Molecular Neurobiology最新文献

Preeclampsia (PE) is a pregnancy-specific hypertension with signs of other organ dysfunction. Despite its unclear mechanism, current data suggest the role of neuroinflammation in blood pressure dysregulation in PE. Considering the role of toll-like receptor 4 (TLR4) in various inflammatory conditions, we hypothesized that centrally expressed TLR4 may promote PE and that its inhibition, with pyridostigmine (PYR), may attenuate this condition in rats. Changes in TLR4 expression in the paraventricular nucleus (PVN) of reduced uterine perfusion pressure (RUPP) were assessed, as well as TLR4 sensitivity. The effect of PYR, at an oral dose of 20 mg/kg/day, on TLR4 signaling in RUPP or lipopolysaccharides (LPS, 5 µg/kg)-infused pregnant rats was assessed. On gestation day 19, mean arterial pressure (MAP) was recorded under urethane anesthesia, and PVN samples were collected and subsequently processed. Placental ischemia increased MAP (p < 0.05), TLR4 expression (p < 0.05) in RUPP, and TLR4 sensitivity in RUPP + LPS rats. LPS infusion elevated MAP to a greater extent in RUPP (37.1 ± 3.5 mmHg) compared to Sham (13.2 ± 6.5 mmHg) (p < 0.01) after 1 h. Such an effect of LPS was associated with increased expression of c-Fos (p < 0.01) in the PVN. PYR significantly reduced MAP in RUPP and LPS-treated dams, as well as TLR4 signaling proteins, ROS, TNF-α, and IL-1β in the PVN. In conclusion, placental ischemia-increased MAP is associated with high TLR4 expression in the PVN and increased TLR4 sensitivity, and PYR could attenuate TLR4 signaling in the PVN, thereby reducing blood pressure.

Intracerebral hemorrhage (ICH) incidence increases with age, and neuronal mitochondrial dysfunction and apoptosis post-ICH contribute to severe secondary brain injury. It is of paramount importance to explore molecular targets for protecting against brain injury after ICH. UBA52, a ubiquitin precursor protein, was found to be upregulated in brain tissues of ICH mice. Intracerebral injection of adeno-associated virus type 9 overexpressing UBA52 (AAV9-UBA52) alleviated neurological deficits and brain edema in ICH mice. In vitro and in vivo experiments demonstrated that UBA52 overexpression reduced hemin or ICH-induced apoptosis, reflected in decreased TUNEL-positive cells and reduced caspase-3 and caspase-9 levels. The augmentation of fluorescence intensity in Mitotracker labeling and the reduction of fluorescence intensity in JC-1 staining suggested that UBA52 overexpression mitigated hemin-induced mitochondrial damage. This was further evidenced by increased cellular ATP content and elevated cytochrome c levels located in mitochondria. In vivo findings showed that UBA52 overexpression reduced the quantity of degenerative neurons. UBA52 and NeuN co-localization verified its direct protective effect on neurons. IP-LC/MS and Co-IP assays identified Daxx as a UBA52-interacting protein, with UBA52 promoting Daxx ubiquitination and degradation. Rescue experiments showed Daxx overexpression abolished the protective effect of UBA52 against hemin-induced apoptosis and mitochondrial dysfunction. Collectively, this study demonstrated that UBA52 ameliorates ICH-induced secondary brain injury by promoting Daxx ubiquitination/degradation to inhibit neuronal apoptosis and mitochondrial damage, suggesting UBA52 as a potential protective target for ICH therapy.

Neurodegenerative diseases, including multiple sclerosis, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, are characterized by progressive neuronal loss and are frequently linked to metal dysregulation, oxidative stress, and immune dysfunction. Metallothioneins (MTs), a family of cysteine-rich, metal-binding proteins, are critical in maintaining metal homeostasis, mitigating oxidative damage, and modulating immune responses, functions highly relevant in these pathologies. MTs regulate essential metals like copper and iron by preventing their participation in harmful redox reactions and control zinc availability for enzymatic and signaling processes. They also detoxify neurotoxic metal(oid)s such as cadmium, mercury, lead, and arsenic, thereby reducing their adverse neurological and immunological effects. In autoimmune neurodegeneration, MTs modulate pro- and anti-inflammatory cytokines (e.g., IL-6, TNF-α, IL-10) and influence immune cell activity, particularly microglia and T cells, which are central to neuroinflammation and autoimmunity. Through these mechanisms, MTs play a dual role in sustaining immune homeostasis and counteracting oxidative stress. Their capacity to integrate metal regulation with immune modulation positions them as promising therapeutic targets, with preclinical and some clinical evidence supporting strategies to enhance MT expression or develop MT-mimetic agents to address both metal dysregulation and immune imbalance. Additionally, MTs show emerging utility as biomarkers, as alterations in MT isoform expression and metal-bound complexes in biofluids have been associated with disease onset, progression, and therapeutic response in specific neurodegenerative conditions. This article reviews the multifaceted roles of MTs in neurodegenerative diseases, emphasizing their function in metal and immune regulation and their emerging potential as therapeutic targets and clinical biomarkers.

Depression is a widespread neuropsychiatric disorder with the current therapeutic approaches achieving only suboptimal efficacy. Neferine is the main bioactive component of Nelumbinis plumula with multiple pharmacological functions. This study sought to investigate the antidepressant activity of neferine and elucidate its underlying mechanisms. Network pharmacology analysis was performed to uncover the molecular targets and pathways involved in neferine's antidepressant effects. The interaction of neferine with the core target was demonstrated by molecular docking and molecular dynamics simulation. The mouse model of depression triggered by chronic corticosterone (CORT) administration was utilized to validate the impact of neferine on core targets and pathways. We found that neferine remarkably attenuated CORT-induced depressive-like behaviors in mice. A total of 178 overlapping targets were acquired through the intersection of neferine and depression-related genes. The protein-protein interaction (PPI) network analysis revealed nine pivotal hub genes, namely AKT1, TNF, ESR1, PPARG, JUN, HIF1A, CASP3, NFKB1, and MMP9. Functional enrichment analysis indicated that these targets predominantly mapped to the TNF signaling pathway in depression. Molecular docking and molecular dynamics simulation showed that neferine has strong binding stability with PPARγ, a key molecule involved in regulating the TNF pathway. The results of animal experiments found that a PPARγ antagonist abolished neferine-induced alleviation of depressive-like behaviors. Moreover, neferine suppressed TNF/NF-κB pathway activation and attenuated neuronal loss in the hippocampus, potentially through activating PPARγ. Collectively, our study suggested that neferine produced antidepressant effects by suppressing hippocampal inflammation and neuronal loss through inhibiting the TNF/NF-κB signaling pathway. These preclinical evidence laid a foundation for further exploring the role of neferine in treating depression.

The transcription factor Nurr1 (NR4A2) serves as an essential element in dopaminergic neuron development since it functions predominantly in the substantia nigra, which becomes severely affected during Parkinson's disease (PD) and Alzheimer's disease (AD). Nurr1 regulates dopamine synthesis, survival-promoting, and oxidative stress genes that affect mitochondrial formation. Nurr1 binds to PGC-1α, allowing for mitochondrial activity regulation. This relationship supports mitochondrial biogenesis. Post-translational changes, including phosphorylation and acetylation, modify Nurr1 transcriptional regulation in order to enhance its ability to regulate mitochondrial genes. The assessment examines Nurr1's involvement in dopaminergic neuron development and mitochondrial formation while showing its role in reducing oxidative damage for an extensive understanding of its neurological disease functionality. Nurr1 serves as a therapeutic candidate for analysis, while the review explores obstacles and potential paths for using Nurr1-based treatments against Parkinson's disease alongside Alzheimer's disease and other neurodegenerative disorders. The extensive research utilized multiple databases, PubMed, Scopus, Medline, and EMBASE, with keywords "Nurr1," "NR4A2," "Neurodegenerative disorders," "Mitochondrial biogenesis," "Oxidative stress," "Parkinson's disease," "Alzheimer's disease," and "Therapeutic target." The analysis examined published research regarding Nurr1-mediated control of dopaminergic function and survival and mitigation of neurological and mitochondrial deficits within the past decade. Nurr1's interactions with important co-regulators like PGCα, its post-translational changes, and its effects on neuroinflammation have also received particular focus. In neurodegenerative illnesses, mitochondrial dysfunction adds to neuronal damage. Nurr1's regulation of mitochondrial biogenesis helps recover mitochondrial function, alleviate oxidative stress, and sustain neuronal survival. Dysregulation of Nurr1 expression is connected to decreased mitochondrial activity and accelerated neurodegeneration.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative diseases characterised by TAR DNA-binding protein 43 kDa (TDP-43) pathology. We previously showed that deletion of glycogen synthase kinase-3 (GSK3) suppresses TDP-43-mediated motor neuron degeneration in Drosophila. Here, we investigated the potential of GSK3 inhibition to ameliorate TDP-43-mediated toxicity in mammalian neurons. We show that TDP-43 activates GSK3 and promotes caspase-dependent cleavage of TDP-43, generating C-terminal fragments. We determine the functional importance of the N-terminal Asp89 caspase cleavage site in regulating TDP-43 proteostasis in both wild-type and ALS-linked TDP-43 variants and show that GSK3 inhibition selectively reduces truncated TDP-43 species, lowers nuclear TDP-43 levels, and improves neuronal survival. Neuroprotective effects were conserved in primary rodent cortical neurons, primary mouse motor neurons, and human iPSC-derived cortical neurons, highlighting the potentially broad therapeutic potential of GSK3 inhibition. We also find that the GSK3 inhibitor CHIR99021 reduces GSK3 RNA and protein expression and increases GSK3 phosphorylation, indicating novel mechanisms by which it acts to inhibit GSK3 activity. Unexpectedly, an N-terminally truncated variant (TDP-43^N-Del), originally designed as a negative transfection control, exerted modest toxicity, potentially through retained susceptibility to caspase cleavage. Together, our findings uncover a caspase-mediated mechanism linking GSK3 activity to TDP-43 turnover, localisation, and neurotoxicity, and position GSK3 inhibition as a promising strategy to mitigate TDP-43-driven neurodegeneration in ALS-FTD.

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.