IntroductionTraumatic brain injury (TBI) is a major risk factor for major depressive disorder (MDD), yet the underlying mechanisms remain poorly defined. This study demonstrates that toll-like receptor 4 (TLR4) activation drives depressive-like behaviors through dysregulation of the kynurenine pathway (KP) in a murine model of moderate TBI.Methods and ResultsUsing male C57BL/6J mice subjected to controlled cortical impact, we observed depression-like phenotypes (reduced sucrose preference, prolonged immobility in forced swimming tests) specifically at 28 days post-TBI, with an incidence of 28.13%. Proteomics and immunofluorescence analyses revealed significant upregulation of hippocampal TLR4 expression and signaling pathway activation, concomitant with microglial activation. Crucially, the TLR4-specific inhibitor TAK-242 (administered i.p. from days 21–28 post-TBI) ameliorated depressive behaviors and suppressed phosphorylation of NF-κB p65. Mechanistically, TBI induced microglia-dependent upregulation of key KP enzymes indoleamine 2,3-dioxygenase 1 (IDO1) and kynurenine monooxygenase (KMO), leading to accumulation of the neurotoxic metabolite quinolinic acid (QUIN). This TLR4-KP axis was validated in vitro: LPS-stimulated BV2 microglia showed increased IDO1/KMO/QUIN expression, which was abolished by TAK-242 pretreatment.ConclusionOur findings establish a novel TLR4–KP–QUIN pathway as a critical mediator of post-TBI depression, providing a mechanistic basis for TLR4-targeted therapies. In addition to neuroinflammatory effects, this work mainly mediates dysregulation of TBI-related neuropsychiatric sequelae through metabolism, highlighting TLR4 inhibition as a promising strategy for mitigating chronic depressive outcomes after brain injury.

Heatstroke causes acute injury and damage across numerous organ systems, during this process, inflammation drives disease progression. In this study, we correlated temporal changes in inflammatory response with barrier breakdown within 24 h following heatstroke onset to explore whether inflammation in circulation can influence inflammation in brain. We found both pro-inflammatory cytokines expression and pathological lesions in tissue were elevated at 1 h and 6 h after heatstroke onset. However, by 24 h after heatstroke onset, while systemic inflammation was sustained at high levels, neuroinflammation and cerebral cortex damage had begun to reverse. The change in microglial phenotype from classic activation at 1 h to alternative activation at 24 h post heatstroke may explain the subsequent abatement of neuroinflammation. Taken together, our results may indicate microglial phenotype transformation drives neuroinflammation independent of systemic inflammation during the acute stage of heatstroke.

Background Selenium (Se) has antioxidant and anti-inflammatory properties that directly target the key mechanisms implicated in postoperative delirium (POD). The current study investigated the association between blood Se and POD risk in elderly orthopedic surgery patients. Methods Patients aged ≥ 65 years who received general anaesthesia were enrolled and blood Se measured by Inductively Coupled Plasma Mass Spectrometry (ICP-MS) in preoperative samples collected before anaesthesia induction (preoperative) and postoperative samples collected at the end of surgery when suture began (postoperative). POD was assessed on the first seven postoperative days or before discharge. The association between perioperative blood Se and POD risk was evaluated by logistic regression and restricted cubic spline (RCS) analyses with subgroup analysis to assess the robustness of the results. Results 58/293 patients (19.8%) developed POD and had lower postoperative blood Se than non-POD patients (median, 0.107; interquartile range [IQR], 0.072–0.197 vs 0.153; 0.092–0.234 mg·L − 1 , P = 0.015). Adjusted models gave an association of lower blood Se with POD (preoperative: OR, 0.032; 95% confidence interval [CI], 0.001–0.640; P = 0.041; postoperative: OR, 0.010; 95% CI, 0.000–0.251; P = 0.009). Greater postoperative decline in blood Se was associated with higher POD risk. (Δ blood Se: OR, 0.469; 95% CI, 0.233–0.874; P = 0.027). Conclusions Lower pre- and postoperative blood Se and greater postoperative decline were associated with higher POD risk in elderly orthopedic patients.

Exercise-induced fatigue is regulated by central nervous system (CNS)-derived factors, including neurotransmitters and metabolic signals; however, the underlying mechanisms remain incompletely understood. This study aimed to test whether lactate activates Gi-protein coupled receptor 81 (GPR81) in the motor cortex to inhibit protein kinase A (PKA) phosphorylation, thereby contributing to central fatigue during exercise. Using a murine weight-loaded swimming model, we found that PKA phosphorylation in the motor cortex increased significantly after 15 min of swimming, but decreased markedly after swimming to exhaustion. Notably, inhibition of PKA phosphorylation by local administration of H-89 in the motor cortex shortened the swimming time of mice (H-89: 20 ± 5 min vs. saline 38 ± 6 min, P < 0.05). In addition, we found that activation of the lactate receptor GPR81 by local administration of 3-chloro-5-hydroxybenzoic acid (CHBA) or l-lactate attenuated exercise-induced upregulation of PKA phosphorylation. Conversely, genetic ablation of GPR81 (GPR81-/-) mitigated the inhibitory effect of lactate on PKA phosphorylation, resulting in a 33% increase in swimming endurance. Despite comparable peripheral fatigue markers (blood lactate, skeletal muscle glycogen, and gastrocnemius p-AMPK/AMPK ratio) after 30 min of swimming, GPR81-/- mice exhibited elevated motor cortical glutamate/GABA ratios, indicating preserved neuronal excitability. Therefore, our study reveals a vital role of the lactate-GPR81 signaling axis in the motor cortex during exercise and provides a potential target for alleviating exercise-induced central fatigue.NEW & NOTEWORTHY Exercise-induced fatigue is regulated by factors derived from the central nervous system (CNS), including neurotransmitters and metabolic signals. However, the underlying mechanisms remain largely obscure. Here, we demonstrate that lactate activates GPR81 in the motor cortex to inhibit PKA phosphorylation, thereby contributing to central fatigue during exercise. These findings reveal a vital role of lactate-GPR81-PKA axis in the motor cortex during exercise and provide a potential target for alleviating exercise-induced central fatigue.

Microglia play a pivotal role in neuroinflammation, and targeting their activation has emerged as a promising therapeutic strategy for brain injury. Oxymatrine (OMT) exhibits anti-inflammatory and neuroprotective properties; however, whether OMT regulates microglial M1/M2 polarization via epigenetic mechanisms, particularly RNA N6-methyladenosine (m6A) modification, remains unknown. Moreover, the molecular link between m6A demethylase FTO and the metabolic regulator PGC-1α in microglial polarization has not been explored. In this study, we investigated the effects of OMT on microglial M1/M2 polarization using an oxygen-glucose deprivation/reperfusion (OGD/R)-induced neuroinflammation model in primary murine microglia. Our findings fill this gap by demonstrating for the first time that OMT attenuates OGD/R-induced neuroinflammation by promoting a shift from the M1 to the M2 phenotype. Mechanistically, this effect was associated with increased expression of fat mass and obesity-associated protein (FTO), which mediated OMT-driven M2 polarization via m6A-dependent upregulation of PPAR-γ coactivator-1α (PGC-1α). Furthermore, the m6A reader protein YTHDF2 regulated PGC-1α mRNA stability, thereby facilitating OMT-induced M2 microglial reprogramming. Collectively, our findings identify the FTO/PGC-1α axis as a novel pathway through which OMT modulates microglial polarization, thus addressing the critical knowledge gap regarding OMT's epigenetic mechanism in neuroinflammation and providing new therapeutic insights for the treatment of neuroinflammatory disorders.

BackgroundMild cognitive impairment (MCI), a condition that falls somewhere between normal aging and severe cognitive dysfunction (e.g., Alzheimer’s disease), is a common manifestation of the neurocognitive function decline that seniors encounter as they age. The fundamental processes causing its beginning are still not well understood yet.MethodsWe employed aged (18-month-old) male C57BL/6J mice, including astrocyte-specific Pantothenate kinases 4 (PANK4) conditional knockout (Pank4f/f;Gfap-Cre, Pank4-CKO) mice. Cognitive function was assessed using the Barnes maze, Y-maze (spatial novelty preference, spontaneous alternation), novel object recognition (NOR) test, and open field test (OFT). Hippocampal PANK4 localization was analyzed via immunofluorescence (IF) and subcellular fractionation/western blotting (WB). Cuproptosis markers (FDX1, LIAS, DLAT), copper transporters (ATP7A, ATP7B, SLC31A1), and copper content (ICP-MS) were quantified in hippocampal tissue. In vitro studies used LPS-stimulated primary astrocytes for RNA-seq and qPCR validation.ResultsAged wild-type (18M+WT) mice exhibited specific deficits in Barnes maze retention and reversal learning, indicative of mild cognitive impairment, while Pank4-CKO mice showed significant rescue. We discovered a novel age-dependent nuclear accumulation of PANK4 in hippocampal cells, which was absent in Pank4-CKO mice. Aged hippocampi displayed upregulated pro-cuproptotic factors (FDX1, LIAS) and reduced DLAT, alongside decreased expression of the copper exporter ATP7A, ATP7B, SLC31A1 and increased copper accumulation. Astrocyte-specific Pank4 knockout reversed these changes: it suppressed FDX1/LIAS upregulation, restored ATP7B expression and DLAT levels, and normalized hippocampal copper content. In vitro, LPS-induced neuroinflammation triggered PANK4 nuclear translocation and selectively downregulated Atp7b expression in astrocytes. Small interfering RNA (siRNA)-mediated knockdown of Pank4 significantly upregulated Atp7b expression.ConclusionThis study identifies a novel pathological mechanism in age-related MCI: the nuclear accumulation of PANK4 in hippocampal exacerbates cuproptosis susceptibility by specifically impairing ATP7B-dependent copper efflux, leading to copper overload. Astrocyte-specific PANK4 ablation mitigates these effects, highlighting PANK4 as a potential therapeutic target for preventing or treating age-associated cognitive decline.

This study investigated how the prebiotic inulin protects against heat-stroke-induced intestinal barrier damage. A classic/passive heat-stroke model was established in C57BL/6J mice. After 4 weeks of dietary intervention with 5% inulin, gut microbiota, fecal short-chain fatty acids, intestinal barrier function, and signaling pathways were examined using 16S rRNA sequencing, gas chromatography-mass spectrometry, Western blotting, and cell models. Inulin decreased the core body temperature and mortality, reshaped the gut microbiota, and increased Bifidobacterium abundance and fecal butyrate. Butyrate activated G protein-coupled receptor 43 (GPR43) and upregulated the tight junction proteins zonula occludens-1 and occludin through protein kinase C-cAMP response element-binding protein signaling, thereby improving barrier integrity and reducing systemic inflammation. These findings indicate that inulin protects against heat stroke through the gut microbiota-butyrate-GPR43 axis and may offer a nutritional intervention strategy.

BACKGROUND:The brain plays a central role in coordinating physiological processes across organ systems, yet population-scale evidence linking brain structure and function alterations, as captured by neuroimaging, to multisystem disease risk remains limited. METHODS:Leveraging multimodal magnetic resonance imaging (MRI) and linked health records from 64,836 participants, we performed a phenome-wide association study (PheWAS) to assess associations between 505 brain imaging-derived phenotypes (IDPs)-including T1-weighted, diffusion, and resting-state functional MRI measures-and 756 incident diseases spanning 15 organ systems, establishing the largest atlas of brain-disease risk to date. FINDINGS:Across approximately 380,000 tests, 1,500 significant IDP-disease pairs were identified, revealing that brain alterations relate not only to neurological but also to peripheral conditions, such as circulatory, digestive, and metabolic disorders. Clustering and network analyses highlighted white matter-related IDPs as a central hub linking brain and multisystem health. Prediction models combining IDPs with clinical covariates improved disease discrimination, and Mendelian randomization suggested potential causal roles of white matter-related IDPs in cerebrovascular disorders. CONCLUSIONS:This PheWAS-based atlas advances population-level understanding of brain-body associations and provides a framework for exploring the potential of neuroimaging in cross-system disease risk assessment and therapeutic development. All associations are available through the open-access brain imaging-disease risk atlas (www.brainphewas.com). FUNDING:This research was supported by the National Natural Science Foundation of China (82271220).

Traumatic brain injury (TBI) is a major cause of disability and mortality among children and adolescents. A central concern in pediatric TBI is not only focal tissue cavitation but also progressive global and regional brain-volume loss, cortical thinning, white matter disruption, and the resulting impairment of neurodevelopmental function. In this review, “immature brain” is used as an umbrella term spanning neonatal, early postnatal or infant, juvenile or childhood, and adolescent stages; these stages are not treated as biologically equivalent. We analyze developmental vulnerability after TBI, compare focal lesion, tissue-loss, and brain-atrophy trajectories while distinguishing direct within-study age comparisons from cross-study interpretations, summarize experimental models with particular attention to focal and diffuse or white matter injury paradigms, and discuss MRI metrics, biomarkers, and candidate therapeutic strategies relevant to pediatric outcomes.

Long-term post-sepsis depression (PSD) is the most common chronic neuropsychiatric sequela among sepsis survivors. But its pathogenesis remains unclear with no targeted interventions currently. As a classic late inflammatory mediator, high mobility group box 1 (HMGB1) has been confirmed to be closely associated with the occurrence of depression and sepsis, but its cellular origin and downstream regulatory network in long-term post-sepsis depression have not been clarified. In this study, we established a cecal ligation and puncture (CLP)-induced mouse model of long-term post-sepsis depression, and systematically resolved the molecular mechanism of HMGB1 regulating post-sepsis depression by combining multiple technologies including behavioral testing, proteomic screening, RNA Scope In Situ Hybridization, stereotaxic viral intervention, proximity ligation assay and transmission electron microscopy. The results showed that: 1) Mice developed significant depressive-like behaviors 28 days (not 14 days) after CLP, accompanied by increased hippocampal HMGB1 translocation and release; 2) Under low-intensity inflammation, microglia are the main source of active HMGB1, and specific knockout of HMGB1 in hippocampal microglia is sufficient to reverse CLP-induced depressive-like behaviors; 3) Proteomic screening identified hippocampus-enriched synaptic adhesion molecule Slitrk2 as a key downstream effector of HMGB1, whose upregulation after CLP was completely blocked by microglial HMGB1 knockout; 4) Mechanistically, HMGB1 activates microglial kynurenine pathway to produce toxic metabolite quinolinic acid (QUIN), which upregulates neuronal Slitrk2 to disrupt hippocampal synaptic excitation-inhibition balance and ultimately induce depression. This study first reveals the core role of HMGB1/Slitrk2 axis in long-term PSD, uncovers a novel mechanism of microglial inflammation driving synaptic dysfunction to mediate mood disorders, and provides a new potential intervention target for PSD and general inflammatory depression.

[This corrects the article DOI: 10.1016/j.heliyon.2024.e40502.].

Rationale: Mitophagy plays an important role in pulmonary hypertension, a progressive disease characterized by excessive proliferation of pulmonary artery smooth muscle cells (PASMCs). Long intergenic non-protein coding RNA 3047 (LINC03047), as a hypoxia-related lncRNA, is involved in the progression of various diseases. This study aims to elucidate the mechanism by which LINC03047 in hypoxic pulmonary hypertension (HPH). Methods: Dysregulated LINC03047 was identified through lncRNA sequencing. Reactive oxygen species assay, mitochondrial membrane potential assay, immunofluorescence staining, cell proliferation experiment, gain- and loss-of-function experiments were conducted to elucidate its role in mitophagy and proliferation of hypoxia-induced PASMCs and HPH progression. The upstream transcription regulation mechanism of LINC03047 was identified and verified by comprehensive methods, including reverse transcription-polymerase chain reaction, western blotting, luciferase assay, chromatin immunoprecipitation and rescue experiments. RNA pulldown, mass spectrometry, and RNA immunoprecipitation were employed to identify the potential interacting proteins of LINC03047, and further elucidate the regulatory mechanism between LINC03047 and its downstream targets. Furthermore, the HPH rat model and serum samples from PH patients were utilized to assess its in vivo impact and clinical relevance. Results: We observed that LINC03047 was significantly upregulated in hypoxia-induced PASMCs and promoted their mitophagy and proliferation.Mechanistically, signal transducer and activator of transcription 3 (STAT3) specifically interacted with the LINC03047 promoter and promoted the transcription of LINC03047. Furthermore, LINC03047 bound to heterogeneous nuclear ribonucleoprotein F (hnRNPF), altering the nuclear transport of hnRNPF, thereby upregulating the stability of connective tissue growth factor (CTGF) RNA. In vivo, targeting hnRNPF can ameliorate pulmonary vascular remodeling and HPH progression. The assessment of serum STAT3 and CTGF levels in PH patients indicated a strong positive correlation between the two biomarkers. Conclusions: The overexpression of LINC03047, driven by STAT3, facilitates PASMCs mitophagy by enhancing hnRNPF-mediated CTGF mRNA stability, thus promoting PASMCs proliferation and HPH progression. These findings highlight the critical role of LINC03047, providing new insights into the pathogenesis and potential treatment of HPH.

Importance Esketamine has been found to reduce the incidence of postpartum depression (PPD) in randomized clinical trials. However, current evidence from randomized clinical trials does not reflect esketamine’s efficacy in clinical settings. Objective To assess the clinical efficacy of intraoperative esketamine administration for preventing PPD among women who underwent cesarean delivery. Design, Setting, and Participants This randomized clinical trial was conducted at The First Affiliated Hospital of Chongqing Medical University in Chongqing, China, from March 2023 to February 2024. Pregnant patients admitted for cesarean delivery were included, while those with intellectual dysfunction or contraindications to esketamine were excluded. All participants were assigned randomly to either the esketamine group or control group in a 1:1 ratio. Data analysis was based on the intention-to-treat principle. Interventions Patients in the esketamine group received an infusion of 0.25 mg/kg esketamine in 20 mL of saline over 20 minutes, whereas patients in the control group received 20 mL saline over 20 minutes. Main Outcomes and Measures The primary outcome was the incidence of PPD at 6 weeks post partum. PPD was assessed using the Edinburgh Postnatal Depression Scale. Results A total of 308 pregnant women were randomly assigned to 1 of 2 groups: esketamine (n = 154; mean [SD] patient age, 31.57 [4.26] years) and control (n = 154; mean [SD] patient age, 32.53 [7.74] years). Incidence of PPD was significantly lower in the esketamine group compared with the control group at 6 weeks post partum (10.4% [16] vs 19.5% [30]; relative risk, 0.53; 95% CI, 0.30-0.93; P = .02). Conclusions and Relevance This randomized clinical trial demonstrated esketamine’s advantage in reducing the incidence of PPD at 6 weeks post partum in patients who underwent cesarean delivery. The efficacy and safety of esketamine in preventing PPD warrant further investigation in clinical practice. Trial Registration Chinese Clinical Trial Registry Identifier: ChiCTR2200065494

The nuclear factor kappa B (NF-κB) signalling pathway plays a crucial role in the regulation of inflammation, and previous research from our lab and others suggests that c-Ski has potential anti-inflammatory effects. However, the role and mechanism of c-Ski, which are related to the regulation of the NF-κB pathway, are still unclear. Here, U937 cells were used, and increasing c-Ski protein levels inhibited inflammatory factor production, invasion, and phagocytosis. The anti-inflammatory effect of c-Ski was similar to that of hormones. Subsequently, immunoprecipitation (IP), Western blot (WB), electrophoretic mobility shift assays (EMSAs), and dual-luciferase reporter assays were used to determine whether increasing c-Ski protein levels could increase c-Ski binding to NF-κB p65 (p65), leading to a decrease in the acetylation level and transcriptional activity of p65. Conversely, decreased p65 expression through targeted small interfering RNA (siRNA) caused the loss of the anti-inflammatory effects of c-Ski. Furthermore, immunoprecipitation confirmed the mutual interaction of c-Ski with HDAC1 and p65, and WB revealed that the anti-inflammatory effect of c-Ski was achieved through the deacetylation of p65 by HDAC1 combined with HDAC1 siRNA and inhibitors. Additionally, through quantitative proteomic analysis, we determined that increasing c-Ski levels had inhibitory effects on the NF-κB pathway. Finally, similar results were also obtained using primary bone marrow-derived macrophages (BMDMs). These findings not only confirm the anti-inflammatory effect of c-Ski but also reveal novel molecular pathways and regulatory molecules of c-Ski, which may be promising targets for direct intervention in the inflammatory response through regulation of c-Ski.

Background The importance of early detection of patients at risk of early neurological deterioration (END) after mechanical thrombectomy (MT) at the time of prognosis provision is paramount. Methods This retrospective study not only sought to determine the predictive variables of post-MT END but also created a prognostic model in the form of a nomogram. A predictive model based on END occurrence (≥ 4 points of NIHSS score increase or death) within 72 hours after the event was created through multivariate logistic regression analysis of the possible risk factors. Results Total that 161 AIS patients undergoing MT were gathered as training cohort and 69 as validation cohort. Multivariate analysis revealed three independent predictors: atherogenic index of plasma (AIP) (OR = 1.239, 95% CI: 1.015–1.513, P = 0.035), systemic immune-inflammation index (SII)(OR = 1.086, 95% CI: 1.007–1.172, P = 0.032), and smoking history(OR = 2.558, 95% CI: 1.030–6.348, P = 0.043). The predictive model based on the three variables achieved an AUC of 0.842 (95% CI: 0.763–0.922), with its calibration curve nearly aligning with the ideal diagonal. Conclusions These results showed that the nomogram has a strong discriminative ability and calibration level, which suggests that it can be used as a viable clinical tool to predict END among acute stroke patients with ischemia and who receive MT.

Importance Esketamine has been found to reduce the incidence of postpartum depression (PPD) in randomized clinical trials. However, current evidence from randomized clinical trials does not reflect esketamine's efficacy in clinical settings. Objective To assess the clinical efficacy of intraoperative esketamine administration for preventing PPD among women who underwent cesarean delivery. Design, Setting, and Participants This randomized clinical trial was conducted at The First Affiliated Hospital of Chongqing Medical University in Chongqing, China, from March 2023 to February 2024. Pregnant patients admitted for cesarean delivery were included, while those with intellectual dysfunction or contraindications to esketamine were excluded. All participants were assigned randomly to either the esketamine group or control group in a 1:1 ratio. Data analysis was based on the intention-to-treat principle. Interventions Patients in the esketamine group received an infusion of 0.25 mg/kg esketamine in 20 mL of saline over 20 minutes, whereas patients in the control group received 20 mL saline over 20 minutes. Main Outcomes and Measures The primary outcome was the incidence of PPD at 6 weeks post partum. PPD was assessed using the Edinburgh Postnatal Depression Scale. Results A total of 308 pregnant women were randomly assigned to 1 of 2 groups: esketamine (n = 154; mean [SD] patient age, 31.57 [4.26] years) and control (n = 154; mean [SD] patient age, 32.53 [7.74] years). Incidence of PPD was significantly lower in the esketamine group compared with the control group at 6 weeks post partum (10.4% [16] vs 19.5% [30]; relative risk, 0.53; 95% CI, 0.30-0.93; P = .02). Conclusions and Relevance This randomized clinical trial demonstrated esketamine's advantage in reducing the incidence of PPD at 6 weeks post partum in patients who underwent cesarean delivery. The efficacy and safety of esketamine in preventing PPD warrant further investigation in clinical practice. Trial Registration Chinese Clinical Trial Registry Identifier: ChiCTR2200065494

Janus hydrogels, defined by their asymmetric architectures and bifunctional interfaces, have emerged as a transformative class of solid-state electrolytes in electrochemical energy storage. By integrating spatially distinct chemomechanical and ionic functionalities within a single matrix, they overcome the intrinsic limitations of conventional isotropic hydrogels, offering enhanced interfacial stability, directional ion transport, and dendrite suppression in lithium- and zinc-based batteries. This mini-review systematically highlights recent breakthroughs in Janus hydrogel design, including interfacial polymerization and layer-by-layer assembly, which collectively enable precise modulation of crosslinking gradients and ion transport pathways. This review uniquely frames Janus hydrogels from a battery-centric and interface-engineering perspective. It elucidates key structure–function correlations, identifies current limitations in scalable fabrication and electrochemical longevity, and outlines future directions toward intelligent, multifunctional platforms for next-generation flexible and biointegrated energy systems.

The significant role of pyroptosis in the early pathogenesis of ischemic stroke underscores the urgent need for effective management strategies. Transcranial direct current stimulation (tDCS), a noninvasive modality for modulating brain activity, has been shown to confer neuroprotection by inhibiting neuroinflammation during the acute phase of stroke. However, the specific mechanisms underlying the effect of tDCS on neuronal pyroptosis remain largely unexplored. We established brain I/R injury in adult male Sprague Dawley rats through a middle artery occlusion (MCAO) model. tDCS treatment began 24 h after MCAO and lasts for 6 consecutive days. Evaluate neurobehavioral deficits through an improved Neurological Severity Score (mNSS), Western blot, immunofluorescence staining, TUNEL staining, transmission electron microscopy (TEM), and enzyme-linked immunosorbent assay (ELISA) were used to evaluate the expression of pyroptosis related proteins, cell morphology, and levels of inflammatory factors. The results showed that tDCS markedly reduced the levels of NLRP3 inflammasome-dependent pyroptosis proteins (NLRP3, ASC, cleaved-Caspase-1, and GSDMD-N), accompanied by a reduction in the number of cell membrane perforation and cell death related to pyroptosis. Moreover, tDCS increased the expression of NTN-1, which inhibited the activation of NLRP3 inflammasome through the peroxisome proliferator-activated receptor gamma (PPAR-γ)/nuclear factor kappa-B (NF-κB) signaling pathway. Knockdown of NTN-1 reversed the anti-pyroptosis and neuroprotective effect of tDCS. In conclusion, tDCS exerted neuroprotection by curbing neuronal pyroptosis through the NTN-1-mediated PPAR-γ/NF- κB pathway, and could be a useful strategy for ischemic stroke recovery.

OBJECTIVE:This study investigated whether cognitive training (CT) ameliorates postoperative delirium (POD) in older patients undergoing total hip and knee arthroplasty. METHODS:This clinical trial was conducted from 18 February to 10 July 2023 and included individuals aged 60-79 who underwent elective total hip and knee arthroplasties with surgery durations ≤3 hours under general anaesthesia. Patients with preoperative cognitive dysfunction and dementia were excluded. The incidence of POD was compared between the CT and routine care (RC) groups as the primary outcome. Secondary outcomes included adverse events, postoperative pain within 48 hours, and POD characteristics. RESULTS:In this study, 122 individuals were divided into two groups. The overall incidence of POD was 8.2% (10 out of 122), with no significant difference between the two groups (9.8% for CT group vs. 6.6% for RC group; P = .509). Secondary outcomes also showed no significant difference between the two groups. The training time was less, and the compliance rate was poor in the CT group (4.0%). Nonetheless, the results revealed a significant difference in POD rates among CT subgroups, and a robust correlation was identified between CT sessions lasting less than the median duration of 12 minutes and the incidence of POD (P = .043). CONCLUSION:The incidence of POD in older patients undergoing total hip or knee arthroplasty may not be mitigated by CT. As POD was exclusively observed in patients with fewer CT sessions, it suggests that the compliance-recommended CT sessions may contribute to the POD.