Neurochemical Research最新文献

{"title":"Nrf2 and STAT3 Pathways in Protecting Against Methylmercury-Induced Oxidative Stress in Hypothalamic Neuronal GT1-7 Cells","authors":"Beatriz Ferrer,&nbsp;Alexey A. Tinkov,&nbsp;Abel Santamaria,&nbsp;João Batista Rocha,&nbsp;Anatoly V. Skalny,&nbsp;Aaron B. Bowman,&nbsp;Michael Aschner","doi":"10.1007/s11064-026-04898-1","DOIUrl":"10.1007/s11064-026-04898-1","url":null,"abstract":"<div><p>Oxidative stress plays a critical role in the methylmercury (MeHg) neurotoxicity, as MeHg induces reactive oxygen species (ROS) generation and impairs antioxidant defense systems. However, the precise molecular mechanisms underlying MeHg-induced neurotoxicity remain elusive. The nuclear factor erythroid 2-related factor 2 (Nrf2) activates antioxidant defense genes in response to acute MeHg exposure. Similarly, the signal transducer and activator of transcription 3 (STAT3), a transcription factor involved in cell growth and anti-apoptotic genes, also contributes to maintaining redox homeostasis. Here, we sought to investigate the roles of Nrf2 and STAT3 in mouse hypothalamic neuronal GT1-7 cells exposed to MeHg. We inhibited STAT3 either pharmacologically with AG490 (a JAK2 inhibitor) or C188-9 (a small-molecule STAT3 SH2 domain inhibitor) or genetically using a lentivirus carrying STAT3 shRNA (vs. scramble control), in GT1-7 cells exposed to 5 µM MeHg. To further dissect the role of Nrf2, the pathway was pharmacologically inhibited using brusatol or activated with sulforaphane (SFN) in GT1-7 cells co-exposed to 5 µM MeHg. Changes in cell viability, reactive species production, and protein and gene expression were analyzed. Our findings reveal that deficits of either the Nrf2 or STAT3 pathways exacerbated MeHg-induced toxicity. Moreover, in MeHg-exposed cells, Nrf2 ablation led to increased STAT3 activity, suggesting a reciprocal and potentially compensatory responses between these two pathways in protecting against MeHg-induced oxidative stress. Our novel findings provide crucial understanding of the molecular mechanisms underlying MeHg neurotoxicity and offer insights into potential therapeutic strategies for mitigating acute MeHg-induced neurotoxicity.</p><h3>Graphical Abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 5","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s11064-026-04898-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149132991","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":"Sonic Hedgehog Protects Against Ischemic Brain Injury Via Modulating DRP1-Dependent Microglial Pyroptosis","authors":"Xiaosong Song,&nbsp;Jun Wen,&nbsp;Hao Tang,&nbsp;Lei Yu,&nbsp;Qin Yang","doi":"10.1007/s11064-026-04900-w","DOIUrl":"10.1007/s11064-026-04900-w","url":null,"abstract":"<div><h3>Background</h3><p>Microglial pyroptosis plays a critical role in the neuroinflammation following ischemic stroke. Although Sonic Hedgehog (SHH) signaling has been shown to exert neuroprotective effects in cerebral ischemia, whether SHH regulates microglial pyroptosis and the underlying mechanisms remain largely unclear.</p><h3>Methods</h3><p>Serum samples from patients with acute ischemic stroke (AIS) and healthy controls were analyzed using ELISA. Middle cerebral artery occlusion/reperfusion (MCAO/R) mice and oxygen-glucose deprivation/reoxygenation (OGD/R)-treated BV2 microglia were established as in vivo and in vitro ischemic models, respectively. SHH and DRP1 expression were manipulated using adeno-associated virus (AAV)-mediated knockdown or siRNA transfection. Pyroptosis-related molecules were evaluated by qRT-PCR, western blotting, immunofluorescence staining, and scanning electron microscopy. Infarct volume and neurological function were assessed by TTC staining, modified neurological severity score (mNSS), and corner test.</p><h3>Results</h3><p>Serum SHH levels were significantly reduced in AIS patients and negatively correlated with circulating inflammatory cytokines. Separately, GEPIA2 analysis of human brain tissue datasets revealed that SHH expression was negatively correlated with the pyroptosis-related genes IL1B, GSDMD, and CASP1. Both in vivo and in vitro ischemic interventions markedly upregulated the expression of SHH, DRP1, and pyroptosis-associated proteins in microglia. SHH knockdown elevated DRP1 expression, aggravated microglial pyroptosis, enlarged cerebral infarct volume, and worsened neurological dysfunction. Rescue experiments confirmed that DRP1 knockdown effectively reversed the pro-pyroptotic and injury-aggravating effects of SHH inhibition in microglia after ischemic stroke.</p><h3>Conclusions</h3><p>SHH protects against cerebral ischemic injury by suppressing DRP1-mediated microglial pyroptosis. The SHH–DRP1 signaling axis represents a previously unrecognized regulatory pathway involved in ischemic stroke and may serve as a potential therapeutic target for limiting neuroinflammation and improving neurological outcomes.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 5","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149102475","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":"Desflurane Increases Hippocampal RAF–MAPK–MSK1 Protein Levels and Reduces CLOCK Expression: Sorafenib Attenuates Cognitive Impairment in Aged Mice","authors":"Chenxu Chou,&nbsp;Yulong Jia,&nbsp;Xiaoyu Zhang,&nbsp;Jiali Bai,&nbsp;Xuying Shang,&nbsp;Xiaguang Duan","doi":"10.1007/s11064-026-04904-6","DOIUrl":"10.1007/s11064-026-04904-6","url":null,"abstract":"<div><p>Postoperative cognitive dysfunction (POCD) is common after anesthesia and surgery in older adults, yet no targeted therapy exists, and the mechanism linking volatile anesthetic exposure to circadian dysregulation in the aged hippocampus is undefined. Here we show that RAF manipulation bidirectionally alters CLOCK protein levels in HT22 hippocampal neurons, and that RAF–MAPK–MSK1 protein abundance is inversely related to CLOCK levels in the aged hippocampus after desflurane exposure. Aged C57BL/6 mice (18 months, both sexes) were exposed to 2% desflurane for 2 h, with or without pretreatment with the multi-kinase RAF inhibitor sorafenib (50 mg/kg), and phenotypes were assessed by Western blot, immunofluorescence, in vivo electroencephalography, whole-cell patch-clamp recordings of CA1 pyramidal neurons, and behavioral testing (righting reflex, contextual fear conditioning, Morris water maze). Parallel dissection in HT22 hippocampal neurons employed RAF knockdown, overexpression, and pharmacological inhibition. Desflurane increased total c-Raf, ERK1/2 (MAPK), and MSK1 protein levels—phosphorylation status was not assessed—while reducing CLOCK in both HT22 cells and aged hippocampus, accompanied by cellular senescence, impaired S-phase entry, increased hippocampal β-galactosidase and α-synuclein immunoreactivity, synaptic excitation–inhibition imbalance, and deficits in contextual fear memory and spatial learning. In HT22 cells, RAF knockdown normalized kinase abundance and restored CLOCK, whereas overexpression exacerbated these changes. In aged mice, sorafenib restored CLOCK, attenuated hippocampal β-galactosidase and α-synuclein immunoreactivity, and improved cognitive performance. These findings support a link between RAF–MAPK–MSK1 protein abundance and hippocampal CLOCK in desflurane-induced cognitive impairment and nominate RAF inhibition as a candidate strategy warranting further preclinical study.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 5","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13638699/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149102462","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":"Electroacupuncture Targeting the NLRP3 Inflammasome in Senescence‑associated Cognitive Impairment: Mechanistic Synthesis and Meta‑analysis of Clinical Randomized Controlled Trials","authors":"Tian Ma,&nbsp;Huating Zhou,&nbsp;Yabo Liu,&nbsp;Xianglin Cheng,&nbsp;Ming Li","doi":"10.1007/s11064-026-04901-9","DOIUrl":"10.1007/s11064-026-04901-9","url":null,"abstract":"&lt;div&gt;&lt;p&gt;Global population aging leads to a growing clinical demand for interventions against age-related cognitive decline (ARCD), including mild cognitive impairment (MCI, termed senescence-associated cognitive impairment [SACI] in this review)—a prodromal pathological stage preceding Alzheimer’s disease (AD) and vascular dementia. Chronic microglia-mediated neuroinflammation, predominantly triggered by excessive NLRP3 inflammasome activation, acts as a key upstream mediator of hippocampal neuronal injury and gradual cognitive decline in preclinical aging models.&lt;/p&gt;&lt;p&gt;Manual acupuncture and electroacupuncture (EA) exert reproducible neuroprotective effects against cognitive deficits, yet a comprehensive, multi-layered regulatory framework unifying NLRP3-centered molecular mechanisms of acupuncture remains absent from current literature. This review systematically summarizes NLRP3‑dependent pathological cascades in SACI and outlines four synergistic signaling axes through which acupuncture may modulate excessive NLRP3‑dependent inflammatory responses to potentially alleviate neurotoxic inflammatory injury.&lt;/p&gt;&lt;p&gt;Persistent overactivation of the NLRP3 inflammasome triggers self-amplifying inflammatory feedback cycles in hippocampal tissue through four interrelated pathological processes: impaired autophagic clearance, disrupted mitochondrial homeostasis, persistent endoplasmic reticulum (ER) stress, and caspase-1/GSDMD-mediated neuronal pyroptosis.&lt;/p&gt;&lt;p&gt;Acupuncture counteracts NLRP3-dependent neural injury through synergistic multi-target modulation: (1) activation of AMPK/mTOR signaling to restore defective autophagy; (2) suppression of the ROS-TXNIP cascade to block NLRP3 transcriptional priming and protein oligomerization; (3) phenotypic reprogramming of microglia from pro-inflammatory M1 toward anti-inflammatory M2 states; (4) inhibition of pyroptotic execution by blunting caspase-1 maturation and GSDMD proteolytic cleavage. Collectively, available pre‑clinical evidence suggests these signaling axes constitute a bidirectionally‑interconnected hypothetical protective network that may mitigate chronic neuroinflammation.&lt;/p&gt;&lt;p&gt;A meta analysis integrating nine eligible randomized controlled trials (published 2015–2025) involving 614 participants was performed. After subject dropout, 599 participants completed the studies. Pooled analyses of heterogeneous acupuncture/electroacupuncture RCTs revealed that intervention was associated with short‑term improvements in MoCA and MMSE scores and reduction in peripheral pro‑inflammatory cytokine IL‑6. Pooled effect sizes were moderately larger in MCI subgroups compared with patients with early AD. Nevertheless, substantial methodological heterogeneity existed across included trials, and these short term observational findings cannot confirm durable disease modifying benefits.&lt;/p&gt;&lt;p&gt;Severe methodological heterogeneity across existing trials—including inconsistent acupoint prescriptions, divergent EA stimul","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 5","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149102466","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":"Uptake of L-proline by Cultured Primary Rat Astrocytes","authors":"Paul Spellerberg,&nbsp;Ralf Dringen","doi":"10.1007/s11064-026-04886-5","DOIUrl":"10.1007/s11064-026-04886-5","url":null,"abstract":"<div><p>The proteinogenic amino acid L-proline can be efficiently metabolized by cultured astrocytes as exogenous substrate to fuel mitochondrial ATP regeneration. To investigate the properties of the transport processes involved in astrocytic L-proline uptake, we used primary rat astrocyte cultures as model system. After application of L-proline, cultured astrocytes efficiently accumulated the amino acid in a time- and concentration-dependent saturable manner. Omission of sodium ions drastically lowered cellular L-proline accumulation to low values that increased proportional to the concentration of L-proline applied. The saturable sodium-dependent L-proline accumulation followed apparent Michaelis-Menten kinetics with a calculated K_M value of around 1.0 mM and a V_max value of around 20 nmol/(5 min x mg). In contrast to L-proline, D-proline was hardly taken up by the cells. L-Proline uptake was strongly affected by lowering the incubation temperature, while alterations of the extracellular pH value did not affect the accumulation of L-proline. An excess of the amino acids L-alanine, L-asparagine, L-methionine, L-serine, L-threonine or L-valine severely lowered the uptake of L-proline. Inhibition of uptake was also found in the presence of L-4-hydroxyproline and L-homocysteine as well as in the presence of the ASCT1 inhibitor L-4-chlorophenylgycine, but not after exposure to inhibitors of other potential astrocytic L-proline transporters. These data suggest that L-proline uptake by cultured rat astrocytes is mainly mediated by the sodium-dependent neutral amino acid transporter ASCT1.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 5","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13627194/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149102426","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":"Long Non-Coding RNA PART1 in Alzheimer’s Disease: Clinical Value and Improvement of Neurotoxicity and Apoptosis via miR-770-5p","authors":"Shasha Zhu,&nbsp;Mingfang Liu,&nbsp;Jing Chen,&nbsp;Lili Zhou,&nbsp;Ruiming Wang,&nbsp;Guangning Zhang","doi":"10.1007/s11064-026-04891-8","DOIUrl":"10.1007/s11064-026-04891-8","url":null,"abstract":"<div><p>Dysregulation of long non-coding RNA (lncRNA) PART1 is associated with neurodegenerative diseases, but its role in Alzheimer’s disease (AD) remains unclear. This study investigated the clinical significance of PART1 in AD and its potential neuroprotective mechanisms, aiming to offer new insights for risk prediction and mechanism research. Serum PART1 levels were detected in 258 participants using real-time quantitative PCR (RT-qPCR), including 70 controls, 88 patients with amnestic mild cognitive impairment (aMCI), and 100 patients with AD. In vitro AD models were established using SH-SY5Y cells treated with amyloid-β peptide 25–35 (Aβ₂₅₋₃₅). Functional assays were performed, including flow cytometry and Cell Counting Kit-8 (CCK-8) assay, along with the detection of oxidative stress levels. Mechanism studies included bioinformatic predictions and luciferase reporter assays. Serum PART1 was significantly downregulated in patients with aMCI and AD, and positively correlated with Mini-Mental State Examination scores. Low PART1 expression was a risk factor for AD and demonstrated good diagnostic value (AUC = 0.843). Aβ downregulated PART1 in SH-SY5Y cells, while PART1 overexpression attenuated Aβ-induced cytotoxicity, apoptosis, and oxidative stress. PART1 directly targeted and negatively regulated miR-770-5p, which was upregulated in AD. The neuroprotective effects of PART1 were reversed by miR-770-5p mimic. Furthermore, bioinformatic analysis and validation experiments identified GRIA2 as a downstream target of miR-770-5p. In summary, serum PART1 is a promising biomarker for AD. PART1 exerts neuroprotective effects against Aβ-induced damage by downregulating the miR-770-5p/GRIA2 axis, suggesting that PART1 is a potential target for intervention strategies in AD.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 5","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149056861","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":"Systemic AR-C155858 During Fixed Treadmill Exercise in MPTP Mice: An Exploratory Study","authors":"Jianda Kong,&nbsp;Lingyun Liu,&nbsp;Guanbo Zhao,&nbsp;Yuan Gao,&nbsp;Zizheng Yang,&nbsp;Ruobing Zeng,&nbsp;Mingli Tan,&nbsp;Haijun Wang,&nbsp;Yang Liu,&nbsp;Wei Chen","doi":"10.1007/s11064-026-04903-7","DOIUrl":"10.1007/s11064-026-04903-7","url":null,"abstract":"<div><p>Treadmill exercise improves motor and dopaminergic phenotypes in toxin-based Parkinson’s disease models, but the contribution of monocarboxylate transport remains uncertain. This small-scale, hypothesis-generating exploratory study tested whether systemic AR-C155858, an MCT1/MCT2 inhibitor used in experimental systems, altered lactate kinetics and recovery-related outcomes in MPTP-treated mice during identical treadmill exercise. Its purpose was to detect a coordinated phenotype that could justify subsequent confirmatory mechanistic testing. The two-group design was not intended to estimate the independent effect of exercise, the effect of AR-C155858 without exercise, or a drug-by-exercise interaction. Male C57BL/6J mice received MPTP (20 mg/kg/day, intraperitoneally, 5 days) and, after 3 days, completed 4 weeks of forced treadmill exercise (16 m/min, 40 min/day, 5 days/week, 5° incline). Mice received vehicle (Ex-Veh) or AR-C155858 (Ex-AR; 10 mg/kg intraperitoneally, 30 min before exercise). Blood lactate was measured in weeks 1 and 4; motor behavior was assessed before MPTP, after MPTP, and after the intervention; endpoint striatal TH, Iba1, GFAP, and dopamine metabolites were measured. AR-C155858 was associated with higher 30-min post-exercise lactate and smaller recovery amplitude, but not altered lactate peak increment or AUC. Ex-AR mice showed smaller changes in open-field distance, pole-test turning, stride length, and fore-hind overlap, together with lower endpoint striatal TH and dopamine and higher Iba1. GFAP and DOPAC did not differ significantly; HVA was not tested because multiple values were below quantification. In male MPTP-treated mice under a common treadmill condition, systemic AR-C155858 was associated with delayed peripheral lactate decline and less favorable motor and endpoint striatal outcomes. Because MCT1/MCT2 expression, localization, and target engagement were not measured, the findings do not establish a brain- or cell-specific MCT mechanism. These findings generate testable hypotheses for a subsequent, larger factorial mechanistic study. Animal-level open-field data, a baseline-adjusted sensitivity analysis, and executable analysis code are supplied as Supplementary materials.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 5","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149035366","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":"Characterization of Cellular Alterations in a Novel NAGLU Enzyme-Deficient Cellular Model Generated from U-87MG Cell Line","authors":"Katherin D. Niño-Traslaviña,&nbsp;Diego A. Suárez,&nbsp;Oscar F. Sánchez,&nbsp;Angela J. Espejo-Mojica,&nbsp;Carlos J. Alméciga-Díaz","doi":"10.1007/s11064-026-04879-4","DOIUrl":"10.1007/s11064-026-04879-4","url":null,"abstract":"<div><p>Mucopolysaccharidosis IIIB (MPS IIIB) is an inherited metabolic disorder caused by mutations in <i>NAGLU</i> gene, resulting in the accumulation of heparan sulphate in lysosomes and cell membranes. This accumulation leads to cellular dysfunction, apoptosis, tissue damage, and organ failure. MPS IIIB is considered a neurodegenerative disease that causes motor impairment, developmental delay, sleep disturbance, and dementia. This is usually diagnosed around 3–4 years of age with an incidence of 1 per 200,000 live births. Current research focuses on cellular defects in the central nervous system, particularly in neurons. Conversely, the effects on glial cell types, such as microglia and astrocytes, which play a key role in brain homeostasis, remain unknown. Currently, there is not any glial cell model that allows us to assess different therapeutic strategies. In this study, we generated a glial cell model deficient in the NAGLU enzyme via CRISPR/Cas9 editing system in the U-87MG cell line. Characterization of this cellular model exhibited typical traits for MPS IIIB, including decreased enzyme activity and mitochondrial mass, as well as increased lysosomal mass, neutral lipids, total glycosaminoglycans, and total reactive oxygen species, along with an altered autophagy flux. Thus, it is expected that this model will contribute to the development and assessment of therapeutic strategies, as well as a better understanding of the molecular and cellular basis of MPS IIIB.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 5","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149035039","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":"Ubiquitin-conjugating Enzyme E2M Destabilizes Heat Shock Protein 70 and Mediates Sleep Deprivation-Induced Cognitive Impairment in Mice","authors":"Xianmei Zhong,&nbsp;Jianchuan Lin,&nbsp;Guoshao Zhu,&nbsp;Yangyi Li,&nbsp;Changsheng Su,&nbsp;Zhenming Kang","doi":"10.1007/s11064-026-04895-4","DOIUrl":"10.1007/s11064-026-04895-4","url":null,"abstract":"<div><p>Sleep deprivation (SD) contributes to cognitive impairment. Heat shock protein 70 (HSP70) protects against SD-induced neuroinflammation and cognitive decline; however, how endogenous HSP70 is regulated under SD conditions, and in particular whether it is controlled by post-translational modifications such as ubiquitination, remains unclear. The present study examined whether the ubiquitin-conjugating enzyme E2M (UBE2M) governs HSP70 protein stability and thereby contributes to SD-related inflammatory and cognitive outcomes. A mouse model of SD was established using the modified multiple-platform water environment method. Protein and mRNA levels of HSP70 and UBE2M in the hippocampus were evaluated by Western blot and qRT-PCR, respectively. Co-immunoprecipitation was used to analyze the interaction between UBE2M and HSP70 and to assess HSP70 poly-ubiquitination. Cycloheximide (CHX) chase assays were performed to determine HSP70 protein stability. Cognitive performance was assessed using the Y-maze and the novel object recognition test, while hippocampal inflammation was evaluated by measuring pro-inflammatory cytokines (TNF-α, IL-1β, MCP-1) using ELISA. Oxidative stress was evaluated by quantifying MDA content, SOD activity and total antioxidant capacity. SD significantly downregulated HSP70 protein levels in the hippocampus without altering its mRNA expression, indicating post-translational regulation. UBE2M expression was markedly upregulated in the hippocampus during SD, and a direct interaction between UBE2M and HSP70 was confirmed. UBE2M promoted HSP70 poly-ubiquitination, leading to reduced HSP70 protein stability as shown by CHX chase assays. Mice treated with recombinant UBE2M showed aggravated cognitive impairment in the Y-maze and the novel object recognition test, together with exacerbated hippocampal oxidative stress and elevated levels of hippocampal pro-inflammatory cytokines. This study identifies UBE2M as a key regulator of HSP70 protein stability and indicates that the UBE2M/HSP70 axis links SD to hippocampal oxidative stress, neuroinflammation and cognitive impairment, thereby suggesting a potential therapeutic target for sleep-related cognitive disorders.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 5","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149035115","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":"Restoration of Normal Occlusion Suppresses the Risk of Dementia","authors":"Munehisa Maeshiba,&nbsp;Hiroshi Kajiya,&nbsp;Keisuke Migita,&nbsp;Kazuko Goto-T,&nbsp;Takayoshi Seki,&nbsp;Takashi Tsuzuki","doi":"10.1007/s11064-026-04892-7","DOIUrl":"10.1007/s11064-026-04892-7","url":null,"abstract":"<div><p>Tooth loss is associated with a progressive decline in cognitive ability. Although occlusal support after tooth loss using dentures may reverse this effect, the underlying mechanisms are unclear, hampering improved evidence-based dentistry for at-risk patients. The current experiments examined the associations of tooth loss and restoration of occlusal support with neuropathology and cognitive decline in a mice model of Alzheimer’s disease (AD). A triple-mutant knock-in mouse model of AD (App^NL−G−F mice), and a single-mutant knock-in control line, (App^NL mice), were divided into three subgroups: untreated, molar extraction at 6 weeks of age, and molar extraction with occlusal support. Animals were examined before occlusal support at 2, 4, and 6 months and after occlusal support at 3, 5, and 7 months of age. We designated 2–3, 4–5, and 6–7 months as the early, middle, and late stages. Cognitive functions were assessed using the 8-arm radial maze test and novel object recognition test, while accumulation or altered expression levels of AD-associated molecules were measured in hippocampus. The App ^NL−G−Fmice and App^NL mice groups showed significant cognitive decline and increased accumulation of Aβ and phosphorylated Tau in the hippocampus during the early and middle stages. Restoring normal occlusal support suppressed the upregulation of AD-related molecules, including Aβ, phosphorylated Tau, and interleukin-1β in App ^NL−G−F mice during the early and middle stages. Restoration of normal occlusal support can mitigate the risk factors of dementia, potentially by reducing neuroinflammation and thereby reversing Aβ and phosphorylated Tau accumulation.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 5","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149029532","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}