Neurochemical Research最新文献

{"title":"Targeting PAI-1 with TM5441 Mitigates Chronic Social Stress-Induced Anxiety-Like Behavior and Stress-Induced Increases in Ethanol Intake and Preference","authors":"Amine Bahi,&nbsp;Jean-Luc Dreyer","doi":"10.1007/s11064-026-04865-w","DOIUrl":"10.1007/s11064-026-04865-w","url":null,"abstract":"<div><p>Chronic stress promotes alcohol use and relapse, yet the mechanisms linking stress-induced anxiety to excessive ethanol consumption remain poorly understood. Plasminogen activator inhibitor-1 (PAI-1), a stress-responsive regulator of neuroplasticity, has recently emerged as a potential therapeutic target; however, its role in stress-induced alcohol-related behaviors remains unknown. This study investigated whether TM5441, a selective inhibitor of plasminogen activator inhibitor-1 (PAI-1), modulates anxiety-like behavior and ethanol consumption following chronic social stress. Male mice were subjected to social defeat chronic stress (SDCS) and treated with TM5441. Behavioral assessments included the elevated plus maze (EPM), open field test (OFT), and two-bottle choice paradigms to assess voluntary intake of ethanol, saccharin, and quinine. Blood ethanol concentration (BEC) was measured to evaluate pharmacokinetic parameters. TM5441 significantly attenuated SDCS-induced anxiety-like behaviors and restored stress-induced increases in ethanol intake and preference toward control levels. These effects were specific to ethanol, as neither TM5441 nor stress altered saccharin or quinine consumption. Importantly, pharmacokinetic analyses revealed no differences in ethanol absorption or clearance, and BEC did not correlate with ethanol intake or preference, indicating that the observed behavioral effects are unlikely to result from differences in ethanol pharmacokinetics. Correlational analyses supported a functional link between anxiety-like behavior and increased ethanol consumption under stress. Together, these findings suggest that PAI-1 may contribute to the link between stress-induced anxiety and alcohol consumption and support further investigation of PAI-1 as a potential target for stress-related alcohol use disorders.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 5","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148783396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CT1812 Attenuates Surgery-Induced Cognitive Impairment and Modulates TMEM97- and PGRMC1-Associated Hippocampal Stress Responses in Aged Mice","authors":"Qianwen Wang,&nbsp;Yanian Wei,&nbsp;Cheng Shen,&nbsp;Wen Kang,&nbsp;Long Wang","doi":"10.1007/s11064-026-04864-x","DOIUrl":"10.1007/s11064-026-04864-x","url":null,"abstract":"&lt;div&gt;&lt;p&gt;Postoperative neurocognitive disorders (PND) are common complications in older surgical patients, but druggable mechanisms linking surgical trauma to hippocampal synaptic and cognitive vulnerability remain poorly defined. The σ-2 receptor (σ-2R), encoded by transmembrane protein 97 (TMEM97), and progesterone receptor membrane component 1 (PGRMC1) intersect membrane lipid biology and synaptic stress signaling; CT1812, a pharmacological σ-2R complex modulator, has shown target engagement in early Alzheimer’s disease trials, but whether this pathway participates in postoperative hippocampal injury is unknown. This study examined whether surgery-induced hippocampal stress in aged mice is associated with TMEM97 and PGRMC1 signaling and whether early CT1812 treatment can attenuate this response. Young adult (2–3 months) and aged (18–20 months) male C57BL/6J mice underwent sham operation or laparotomy; aged mice were further treated with vehicle or CT1812 (3 mg/kg, intravenous injection, days 0–3). Hippocampal molecular changes were assessed by western blotting and immunofluorescence on day 3, and behavior was evaluated by open field test (OFT) and Morris water maze (MWM) on days 6–10. Laparotomy increased hippocampal TMEM97 and PGRMC1 expression and induced anxiety-like and spatial-memory deficits preferentially in aged mice, without evidence that locomotor impairment explained the behavioral phenotype. TMEM97 and PGRMC1 were detected in neuronal nuclei (NeuN)-positive neurons, ionized calcium-binding adapter molecule 1 (Iba-1)-positive microglia, and glial fibrillary acidic protein (GFAP)-positive astrocytes in hippocampal cornu ammonis 1 (CA1), supporting multicellular pathway involvement. In aged surgical mice, CT1812 significantly reduced upregulation of TMEM97 and PGRMC1, improved OFT center-zone occupancy and MWM performance, and restored the synaptic markers postsynaptic density protein 95 (PSD95) and synaptophysin. CT1812 also normalized lipid-handling proteins, including apolipoprotein E (ApoE), ATP-binding cassette transporter A1 (ABCA1), cholesterol 24-hydroxylase (CYP46A1), and low-density lipoprotein receptor (LDLR), and reduced perilipin 2 (PLIN2) accumulation in neurons and microglia. In parallel, CT1812 attenuated a selective endoplasmic reticulum (ER) stress response involving binding immunoglobulin protein (BIP) and protein kinase R-like endoplasmic reticulum kinase (PERK)–eukaryotic initiation factor 2α (eIF2α) signaling in hippocampal neurons, and suppressed microglial nuclear factor κB (NF-κB)/NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammatory activation, whereas C/EBP homologous protein (CHOP) was not significantly changed. These findings support a model in which postoperative injury in the aged hippocampus engages a lipid-proteostatic and inflammatory stress program associated with TMEM97 and PGRMC1, and suggest that CT1812 attenuates cognitive vulnerability by restraining this coupled response.&lt;/p&gt;&lt;/","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 5","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148783395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NOTCH3 Mutations in CADASIL Alter Lipid Metabolism: Insights from Patient Plasma and In Vitro Models","authors":"Ruihua Sun,&nbsp;Xiaoyi Ji,&nbsp;Wenjian Hu,&nbsp;Wanyue Li,&nbsp;Ying Zhao,&nbsp;Wan Wang,&nbsp;Yaru Lu,&nbsp;Anqi Li,&nbsp;Yifan Huang,&nbsp;Jiewen Zhang","doi":"10.1007/s11064-026-04866-9","DOIUrl":"10.1007/s11064-026-04866-9","url":null,"abstract":"<div><p>Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common monogenic form of cerebral small vessel disease (CSVD), is caused by mutations in <i>NOTCH3</i>. However, the effects of <i>NOTCH3</i> mutations on lipid metabolism remain poorly understood. In this study, plasma samples from CADASIL patients and matched healthy controls were subjected to lipidomic analysis. Stable 293T cell lines expressing an empty vector (NC), wild-type (WT) <i>NOTCH3</i>, or CADASIL-associated <i>NOTCH3</i> mutants (R110C, R133C, R1175W, and R544C), as well as hCMEC/D3 cell lines expressing NC, WT, or R544C, were established to investigate lipid metabolic alterations. Lipid droplet (LD) accumulation, cholesterol levels, and the expression of cholesterol transport-related molecules were assessed. Lipidomic profiling revealed significant alterations in plasma lipid profiles in CADASIL patients compared with healthy controls. In 293T cells, LD accumulation was significantly increased in the R110C, R1175W, and R544C groups, but not in the R133C group, whereas cholesterol levels were elevated in all mutant groups. In hCMEC/D3 cells, expression of the R544C mutant markedly promoted cholesterol accumulation and reduced the expression of the cholesterol transporters <i>ABCA1</i> and <i>ABCG1</i>. These findings indicate that <i>NOTCH3</i> mutations are associated with disrupted cellular lipid homeostasis and suggest that lipid metabolic dysregulation may represent a potential mechanism contributing to CADASIL pathogenesis.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 5","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148783412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cenobamate and Trazodone Combination Suppresses Seizures, EEG Alterations, Preserves Neuronal Architecture and Normalizes the BDNF/TrkB Expression in PTZ‑Kindled Mice","authors":"Waleed Shakeel,&nbsp;Khaled Ahmed Saghir,&nbsp;Waseem Ashraf,&nbsp;Saleh A. Alqarni,&nbsp;Syed Muhammad Muneeb Anjum,&nbsp;Fakhir Hannan,&nbsp;Faleh Alqahtani,&nbsp;Imran Imran","doi":"10.1007/s11064-026-04859-8","DOIUrl":"10.1007/s11064-026-04859-8","url":null,"abstract":"<div><p>Polytherapy is increasingly needed to overcome the limitations of monotherapy in epilepsy and its comorbidities. Therefore, we investigated the effect of cenobamate (CNB, 30 mg/kg) and trazodone (TZ, 10 mg/kg), alone and in combination, in PTZ-kindling model, where mice received 11 doses of pentylenetetrazole (PTZ, 40 mg/kg) every other day for three weeks. Behavioral seizure scoring, electroencephalographic (EEG) changes at the 1st, 5th, and 11th injections, molecular markers, and hippocampal histopathology were assessed. TZ + CNB suppressed seizure progression with no tonic-clonic seizures observed throughout kindling period (<i>p</i> &lt; 0.0001), whereas monotherapy by these drugs showed no significant suppression. PTZ produced the most pronounced EEG abnormalities, which CNB and TZ alone did not differ significantly. Combination therapy revealed the greatest reductions across all EEG parameters (q = 0.0004–0.0014), approaching near-baseline values by the 11th injection. Furthermore, brain homogenates were assessed for BDNF, GFAP, and TrkB expression levels by RT-PCR. CNB showed mixed effects (<i>p</i> = 0.0081–0.0631), while TZ (<i>p</i> = 0.0971–0.1422) produced no significant difference from PTZ40. TZ + CNB shifted these markers toward normal levels (<i>p</i> = 0.0001–0.0054), outperforming monotherapies. Hippocampal Nissl-stained sections showed neurodegenerative damage with monotherapies across all regions, while TZ + CNB exhibited substantial preservation, with minimal alteration in hippocampal and cortical architecture. These parallel findings suggest that positive allosteric GABA_A modulation and persistent sodium-current inhibition by CNB, combined with TZ serotonergic modulation, reduce hyperexcitability, pathological neuroplasticity, and glial reactivity. Collectively, TZ + CNB is a promising mechanistically complementary regimen that suppresses seizure progression and associated molecular and neurostructural pathology, which needs further preclinical optimization and translational investigations.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 4","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148751544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PARK7/HSPB1-Mediated Neuroprotective Effects of SHED in an In vitro Parkinson’s Disease Model","authors":"Yiqi Yu,&nbsp;Hongyu Chen,&nbsp;Jinglei Zheng,&nbsp;Shuting Liu,&nbsp;Xiao Wang,&nbsp;Cencan Xing,&nbsp;Hongwu Du","doi":"10.1007/s11064-026-04854-z","DOIUrl":"10.1007/s11064-026-04854-z","url":null,"abstract":"<div><p>Parkinson’s disease (PD) is a neurodegenerative disease characterized by progressive loss of dopaminergic neurons. Studies have shown that mesenchymal stem cells (MSCs) have prominent neuroprotective potential to improve PD. Previous study found that dental pulp‑derived MSCs, including stem cells from human exfoliated deciduous teeth (SHED), significantly ameliorated PD-related pathology, but the underlying molecular mechanism remains unclear. In this study, HSPB1 and PARK7 were initially identified through transcriptomic analyses of mouse and clinical samples, immunoprecipitation‑mass spectrometry (IP‑pulldown), and protein‑protein interaction (PPI) network analysis. Using an MPTP-induced SH-SY5Y cell model of PD, we found that SHED treatment alleviated oxidative stress, restored mitochondrial membrane potential, and inhibited apoptosis, accompanied by significant upregulation of HSPB1 and PARK7. Using siRNA interference, we confirmed that both HSPB1 and PARK7 are involved in the improvement of PD by SHED. Rescue experiments showed that HSPB1 overexpression partially restored the neuroprotective effects impaired by PARK7 knockdown, whereas PARK7 overexpression failed to compensate for HSPB1 deficiency, suggesting a functional dependence between PARK7 and HSPB1 in SHED-mediated neuroprotection. This study demonstrates that SHED improves PD pathological progression through the PARK7/HSPB1-related mechanism and indicates that HSPB1 may serve as a potential therapeutic target for PD.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 4","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148751542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating the Cellular Activity and Differential Gene Expression of Human Astrocytes in Interaction with Protein Composite Nanofibers","authors":"Li Yao,&nbsp;Karen Bustamante-Fuchs,&nbsp;Kayla Cantu,&nbsp;Teresa Shippy","doi":"10.1007/s11064-026-04855-y","DOIUrl":"10.1007/s11064-026-04855-y","url":null,"abstract":"<div><p>Collagen is a major extracellular matrix component, and soy protein has been reported to influence cellular and immune-related processes. Nanofiber scaffolds incorporating collagen and soy protein isolate (SPI) may provide a platform for modulating cell–material interactions in neural systems. In this study, we fabricated electrospun nanofibers composed of collagen (CO), SPI, and polycaprolactone (PCL) and investigated the cellular and transcriptional responses of human astrocytes to these scaffolds in vitro. The nanofibers were characterized by scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy, and contact angle analysis. Human fetal astrocytes exhibited high viability on all nanofiber scaffolds. Flow cytometry analysis indicated that incorporation of SPI into CO/PCL nanofibers did not alter cell cycle distribution. Aligned nanofibers provided directional guidance for astrocyte migration. RNA-sequencing analysis revealed enrichment of the “neurodegeneration” and “antigen processing and presentation” pathways among the down-regulated genes in cells on CO/SPI/PCL fibers compared with CO/PCL fibers. Down-regulated genes in these pathways include IL1B, IL6, HLA-B, HLA-DMB, HLA-DPA1, and HLA-DRA. The “focal adhesion” pathway is enriched among up-regulated genes, which include COL4A1, COL4A2, FN1, LAMB1, LAMB2, AKT2, RAC1, RAC2, ROCK2, and PIP5K1A. These results demonstrate that incorporation of SPI into collagen-based nanofibers modulates astrocyte migration and gene expression profiles associated with focal adhesion and immune-related pathways, providing a foundation for further investigation of SPI-containing biomaterials in neural tissue engineering applications.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 4","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s11064-026-04855-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148751545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sinomenine Liposomes Alleviate Neuropathic Pain in a Spared Nerve Injury Model by Regulating Astrocyte Reactivity Associated with Inhibition of the JAK2/STAT3 Pathway","authors":"Zhipeng Han,&nbsp;Xing Li,&nbsp;Li Yang,&nbsp;Jinglin Li,&nbsp;Kaiyang Zhao,&nbsp;Junxiong Xie,&nbsp;Siyuan Zhou,&nbsp;Wenli Shi,&nbsp;Xiaolina Zhang","doi":"10.1007/s11064-026-04839-y","DOIUrl":"10.1007/s11064-026-04839-y","url":null,"abstract":"<div><p>Neuropathic pain (NP) is chronic pain caused by injury or disease affecting the nervous system. SIN@Lip-HA was prepared and characterised for particle size, zeta potential, encapsulation efficiency and morphology. Sprague-Dawley rats with spared nerve injury (SNI) were randomly divided into the six groups. Analgesic effects were assessed via behavioural tests. Histopathological changes were examined using H&amp;E staining. Astrocyte polarisation was detected using immunofluorescence, and Western blotting was used to assess related protein expression. qRT-PCR measured mRNA level of genes, while ELISA evaluated inflammatory cytokines and oxidative stress markers. The study showed that the particle size of SIN@Lip-HA was 111 ± 5.13 nm, with an encapsulation efficiency of 85.47% and a zeta potential of -24.86 ± 1.20 mV. The in vitro release profile showed sustained drug release, and the formulation remained stable for 3 months. Compared with the model group, SIN@Lip-HA significantly increased PWT and PWL, alleviated spinal cord pathology and was associated with a shift in astrocyte reactivity, as indicated by a reduction in A1-related markers and an increase in A2-related markers. SIN@Lip-HA downregulated CGRP/SP and GFAP. It was also found to inhibit JAK2/STAT3 pathway activation by reducing p-JAK2/p-STAT3 expression and decrease TNF-α, IL-1β and IL-6 whilst increasing IL-10. It also mitigated oxidative stress. Concomitant use with gabapentin markedly enhanced therapeutic efficacy. These findings suggest that sinomenine liposomes alleviate NP in SNI rats in a manner associated with inhibition of JAK2/STAT3 signaling and correlated with astrocyte reactivity, and reduced pain mediators.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 4","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148752012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IMD-1 Protects SH-SY5Y Cells Against H2O2-Induced Oxidative Injury Through Modulation of Oxidative Stress, Mitochondrial Bioenergetics, Inflammatory Mediator Release, and Apoptosis-Related Responses","authors":"Muazzez Derya-Andeden,&nbsp;Pinar Altin-Celik,&nbsp;Naciye Elif Tokguner,&nbsp;Ali Turan,&nbsp;Hamiyet Eciroglu-Sarban,&nbsp;Hamiyet Donmez-Altuntas","doi":"10.1007/s11064-026-04861-0","DOIUrl":"10.1007/s11064-026-04861-0","url":null,"abstract":"<div><p>Oxidative stress, mitochondrial dysfunction, inflammation-associated cellular responses, and apoptosis are closely associated with the pathogenesis of neurodegenerative disorders. Therefore, identifying small molecules capable of modulating these interconnected cellular processes is important for the development of potential neuroprotective strategies. The present study investigated the protective effects of the imidazole derivative (IMD)-1 against hydrogen peroxide (H₂O₂)-induced oxidative injury in SH-SY5Y human neuroblastoma cells using integrated in vitro and in silico approaches. IMD-1 exhibited strong radical scavenging activity in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, reaching 96.8% inhibition at 1000 µg/mL, which was comparable to the butylated hydroxyl toluene (BHT). IMD-1 pre-treatment significantly restored cell viability, reduced reactive oxygen species (ROS) production, and preserved mitochondrial membrane potential. IMD-1 also attenuated adenosine triphosphate (ATP) depletion. Moreover, IMD-1 reduced H₂O₂-induced increases in selected inflammation-associated mediators, including interleukin (IL)-2, IL-6, IL-12, vascular endothelial growth factor (VEGF), monocyte chemoattractant protein (MCP)-1, and interferon-gamma (IFN-γ). IMD-1 reduced apoptotic cell death and modulated apoptosis-related cellular and transcriptional responses. Molecular docking suggested a possible interaction between IMD-1 and caspase-8, providing hypothesis-generating support for the apoptosis-related findings. Overall, these findings suggest that IMD-1 attenuates H₂O₂-induced oxidative injury in SH-SY5Y cells as evidenced by changes in oxidative stress, mitochondrial dysfunction, ATP-associated bioenergetic impairment, inflammatory mediator release, and apoptosis-related responses. However, further protein-level, biochemical, and in vivo studies are required to determine the broader neurobiological and translational relevance of these findings.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 4","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148719691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Microglial C5aR1 with PMX205 Attenuates Neuroinflammation and Improves Neurological Recovery After Intracerebral Hemorrhage","authors":"Xuan Shi,&nbsp;Xueyan Li,&nbsp;Haojie Ding,&nbsp;Chang Cao,&nbsp;Jiale Liu,&nbsp;Shuangkai Li,&nbsp;Youjia Qiu,&nbsp;Haiying Li,&nbsp;Xiang Li Jr.","doi":"10.1007/s11064-026-04858-9","DOIUrl":"10.1007/s11064-026-04858-9","url":null,"abstract":"<div><p>Activation of microglia and inflammatory response play a central role in the pathological process following intracerebral hemorrhage (ICH). In this study, single-nucleus transcriptomic and proteomic profiling was performed to investigate microglial changes after ICH. A significant upregulation of complement receptor C5aR1 was identified, particularly enriched in microglial subsets exhibiting a pro-inflammatory phenotype. The cellular localization and temporal expression dynamics of C5aR1 were validated by immunofluorescence staining, Western blotting, and quantitative PCR, demonstrating its sustained elevation in microglia after ICH. Pharmacological inhibition with the selective C5aR1 antagonist PMX205 markedly reduced the release of inflammatory cytokines, alleviated neuronal damage, and improved neurological function. Proteomic profiling and subsequent validation suggested that CCR5 may be associated with C5aR1-related inflammatory responses after ICH. Collectively, these findings suggest that C5aR1 serves as a regulatory factor in microglia-mediated neuroinflammation following ICH, and that targeting this pathway may offer a promising therapeutic strategy for hemorrhagic stroke.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 4","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148697005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serum miR-369-3p Downregulation Correlates with Poor Prognosis in Acute Ischemic Stroke and Mitigates Endothelial Injury by Targeting VAV3","authors":"Meijie Zhang,&nbsp;Lida Yin,&nbsp;Zhixin Liu,&nbsp;Yanru Meng,&nbsp;Yue Li,&nbsp;Jinhui Meng,&nbsp;Xueyong Yin","doi":"10.1007/s11064-026-04852-1","DOIUrl":"10.1007/s11064-026-04852-1","url":null,"abstract":"<div><p>Globally, acute ischemic stroke (AIS) continues to be a major contributor to death and long-term functional impairment. The present work investigates the clinical relevance of miR-369-3p in AIS and how it regulates brain microvascular endothelial cells. Quantitative measurements of serum miR-369-3p were conducted in a cohort comprising 138 individuals with AIS and 120 healthy controls. ROC curve analysis and Cox proportional hazards regression were employed to evaluate diagnostic and prognostic performance of miR-369-3p. Human brain microvascular endothelial cells (hCMEC/D3) were exposed to oxygen-glucose deprivation followed by reoxygenation (OGD/R), allowing assessment of how miR-369-3p influences cell viability, inflammatory responses, and the expression of adhesion molecules. Downstream target genes were identified through bioinformatics analysis and validated using a dual-luciferase assay. A statistically significant reduction in serum miR-369-3p levels was observed among AIS patients relative to controls (<i>P</i> &lt; 0.001), and this miRNA demonstrated favorable diagnostic accuracy. Lower expression of miR-369-3p emerged as an independent predictor of poorer functional outcomes, as assessed by the modified Rankin Scale (mRS) score at 90 days post‑stroke. In cellular studies, upregulation of miR-369-3p mitigated the loss of cell viability induced by OGD/R, reduced the production of pro‑inflammatory cytokines and lowered the levels of ICAM‑1 and VCAM‑1. Furthermore, VAV3 was confirmed as a direct target of miR-369-3p; restoring VAV3 expression counteracted the protective effects conferred by miR-369-3p. Serum miR-369-3p may serve as a non-invasive diagnostic and prognostic biomarker for AIS. Mechanistically, miR-369-3p protects against ischemic endothelial injury by targeting VAV3 and mitigating inflammation and adhesion molecule expression.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 4","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148697002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}