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关键词： Tau   Microglia   Tau spread   LRP1   Endo-lysosomal dysfunction   Inflammation  

摘要： Microglia are the tissue resident macrophages of the brain and their contribution to tau pathology progression remains to be fully understood. In this study, we developed a quantitative platform to elucidate the processing of extracellular tau within human induced pluripotent stem cell (iPSC)-derived microglia. We show that iPSC-derived microglia internalize monomeric and fibrillar tau through different cellular mechanisms and with different clearance kinetics. Acute inflammatory activation of microglia alters tau endocytosis, but surprisingly does not impact tau clearance. These results highlight the importance of the microglial endo-lysosome system as a regulator of tau pathology that is decoupled from acute microglial activation.

关键词： Carvedilol   Interleukin 1β   Intestinal ischemia reperfusion   Vascular endothelial growth factor  

摘要： Intestinal ischemia reperfusion (IIR) is a life threating clinical disorder and a serious emergency case with high mortality rate. Finding ameliorative agents is a critical requisite to safeguard the tissue against its harmful effect not only on the intestine, but also on other organs especially the heart. Therefore, we tried in the current study to evaluate the role of carvedilol (CAR); an effective beta and alpha blocker with anti-oxidant, anti-apoptotic, anti-inflammatory properties and a metabolic regulator, on both cardiac and intestinal tissue in a model of IIR. Rats were randomly allocated into 4 groups: Sham group, IIR group and CAR treated groups with IIR in 2 different doses; CAR treated group in low dose (CLD) (10 mg/kg), CAR treated group in high dose (CHD) (20 mg/kg). Interestingly, CAR significantly decreased the elevated levels of cardiac enzymes, tissue malondialdehyde (MDA), inflammasome, interleukin 1β (IL1β), tumor necrosis factor alpha (TNFα) and caspase3. However, CAR co-administration normalized the tissue level of vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), antioxidant parameters; reduced glutathione (GSH), total antioxidant capacity (TAC) with obvious improvement of the histopathological changes. CAR could ameliorate IIR induced damage in a dose dependent manner via its anti-oxidant and anti-inflammatory properties with regulation of eNOS/VEGF-A and inflammasome/IL1β/TNFα pathways and it can be considered as a potential therapeutic agent against such injury.

关键词： Stroke   Obesity   Tumor necrosis factor   Neuroinflammation   Functional outcomes   CXCL1   chemokine (C-X-C motif) ligand 1   DAB   3,3′-Diaminobenzidine   DAPI   4′,6-diamidino-2-phenylindole   FBS   fetal bovine serum   FDR   false discovery rate   GFAP   glial fibrillary acidic protein   HRP   horse radish peroxidase   IFN-γ   interferon-gamma   IL   Interleukin   LLOD   lower level of detection   LPS   lipopolysaccharide   MBP   myelin basic protein   MetSy   metabolic syndrome   NeuN   neuronal nuclei   NF-L   neurofilament light-chain   NG2   Neural/glial antigen 2   i.p   intraperitoneally   PBS   phosphate buffered saline   PFA   paraformaldehyde   RM   repeated measures   SEM   standard error of mean   SD   standard deviation   TBS   tris buffered saline   TBS-T   tris buffered saline + triton   TNF   tumor necrosis factor   TNFR1   tumor necrosis factor receptor 1   TNFR2   tumor necrosis factor receptor 2  

摘要： Obesity is a significant global health concern that exacerbates the risk and severity of ischemic stroke through chronic low-grade systemic inflammation and metabolic dysregulation. Tumor necrosis factor (TNF) signaling, particularly through its TNF receptor 1 (TNFR1), is involved in obesity-driven inflammation and adverse stroke outcomes. To assess the potential of TNFR1 blockade as a treatment strategy, we employed a diet-induced obesity model of ischemic stroke. Male C57BL/6 mice were fed a regular diet or high-fat diet for 6 weeks prior to stroke induction via photothrombosis and treated with either a TNFR1-neutralizing antibody or isotype control antibody. Outcomes were evaluated using motor function assessments, systemic inflammatory biomarker measurements, and brain tissue analysis, including evaluation of microglia, astrocytes, oligodendrocytes, myelin integrity, and stroke size. Results showed that obese mice exhibited worsened motor deficits and heightened systemic inflammation following stroke compared to non-obese controls. Treatment with anti-TNFR1 antibody did not ameliorate the increased functional deficits but did improve interleukin-6 cytokines levels after stroke in obese mice, while it had no effects on non-obese controls. Moreover, anti-TNFR1 therapy did not impact infarct size, microglial and astrocyte reactivity, or myelin integrity in both dietary groups. Overall, TNFR1-targeted therapy had a limited impact on obesity-exacerbated stroke outcomes, suggesting the need to explore broader or combination immunomodulatory approaches. These findings also emphasize the importance of considering comorbidities such as obesity in stroke, as they can influence both disease progression and treatment effectiveness.

关键词： C. striatum   Neutrophilic asthma   Interleukin-17  

摘要： Corynebacterium striatum has recently been recognized as an emerging multidrug-resistant pathogen capable of causing both nosocomial and community-acquired infections, particularly in immunocompromised individuals and those with chronic conditions. However, direct evidence regarding the pathogenicity of C. striatum and its association with neutrophilic asthma remains poorly understood. In this study, a BALB/c mouse model infected with C. striatum was established at first to investigate its potential role in acute lung injury. The results demonstrated that C. striatum infection induced significant lung inflammation and pathological alterations, with more pronounced inflammatory responses observed in immunocompromised mice. Hematological analysis and fluorescence in situ hybridization (FISH) revealed a marked increase in neutrophil levels and confirmed the colonization of C. striatum in lung tissues. Furthermore, in an ovalbumin (OVA)-induced asthma model, C. striatum infection exacerbated neutrophilic inflammation and induced the significant upregulation of Interleukin (IL)-17, IL-6, and CXCL-8, alongside activation of the NF-kappa B signaling pathway. These findings suggest that C. striatum drives neutrophil recruitment and amplifies inflammatory responses by promoting a Th2/Th17 immune shift, highlighting the critical involvement of the IL-17 signaling pathway in C. striatum-associated asthma. This study provides novel experimental evidence supporting C. striatum as a respiratory pathogen and offers further theoretical rationale for targeting IL-17 in the treatment of C. striatum-related neutrophilic asthma.

关键词： Macrophages  

摘要： Rheumatoid arthritis (RA) is a chronic, progressive inflammatory autoimmune disease marked by relentless synovial inflammation and joint destruction, for which long-term remission remains challenging. Although dexamethasone (DEX) is commonly employed to rapidly control disease activity, its therapeutic effectiveness is often undermined by the development of glucocorticoid resistance (GCR) and cumulative systemic toxicities. Recent insights suggest that TNF-α-driven inflammation not only perpetuates joint pathology but also sustains a molecular landscape that favors GCR, underscoring an urgent need for therapeutic strategies that jointly target inflammatory signaling and steroid sensitivity. Here, we report a nanomedicine-enabled sequential therapy, in which TNF-α specific siRNA (siTNFα) and DEX are separately encapsulated within macrophage-targeted polymersomes (MTP-T and MTP-D, respectively). Through intravenous administration of MTP-T, followed by the intraperitoneal delivery of MTP-D (designated as MTP-T/D(seq)), this sequential therapy acheives efficient knockdown of TNF-α in inflammatory macrophages, leading to enhanced expression of glucocorticoid receptor (GR), an elevated GRα/GRβ ratio, and a substantial reversal of GCR. This modulation sensitizes macrophages to DEX, enabling rapid and effective suppression of pro-inflammatory mediators while reducing toxicity. Our findings demonstrate that our sequential therapy in collagen-induced arthritis (CIA) mouse models not only mitigates joint inflammation and mitochondrial dysfunction but also normalizes the M2/M1 macrophage balance, attenuating synovial hyperplasia and cartilage damage as confirmed by molecular and histological analyses. These findings validate a precision-engineered immune microenvironment remodeling strategy that restores glucocorticoid responsiveness and confers potent therapeutic benefits, offering a compelling blueprint for overcoming steroid resistance in RA. © 2025 Elsevier B.V.

关键词： High-power   Low-temperature plasma (LTP)   Psoriasis   NO   Th17/IL-23 cell axis  

摘要： This study aims to evaluate the therapeutic efficacy and potential underlying mechanisms of a novel high-power low-temperature plasma (hLTP) therapy for treatment of psoriasis. Imiquimod (IMQ)-induced rat psoriasis model was used to evaluate the therapeutic efficacy of hLTP. Potential mechanisms were explored using bioinformatics analysis and molecular biology validation based on transcriptomic data. hLTP treatment alleviated IMQ-induced psoriasis as evidenced by a significantly reduced psoriasis area and severity index scores (PASI), and pathological changes. Based on the transcriptomic data, the differential expressed genes (DEGs) positively or negatively related to the hLTP treatment was identified and bioinformatics analysis was further performed. The results of the verification experiment indicate that hLTP treatment significantly elevated nitric oxide (NO) levels and FKBP5 expression in psoriasis, which was associated with inhibition of the NF-kappa Bpathway, as indicated by reduced p-IKK/IKK and p-P65/P65 ratios. Apoptosis was suppressed, evidenced by a decreased cleavedcaspase3/caspase3 ratio and lower self-DNA levels. Antioxidant capacity was enhanced, shown by increased glutathione (GSH) levels, while the inflammatory response was mitigated with reduced cathelicidin (LL-37) levels. These effects resulted in reduced psoriasis-related pro-inflammatory cytokines (IL-23, IL-6, and TGF-beta) from dendritic cells and macrophages, preventing Th17 cell differentiation and suppressing it related cytokines (IL-17 A, IL-22, IL-17F, TNF-alpha). Consequently, the Th17/IL-23 cell axis was disrupted under hLTP *** is a novel study that provides conclusive data demonstrating that hLTP exerts significant therapeutic effects on psoriasis through its anti-inflammatory, antioxidant, and anti-apoptotic effects by significantly up-regulating NO and FKBP5, while inhibiting NF-kappa B pathway and Th17/IL-23 cell axis.

关键词： Crosstalk  

摘要： Mortality resulting from sepsis is highly associated with secondary acute lung injury, and although the gut-lung axis is of significant importance, treatment strategies leveraging this understanding remains limited. Here, we developed an Escherichia coli strain named ΔPESI that highly expresses IL-1Ra via outer membrane vesicles (OMVs) and PEGylated this strain through the SpyCatcher-SpyTag system for enhanced activity and colonization. Oral administration of ΔPESI reinforces epithelial barrier integrity in the gut, inhibits inflammatory cascade in the peripheral circulation, modulates macrophage polarization and pyroptosis in the lung, thereby significantly mitigating the dysregulated systemic inflammatory response. Furthermore, ΔPESI exhibits favorable biosafety characteristics, thus demonstrating strong potential for clinical translation. Hence, this study proposes a promising strategy for the oral administration of engineered probiotics to effectively alleviate intestinal and pulmonary inflammatory responses through modulation of the gut–lung crosstalk. © 2025

关键词： 脑梗死   预后   生物标志物   细胞因子   微小核糖核酸   外泌体   综述  

摘要： 缺血性卒中(又称脑梗死)作为导致全球残疾和死亡的主要原因之一,近年来,其预后生物标志物的研究取得了显著进展。本文综述了包括血细胞分析指标(如红细胞体积分布宽度)、ω-3多不饱和脂肪酸、细胞因子(如白介素6、肿瘤坏死因子α)、微小核糖核酸(miRNA,如miR-21、miR-155、miR-126)和外泌体在内的多种生物标志物在缺血性脑卒中中的作用机制及其在预后评估中的研究进展。综述得出,血细胞分析相关指标、ω-3多不饱和脂肪酸、白介素6、肿瘤坏死因子α的浓度与缺血性脑卒中的严重程度和预后密切相关。其中,较高基线红细胞体积分布宽度与复发性缺血性脑卒中的风险增加相关,并且与缺血性脑卒中的复发时间呈负相关。特定miRNA(如miR-21)通过抑制细胞凋亡和促进神经元存活,改善神经功能恢复;而miR-155通过调控炎症反应加剧脑损伤,其表达水平可预测缺血性脑卒中的复发;此外,miR-126在血管生成和神经保护中发挥关键作用。外泌体则通过携带抗炎因子、神经营养因子、抗氧化酶和热休克蛋白等,显著减轻缺血再灌注引起的炎症和损伤,从而影响缺血性脑卒中的预后。尽管这些生物标志物在缺血性脑卒中预后评估中显示出巨大潜力,但其临床应用仍面临诸多挑战,包括个体间差异、长期效应和安全性研究不足以及技术标准化问题。未来研究应进一步探讨这些标志物的作用机制,开发标准化的检测方法,并进行大规模临床验证,以便将其应用于临床,改善缺血性脑卒中患者的预后和生活质量。

关键词： 创伤性脑损伤   骨痂   骨折愈合   炎症反应   细胞因子   激素   神经肽   基因   干细胞  

摘要： 背景:骨折延迟愈合和不愈合是常见的临床问题。在临床观察中,常见到合并创伤性脑损伤的四肢骨折患者的骨折愈合速度明显快于无脑损伤的患者。这一现象背后的可能机制已成为当前研究的重要焦点。近年来的研究表明,创伤性脑损伤通过调控细胞因子、激素、神经信号以及干细胞等机制,显著加速了骨痂形成和骨折愈合过程。目的:总结创伤性脑损伤促进骨痂形成及骨折愈合机制的最新研究进展,为临床应用提供理论依据。方法:文章第一作者通过检索中国知网、万方、维普、PubMed、Embase、Web of Science及Cochrane Library数据库2013年1月至2024年10月相关文献,个别文献追溯至20年前。检索词为“创伤性脑损伤,骨痂,骨折愈合,炎症反应,细胞因子,激素,神经肽,基因,干细胞”“traumatic brain injury,callus,fracture healing,inflammatory response,cytokines,hormones,neuropeptides,genes,stem cells”,最终选取符合纳入标准的文献共计83篇。结果与结论:创伤性脑损伤对骨痂形成及骨折愈合的促进作用机制极其复杂,涉及细胞因子、激素、神经系统和干细胞等多个调节环节。然而,目前关于创伤性脑损伤促进骨痂形成及骨折愈合的具体机制尚未得到全面、清晰的理解,仍需进一步深入研究。现有研究表明,创伤性脑损伤主要通过促进细胞因子(如胰岛素样生长因子1)和激素(如生长激素及瘦素)的释放,调控神经系统,促进干细胞的增殖与分化等机制来加速骨痂形成和骨组织再生。此外,创伤性脑损伤会引发一系列免疫反应,包括炎症因子的释放和免疫细胞的激活,这些反应能够调节骨折修复的过程。具体而言,免疫反应通过增强局部血流、促进细胞迁移和激活成纤维细胞,从而支持骨愈合的不同阶段。同时,创伤性脑损伤诱发的干细胞活化也在骨折修复中发挥了关键作用。活化的干细胞能够分化为骨细胞、软骨细胞和脂肪细胞,促进骨组织再生和修复。因此,创伤性脑损伤诱发的免疫反应与干细胞的活化共同作用,为骨折愈合提供了必要的支持。这些机制能够加速骨愈合过程,显著缩短愈合时间,提升骨折患者的预后。综上所述,创伤性脑损伤通过多重机制促进骨痂形成和骨折愈合,展现其在骨修复中的重要性。未来研究应聚焦创伤性脑损伤影响骨愈合的信号通路及调控因子,深入理解其作用机制,这将为开发靶向治疗、干细胞及神经调控疗法提供理论基础,具有缩短愈合时间、优化康复方案、改善预后的临床价值。因此,探索创伤性脑损伤引发的生物效应将为骨折治疗开辟新途径。

关键词： Interleukin 6   Procalcitonin   Prognosis   Traumatic brain injury  

摘要： Background Inflammation is a critical secondary injury mechanism in craniocerebral trauma, which contributes to further tissue damage and long-term neurological deficits. This inflammatory response is primarily a neurotoxic injury mediated through the production of inflammatory factors by the inflammatory cells. Among these, IL-6 is the most promising biomarker for the clinical diagnosis of brain injury, and procalcitonin (PCT) is a promising biomarker specific for bacterial infection. This study aimed to investigate the relationship between IL and 6 and PCT concentrations at admission and the Glasgow Outcome Score (GOS) at 6 months post-discharge in patients with moderate-to-severe traumatic brain injury (TBI). Methods This retrospective study included 122 patients with moderate-to-severe TBI (Glasgow Coma Scale [GCS] 3–12) admitted to Shenzhen Second People’s Hospital between January 2019 and June 2024. GOS scores at 6 months after discharge were recorded. Outcomes were dichotomized into favorable and unfavorable. Associations between IL and 6, PCT, and clinical characteristics were assessed via chi-square tests. Multivariate logistic regression identified independent prognostic factors for GOS, whereas ROC analysis evaluated the predictive performance (AUC) of biomarkers and composite models. Results In total, 50 and 72 patients were categorized into the poor and good prognosis groups, respectively. Among these, 14 cases resulted in fatality. Initial serum analysis demonstrated significantly higher PCT (p < 0.001) and IL-6 (p = 0.001), but lower hemoglobin (p = 0.003) in the poor-prognosis group. Multivariate analysis identified six independent predictors of 6-month GOS outcomes: hemoglobin (OR = 1.03, p = 0.002), albumin (OR = 1.06, p = 0.035), IL-6 (OR = 1.00, p = 0.003), PCT (OR = 0.74, p = 0.015), GCS (OR = 1.49, p < 0.001), and creatinine (OR = 0.97, p = 0.001). Prognostic performance analysis demonstrated that the individual biomarkers IL-6 and PCT achieved