Introduction Oxymatrine (OMT) alleviates damage to dopaminergic (DA) neurons and microglia-mediated neuroinflammation in an MPTP mouse model of parkinsonism by inhibiting the High-mobility group protein B1 (HMGB1) pathway. However, the precise mechanism by which OMT inhibits HMGB1 remains unclear. Although miR-141-3p is downregulated in the peripheral blood serum of Parkinson’s disease (PD) patients, its potential relationship with HMGB1 remains unclear. Methods TargetScan software and dual-luciferase reporter gene assays predicted that miR-141-3p binds to the 3’-UTR of HMGB1 mRNA. BV2 cells were transfected with miR-141-3p mimics and stimulated with MPP + in vitro experiments. C57BL/6 J mice received stereotaxic injections of miR-141-3p agomir or miR-141-3p antagomir into the bilateral substantia nigra pars compacta (SNpc). Subsequently, the mice were intraperitoneally injected with MPTP four times within a single day. After miR-141-3p antagomir injection, OMT was administered continuously by injection for 7 days. Behavioral tests were assessed using the rotarod and open field tests. Real-time PCR, western blot, ELISA, and immunofluorescence staining were performed on BV2 cells and SNpc tissues. Results Our study showed an inverse correlation between HMGB1 and miR-141-3p expression in both BV2 microglia exposed to MPP + and MPTP-treated mice. TargetScan analysis identified complementary binding sites between miR-141-3p and the 3’-UTR of HMGB1 mRNA, which was subsequently confirmed through dual-luciferase reporter assays. Through experiments in BV2 microglia exposed to MPP + and in MPTP-treated mice, miR-141-3p downregulates HMGB1, reduces pro-inflammatory cytokine readouts, and in vivo is associated with improved rotarod and open-field performance and attenuated Tyrosine Hydroxylase (TH)-positive neuronal loss. OMT increases miR-141-3p in the MPTP model, alongside reduced HMGB1 and inflammatory readouts, and these effects are diminished by miR-141-3p inhibition. Conclusion miR-141-3p targets HMGB1 to inhibit microglial reaction and mitigate neuroinflammation both in vivo and vitro experiments, reduce TH-positive neuronal loss in the MPTP model. OMT increases miR-141-3p in the MPTP model, alongside reduced HMGB1 and inflammatory readouts, and these effects are diminished by miR-141-3p inhibition.

Experimental advancements in neuroscience have identified cellular engrams—ensembles of neurons whose activation is necessary and sufficient for memory retrieval. Synaptic plasticity, including long-term potentiation, is fundamental to memory encoding and recall, but the relationship between learning-induced dendritic spine potentiation and neuron-wide activation remains unclear. In this study, we employed a post-synaptic translation-dependent reporter consistent with potentiation (SA-PSDΔVenus) and a neuronal activation reporter (ESARE-dTurquoise) to determine their spatiotemporal correlation in the mouse hippocampal CA1 following contextual fear conditioning (CFC). SA-PSDΔVenus+ spines were enriched in ESARE-dTurquoise+ neurons, with distribution varying across CA1 layers at different phases of memory: SA-PSDΔVenus+ were more frequent in activated neurons in stratum oriens and stratum lacunosum moleculare after CFC (encoding), while recall-activated neurons showed a larger number of SA-PSDΔVenus+ in the stratum radiatum. These findings demonstrate that the relative weight and spatial distribution of potentiated synaptic inputs to hippocampal CA1 pyramidal neurons change between the encoding and retrieval phases of memory.

Autism is a common childhood disorder, often comorbid with epilepsy. Both autism and epilepsy are highly heterogeneous in terms of disease etiology and frequently co-occur with other neuropsychiatric phenotypes. Advances in genetic sequencing technologies have significantly improved our understanding of the biological pathways involved in these disorders, particularly in genetic epilepsy (GE). One critical pathway involves gamma-aminobutyric acid (GABA), a key neurotrophic signal during early brain development. GABA plays a central role in maintaining neural excitatory-inhibitory balance, and its dysfunction has been implicated in both autism and epilepsy. GABA acts through its receptors and transporters to regulate neuronal signaling, and disruptions in this system can lead to neural circuit abnormalities. Recent studies have identified that mutations in GABAA receptors and the GABA transporter 1(GAT-1) encoding SLC6A1 result in defective protein folding and retention in the endoplasmic reticulum (ER), leading to impaired proteostasis. This common cellular defect has been observed in a subset of patients with autism and epilepsy, suggesting a shared pathogenic mechanism. We propose that ER retention of mutated proteins and impaired trafficking contribute to disease phenotypes associated with monogenic de novo mutations. Consequently, therapeutic strategies aimed at enhancing protein folding and trafficking, such as the use of chemical or pharmacological chaperones like 4-phenylbutyrate, may provide cross-cutting benefits for both disorders. Our hypothesis highlights the potential for a unified therapeutic approach targeting cellular protein homeostasis in genetically defined subsets of autism and epilepsy.

Enzymes within the cholesterol biosynthesis pathway, particularly those in post-squalene biosynthesis, have been linked to abnormal neurodevelopment. Alterations of individual enzymes manifest unique brain phenotypes, suggesting each enzyme has distinct roles within the mammalian neural cell. However, a comprehensive characterization of cholesterol biosynthesis enzymes to understand these differences has yet to be fully obtained. Therefore, this study aimed to contribute to this growing body of knowledge by characterizing the subcellular localization of the cholesterol biosynthesis enzyme Hydroxysteroid-17-beta7 (Hsd17b7) within a mammalian neural cell line. Using mouse Neuro2a cells, we compared expression patterns between both endogenous Hsd17b7 and GFP-tagged constructs. Using confocal microscopy, we noted Hsd17b7 absence in the Golgi and lysosomes while confirming its presence in the endoplasmic reticulum. Of interest, we also observed co-localization with the nuclear membrane, which had not been established. Upon 24-hour serum deprivation, patterns of Hsd17b7-GFP in differentiated cells were still observed in the cell body, as seen in the undifferentiated cells. However, we also observed evidence of GFP-positive protein localization within MAP2-positive neurites. Co-staining with Hsd17b7 antibody and conjugated Phalloidin further supported the localization of Hsd17b7 within developing neurites. Together, this suggests a potential role for Hsd17b7 within early axons and dendrites, however, further investigation is needed to determine potential implications on neural differentiation.

[This retracts the article DOI: 10.3389/fnmol.2020.00084.].

Parkinson’s disease (PD) symptom onset is typically unilateral, which may be related to molecular differences underlying hemispheric vulnerability. Here we sampled prefrontal cortex bilaterally from people with PD and healthy controls and performed RNA-seq on neuronal nuclei to determine hemispheric and disease-related differences. Brain hemispheres were categorized based on whether they corresponded to the side of symptom onset (severe) or the opposite side (moderate) and compared for differences in gene expression. We employed two a priori approaches; first we identified genes differentially expressed between PD and controls and between PD brain hemispheres. Second, we examined the presence of, and correlates to, variations in the asymmetry for some differentially expressed genes. We found large variation among individuals with PD, and so PD stratification by gene expression signature was required for patterns of genetic asymmetry to emerge. For a subset of PD brains, hemispherical variation of CCT gene levels correlated with the side of PD symptom onset. In a mouse model of PD, neurons with α-synuclein inclusions had decreased Cct expression. These results suggest that CCT expression plays a protective role in PD.

IntroductionNeuropathic pain (NP) is a kind of common and intractable chronic pain. Hydrogen (H2)-rich water exhibited protective effects in NP by intrathecal injection, drinking, and intraperitoneal injection. The nanobubble H2-dissolved water (NHW) is a solution that contains H2 bubbles and H2 in lysis state. Therefore, this study aimed to observe the effects of ultrasound-guided local injection with NHW in the model of NP, and try to find its possible mechanism.MethodsThe rat sciatic nerve was ligated to establish chronic constriction injury (CCI)-induced NP model. The CCI rats received NHW at low or high concentrations 1 or 3 times (n = 6). During the experiment, the paw withdrawal thresholds (PWT) and paw withdrawal latency (PWL) were detected. At 14 days after CCI, the organizational structure of nerve, inflammatory response, and oxidative stress damage were measured. Additionally, the Nrf2/HO-1 and sulfiredoxin-1 were also detected by western blotting and RT-PCR.ResultsCompared with low concentration, in the high concentration group, the PWT and PWL were attenuated on Day 1, 3, 5, 7, and 14 after CCI (p < 0.05). On Day 14, nerve injury, inflammatory response, and oxidative stress injury were relieved significantly in high concentration than at low concentration, and the effect was greater at multiple doses (3 times) at high concentrations (p < 0.05), as were the increase in the protein and mRNA levels of Nrf2/HO-1 and sulfiredoxin-1.ConclusionUltrasound-guided early local injection of NHW attenuated sciatic nerve injury, alleviated mechanical allodynia and thermal hyperalgesia and inhibited inflammation and oxidative stress damage via the Nrf2/HO-1-sulfiredoxin1 pathway in a rat model of CCI.

IntroductionAlzheimer’s disease (AD) is characterized by the accumulation of amyloid-beta (Aβ) peptides, which contribute to synaptic dysfunction, neuronal toxicity, and gene expression alterations. In a previous study, we identified a phage displaying a peptide that selectively interacts with Aβ autoantibodies.MethodsHere, we assessed whether this phage also directly interacts with Aβ, as predicted through bioinformatic analyses. We evaluated its functional effects in a neuronal cell line exposed to Aβ and performed transcriptomic profiling by RNA sequencing.ResultsWe demonstrate that the phage directly interacts with Aβ, consistent with bioinformatic predictions. Functionally, the phage protected the neuronal cell line from Aβ-induced toxicity. RNA sequencing revealed that the phage prevented Aβ-induced alterations in the expression of 1,819 genes, suggesting a role in modulating Aβ-associated metabolic changes.DiscussionThese findings highlight the therapeutic potential of phage-displayed peptides in counteracting Aβ toxicity and restoring cellular homeostasis, laying a foundation for future investigations into phage-based interventions for AD.

IntroductionSciatica is a prevalent and highly debilitating condition that is clinically characterized by pain radiating along the distribution of the sciatic nerve. Despite its common occurrence, the progression of early sciatica remains not yet fully elucidated. The aim of this study is to explore the potential molecular mechanism underlying early-stage sciatica progression.MethodsA total of 20 rats were collected, with 9 in the control group and 11 rats in the chronic constriction injury (CCI) model group. The sciatic nerve tissues of rats were collected at three time points 1, 3, and 7 days post surgery. Protein microarray was used to detect the expression levels of 27 cytokines in sciatic nerve tissues at different times. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used for functional and pathway analysis of the differentially expressed proteins (DEPs). ELISA was used to detect the levels of chemokine CINC-2 and neurotrophic growth factors (CNTF).ResultsA total of 11 proteins showed significant differential expression between the CCI and control groups at all three time points (days 1, 3, and 7) after sciatic nerve injury. Specifically, Cytokine-Induced Neutrophil Chemoattractant-2 (CINC-2), Cytokine-Induced Neutrophil Chemoattractant-3 (CINC-3), Lipopolysaccharide-Induced CXC chemokine (LIX), Lymphocyte-Selectin (L-Selectin), Platelet-Derived Growth Factor-AA (PDGF-AA), Interleukin-1 alpha (IL-1α), Interleukin-6 (IL-6), Tissue Inhibitor of Metalloproteinase-1 (TIMP-1), and beta-Nerve Growth Factor (β-NGF) were significantly upregulated (p < 0.05), whereas the neurotrophic-related protein CNTF was significantly downregulated (p < 0.05). KEGG pathway analysis revealed that these DEPs were primarily enriched in key inflammatory signaling pathways, including the JAK–STAT, Cytokine-cytokine receptor interaction, Chemokine, Tumor Necrosis Factor (TNF), NOD-like receptor, and NF-kappa B signaling pathways. GO analysis indicated their involvement in biological processes such as immune response and cellular chemotaxis. Protein function analysis further confirmed the close correlation of these DEPs with cellular recognition and neuroinflammation. Additionally, ELISA validation showed that the key protein CINC-2 was upregulated and CNTF was significantly downregulated in the early CCI group.DiscussionThe progression of early sciatic is closely associated with neuroinflammation triggered by the overexpression of inflammatory factors and nerve dysfunction mediated by neurotrophic-related proteins.