. We identify major research hotspots such as vascularization and microenvironment optimization and also highlight critical milestones such as the development of fused organoid systems and vascularized models. This study not only provides a historical perspective on brain organoid research but also offers valuable insights for future directions, emphasizing the need for standardized protocols, enhanced international and multidisciplinary collaboration, and balanced ethical frameworks to sustain progress in this transformative field.

Receptor-interacting protein kinase 1 (RIPK1) is a pivotal molecule regulating cell death and inflammatory signaling pathways, with its activity tightly modulated by multiple post-translational modifications. While its involvement in various pathological processes is recognized, its precise regulatory roles and underlying mechanisms in ischemic stroke remain incompletely defined. Accumulating evidence indicates that RIPK1 modulates apoptotic and necroptotic cascades, neuroinflammation, and NF-κB pathway activation, thereby serving as a contributing factor that collaborates with other molecular pathways to influence stroke progression and outcome. In this review, we first summarize current insights into the molecular structure and biological functions of RIPK1, emphasizing the regulatory networks established by its post-translational modifications. We then dissect the multifaceted mechanisms by which RIPK1 participates in ischemic stroke pathology, including its roles in cell death, neuroinflammation, and blood-brain barrier integrity, as well as its potential as a diagnostic indicator for ischemic brain injury. Finally, we present a concise overview of the development status of RIPK1 inhibitors, which covers preclinical candidates and clinical trial-stage agents, aiming to inform future research endeavors and guide clinical translation for ischemic stroke treatment.

Traumatic brain injury (TBI) is one of the leading causes of disability and death worldwide. Zipper-interacting protein kinase (ZIPK) is a serine/threonine kinase, whose main function is to regulate cell death, inflammation and smooth muscle contraction. ZIPK dysregulation has been implicated in a range of neurological disorders, including ischemic stroke, Alzheimer's disease, and TBI. Downregulation of ZIPK expression level or pharmacological inhibition of ZIPK kinase activity alleviates neuronal injury. ZIPK has a nuclear localization signal sequence and transcriptional regulatory activity. However, whether ZIPK affects gene expression in the brain after TBI remains unknown. In this study, transcriptome sequencing analysis was employed to compare the differences in gene expression in the peri-injury tissues between wild-type and ZIPK heterozygous mice after TBI. Our results indicated that ZIPK regulates a variety of genes and signaling pathways, including pathways related to synaptic function, learning and memory, vascular function, and DNA replication, after TBI. Gene set enrichment analysis highlighted the important role of ZIPK in synapses during TBI. In addition, quantitative real-time PCR analysis validated changes in the expression of multiple genes related to synaptic function, including Drd1, Grin2a, Grin2b, Dlg4, Fn1, and Pecam1, which were identified by gene correlation analysis and protein-protein interaction analysis. Immunofluorescence staining revealed that partial deletion of ZIPK alleviates synaptic protein loss induced by TBI. In conclusion, our data suggest a role for ZIPK in the regulatory network in the brain, especially in relation to synaptic damage, after TBI, providing a new therapeutic strategy for this condition.

Alzheimer's disease (AD), a debilitating neurodegenerative disorder, currently lacks effective curative treatments. Growing evidence implicates aluminium, a widely prevalent environmental metal, in the pathogenesis of AD due to its ability to induce oxidative stress, neuroinflammation, cholinergic dysfunction, and amyloid-beta (Aβ) deposition, ultimately leading to cognitive decline. Biochanin A (BCA), a naturally occurring isoflavone, exhibits well-documented antioxidant, anti-inflammatory, and neuroprotective activities, including acetylcholinesterase (AChE) inhibition. However, its specific therapeutic potential in AD models has remained largely unexplored. This study evaluates the protective effects of BCA against aluminium chloride (AlCl₃)-induced AD-like pathology in mice. Animals received daily oral administration of AlCl₃ (100 mg/kg) for 6 weeks, with or without concurrent BCA treatment (5, 10, and 20 mg/kg). During the final week, comprehensive neurobehavioral assessments were conducted. Thereafter, hippocampal tissues were analyzed for biochemical, molecular, and elemental analyses, and intact brains were examined histologically. AlCl₃ exposure significantly impaired neurobehavioral performance, elevated oxidative stress, disrupted cholinergic function, intensified neuroinflammation, promoted amyloid aggregation, and induced neurodegeneration. Notably, BCA supplementation dose-dependently ameliorated these pathological alterations. BCA treatment improved neurobehavioral deficits (P < 0.05), reduced oxidative markers (P < 0.01), restored cholinergic function by lowering AChE activity (P < 0.01), attenuated inflammatory mediators (P < 0.01), reduced amyloid and aluminium deposition (P < 0.001), and alleviated AlCl₃-induced neurodegeneration. Overall, our findings indicate that BCA confers neuroprotection primarily through activation of the NRF2-HO-1 signaling pathway and through suppression of the NLRP3 inflammasome, highlighting its promise as a potential therapeutic candidate for AD.