Traumatic brain injury (TBI) induces profound neuroinflammation, leading to secondary brain damage and neurological dysfunction. Emerging evidence highlights the critical role of neutrophil extracellular traps (NETs) in amplifying inflammatory responses after injury. This study investigates the involvement of the NLRP3 inflammasome and gasdermin D (GSDMD) in regulating NET formation and subsequent microglia-mediated neuroinflammation after TBI. Using a male mouse model of TBI, we demonstrate that activation of the NLRP3/GSDMD axis significantly enhances NET release from neutrophils. These NETs further activate microglia, promoting the secretion of proinflammatory cytokines, exacerbating blood-brain barrier damage, and worsening neurological deficits. Pharmacological inhibition of NLRP3 and GSDMD markedly attenuates NET formation, reduces microglial activation, and ameliorates neuroinflammation and neurological deficits. Collectively, our findings reveal a mechanistic pathway linking NLRP3/GSDMD-dependent NET formation with microglia-driven neuroinflammation, providing potential therapeutic targets for mitigating secondary injury following TBI.

The understanding of neuroimmune function has evolved from concepts of immune privilege and protection to a new stage of immune interaction. The discovery of skull meninges channels (SMCs) has opened new avenues for understanding central nervous system (CNS) immunity. Here, we characterize skull bone marrow and SMCs by detailing the anatomical structures adjacent to the skull, the differences between skull and peripheral bone marrow, mainstream animal processing methods, and the role of skull bone marrow in monitoring various CNS diseases. Additionally, we highlight several unresolved issues based on current research findings, aiming to guide future research directions.

Background:Type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD) are closely related conditions. Aim:This study investigated a group of individuals with NAFLD to evaluate if liver fibrosis, identified by FibroScan, correlated with T2DM. Methods:154 NAFLD patients obtained FibroScan, liver ultrasonography (US), and a thorough assessment of clinical implications and chemical biomarkers. Results:In comparison to the NAFLD without T2DM group, the hemoglobin A1c(HBA1c)(mmol/mol%), homeostasis model of assessment for insulin resistance index (HOMA-IR), gamma-glutamyl transferase (GGT), fibrosis indices, and liver stiffness measurement (LSM) values were all considerably higher in the NAFLD with T2DM group. Patients with NAFLD and T2DM had considerably lower serum uric acid(SUA) levels than those with NAFLD alone.Those with severe fibrosis (79.3%, 23/29) in the NAFLD group showed a greater frequency of T2DM than those with mild fibrosis (45.6%, 21/46) or no fibrosis (27.85%, 22/79) (P=0.000). LSM value and elements of the metabolic syndrome (MetS) were independent risk factors for incident T2DM among NAFLD patients (OR=1.466, 95% CI [1.139-1.888], P=0.003; and OR=0.273, 95% CI [0.081-0.916], P=0.036). Conclusion:FibroScan can identify significant fibrosis, which is independently linked to a higher prevalence of T2DM. As a result, it is crucial to make use of this technology to predict T2DM in NAFLD patients.

Recent advances in neuroscience have transformed our understanding of the meninges, the layers surrounding the central nervous system (CNS). Two key findings have advanced our understanding: researchers identified cranial bone marrow as a reservoir for meningeal immune cells, and rediscovered a brain lymphatic system. Once viewed merely as a protective barrier, the meninges are now recognized as a dynamic interface crucial for neuroimmune interactions. This shift in perspective highlights their unique role in maintaining CNS balance, shaping brain development, and regulating responses to injury and disease. This review synthesizes the latest insights into meningeal anatomy and function, with a focus on newly identified structures such as dural-associated lymphoid tissues (DALT) and arachnoid cuff exit (ACE) points. We also examine the diverse immune cell populations within the meninges and their interactions with the CNS, underscoring the emerging view of the meninges as active participants in brain immunity. Finally, we outline critical unanswered questions about meningeal immunity, proposing directions for future research. By addressing these knowledge gaps, we aim to deepen our understanding of the meninges’ role in brain health and disease, potentially paving the way for novel therapeutic approaches.

Neutrophil extracellular traps are primarily composed of DNA and histones and are released by neutrophils to promote inflammation and thrombosis when stimulated by various inflammatory reactions. Neutrophil extracellular trap formation occurs through lytic and non-lytic pathways that can be further classified by formation mechanisms. Histones, von Willebrand factor, fibrin, and many other factors participate in the interplay between inflammation and thrombosis. Neuro-immunothrombosis summarizes the intricate interplay between inflammation and thrombosis during neural development and the pathogenesis of neurological diseases, providing cutting-edge insights into post-neurotrauma thrombotic events. The blood-brain barrier defends the brain and spinal cord against external assaults, and neutrophil extracellular trap involvement in blood-brain barrier disruption and immunothrombosis contributes substantially to secondary injuries in neurological diseases. Further research is needed to understand how neutrophil extracellular traps promote blood-brain barrier disruption and immunothrombosis, but recent studies have demonstrated that neutrophil extracellular traps play a crucial role in immunothrombosis, and identified modulators of neuro-immunothrombosis. However, these neurological diseases occur in blood vessels, and the mechanisms are unclear by which neutrophil extracellular traps penetrate the blood-brain barrier to participate in immunothrombosis in traumatic brain injury. This review discusses the role of neutrophil extracellular traps in neuro-immunothrombosis and explores potential therapeutic interventions to modulate neutrophil extracellular traps that may reduce immunothrombosis and improve traumatic brain injury outcomes.

Obesity,and metabolic dysfunction-associated fatty liver disease (MAFLD) have reached epidemic proportions globally. Obesity and MAFLD frequently coexist and act synergistically to increase the risk of adverse clinical outcomes (both hepatic and extrahepatic). Type 2 diabetes mellitus (T2DM) is the most important risk factor for rapid progression of steatohepatitis and advanced fibrosis. Conversely, the later stages of MAFLD are associated with an increased risk of T2DM incident. According to the proposed criteria, MAFLD is diagnosed in patients with liver steatosis and in at least one in three: overweight or obese, T2DM, or signs of metabolic dysregulation if they are of normal weight. However, the clinical classification and correlation between obesity and MAFLD is more complex than expected. In addition, treatment for obesity and MAFLD are associated with a reduced risk of T2DM, suggesting that liver-based treatments could reduce the risk of developing T2DM. This review describes the clinical classification of obesity and MAFLD, discusses the clinical features of various types of obesity and MAFLD, emphasizes the role of visceral obesity and insulin resistance (IR) in the development of MAFLD,and summarizes the existing treatments for obesity and MAFLD that reduce the risk of developing T2DM.

To assess the relationship between clinical biochemical characteristics and steatosis or fibrosis by Fibroscan in non-alcoholic fatty liver disease (NAFLD) patients in order to seek the simple effective screening method closed to the results of the fibroScan measurement. A cross-sectional study was conducted on 188 patients with NAFLD who underwent FibroScan examinations. Demographic data and clinical biochemical characteristics were collected and analyzed. The result showed elevated serum uric acid (SUA) (P = .023, odds ratio [OR = 1.005, 95% CI (1.001-1.009) and metabolic syndrome (MetS) (P = .000, OR = 4.549, 95%CI (1.974-10.484) were associated with severe steatosis (controlled attenuation parameter, CAP = 300 dB/m). The magnitude of liver stiffness measured using FibroScan was positively correlated with aspartate transaminase/alanine aminotransferase (AST/ALT) ratio (R = 0.419, P = .000), AST to platelet ratio index (APRI) score (R = 0.309, P = .000), and Fibrosis-4 score (FIB-4) (R = 0.507, P = .000). The areas under the receiver operating curve (ROC) of AST/ALT, APRI, and FIB-4 for mild or severe fibrosis were 0.563, 0.696, and 0.728, respectively, and those for advanced fibrosis were 0.648, 0.750, and 0.821, respectively. The FIB-4 index cutoff value was 1.65 with a sensitivity of 68.3% and specificity of 89.8% during the diagnosis of advanced fibrosis. MetS and elevated SUA are associated with severe steatosis according to the CAP value screen, whereas FIB-4, as the fibrosis score method, is closer to the liver stiffness measurement results from FibroScan, which may facilitate early warning of NAFLD in the community or in remote areas.

Abstract Intense neuroinflammatory response with widespread microglia/macrophage activation and leucocyte infiltration occurring during the acute phase of traumatic brain injury (TBI) is an important mediator of secondary neurological injury. Neutrophils, as the most abundant leukocytes in peripheral circulation and the first-line transmigrated immune cells at the contused parenchyma following TBI, are suggested to worsen TBI outcomes and exacerbate TBI-related neuroinflammation, via unclear mechanisms. We hypothesized that neutrophil extracellular trap (NET) formation as a key mechanistic regulator, exacerbate microglia/macrophage-mediated neuroinflammation and acute neurological deficits after TBI. In this study, we observed massive NET formation in contused brain tissue of TBI patients and elevated plasma NET biomarkers correlated with upregulated cGAS-STING pathway. Overexpression of peptidylarginine deiminase 4 (PAD4) induces an increase in the NET formation that is accompanied by upregulation of the cGAS-STING pathway and exacerbation of microglia/macrophages-mediated neuroinflammation and neurological injury. Additionally, degradation of NETs-associated DNA by DNase 1 and inhibition of NET formation by pharmacological inhibition of PAD effectively inhibit cGAS-STING pathway activation and ameliorate microglia/macrophages-mediated neuroinflammatory responses. Collectively, our data highlight that targeting NETs is a promising therapeutic strategy for TBI treatment.

高钾血症是指血清钾浓度超过5 .5 mmol/L的一种病理生理状态,急诊发生率为3.6％[1].美国急诊每年高钾血症相关疾病超过80 万例,其中近7万例以高钾血症为第一诊断,45～84岁年龄段占75％[2].高钾血症具有潜在心律失常的致命性风险,尤其对有基础疾病患者.多项研究发现,老年患者高钾血症与心血管病病死率升高相关,增加室性心律失常的风险[3,4].武警特色医学中心消化科收治1例腹泻后高钾血症致严重心律失常的高龄患者,治疗效果良好.

Extracellular vesicles are composed of fragments of exfoliated plasma membrane, organelles or nuclei and are released after cell activation, apoptosis or destruction. Platelet-derived extracellular vesicles are the most abundant type of extracellular vesicle in the blood of patients with traumatic brain injury. Accumulated laboratory and clinical evidence shows that platelet-derived extracellular vesicles play an important role in coagulopathy and inflammation after traumatic brain injury. This review discusses the recent progress of research on platelet-derived extracellular vesicles in coagulopathy and inflammation and the potential of platelet-derived extracellular vesicles as therapeutic targets for traumatic brain injury.

Background: Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) is associated with neuroinflammation and subsequent cell death following traumatic brain injury (TBI). The sigma-1 receptor (Sig-1R) acts as a dynamic pluripotent modulator of fundamental cellular processes at the mitochondria-associated membranes (MAMs). The activation of Sig-1R is neuroprotective in a variety of central nervous system diseases, but its impact on ER stress induced by traumatic brain injury is not known. This study investigated the role of Sig-1R in regulating the ER stress-mediated microglial activation and programmed cell death (apoptosis and pyroptosis) induced by TBI. Methods: Ten human brain tissues were obtained from The Tianjin Medical University General Hospital. Four normal brain tissues were obtained from patients who underwent surgery for cerebral vascular malformation, through which peripheral brain tissues were isolated. Six severe TBI tissues were from patients with brain injury caused by accidents. None of the patients had any other known neurological disorders. Mice with Sig-1R deletion using CRISPR technology were subjected to controlled cortical impact-induced injury. In parallel, wild type C57BL/6J mice were analyzed for outcomes after they were exposed to TBI and received the Sig-1R agonist PRE-084 (10 mg/kg daily for three days) either alone or in combination with the Sig-1R antagonist BD-1047 (10 mg/kg). Results: The expression of Sig-1R and the 78 kDa glucose-regulated protein, a known UPR marker, were significantly elevated in the injured cerebral tissues from TBI patients and mice subjected to TBI. PRE-084 improved neurological function, restored the cerebral cortical perfusion, and ameliorated and brain edema in C57BL/6J mice subjected to TBI by reducing endoplasmic reticulum stress-mediated apoptosis, pyroptosis, and microglia activation. The effect of PRE-084 was abolished in mice receiving Sig-1R antagonist BD-1047. Conclusions: ER stress and UPR were upregulated in TBI patients and mice subjected to TBI. Sig-1R activation by the exogenous activator PRE-084 attenuated microglial cells activation, reduced ER stress-associated programmed cell death, and restored cerebrovascular and neurological function in TBI mice.

Objective:To analyze the factors affecting the recurrence of patients with non-varices upper gastrointestinal bleeding (NVUGIB) after receiving digestive endoscopy.Methods:The clinical data of 120 patients with NVUGIB who received digestive endoscopy were retrospectively analyzed. The patients were divided into recurrence group and non-recurrence group according to their recurrence status, and the risk factors affecting recurrence were analyzed.Results:The results of univariate analysis showed that there was no significant difference in age, gender and body mass index between the relapsed group and the non-relapsed group (all P>0.05), and there was significant difference in Forrest grade, hemoglobin concentration, platelet count, peptic ulcer, shock, improper diet, premature getting out of bed, constipation and subsequent proton pump inhibitors (all P<0.05). The results of multivariate logistic regression analysis showed that the Forrest grade(Ⅰa), hemoglobin level (<100 g/L), platelet count (<100×10 9/L), peptic ulcer, shock, improper diet, premature getting out of bed, constipation and subsequent proton pump inhibitorsare the risk factors of recurrence in patients with NVUGIB (all P<0.05). Conclusions:Clinically, targeted preventive measures should be taken based on the risk factors that affect the recurrence of patients with NVUGIB after digestive endoscopic treatment.

Abstract Background Gastroesophageal reflux disease (GERD) is strongly associated with sleep disturbances. Proton pump inhibitors (PPIs) are the main treatment to improve the symptom of GERD. This study was to investigate the efficacy of PPIs on nighttime GERD symptoms and associated sleep disturbances in general Chinese GERD population. Methods Adult patients with mild or more serious nighttime GERD symptoms were included. The efficacy was evaluated by the relief rate of nighttime GERD symptoms and GERD-related sleep disturbances after 4 weeks PPIs treatment. Sleep quality was evaluated using the Pittsburgh Sleep Quality Index Score (PSQI). Results A total of 750 patients were included in the final analysis. Overall, 51.3% of the patients had achieved a relief of nighttime GERD symptoms after 4 weeks of PPIs treatment. By week 4, the percentages of patients with completely resolved nighttime GERD symptoms and GERD-related sleep disturbances were 32.5% and 51.5%, respectively. PSQI score was significantly improved from 6.82 ± 0.12 at baseline to 4.56 ± 0.09 at 4 weeks (P༜0.001). Conclusion PPIs treatment can provide an effective relief of nighttime GERD symptoms and associated sleep disturbances, improving sleep quality of general GERD patients in northern China. Trial registration: Trial registration: CHiCTR, ChiCTR1800017652. Registered 08 August 2018, http://chictr.org.cn/index.aspx

The current prostate special antigen (PSA) test causes the overtreatment of indolent prostate cancer (PCa). It also increases the risk of delayed treatment of aggressive PCa. DNA methylation aberrations are important events for gene expression dysregulation during tumorigenesis and have been suggested as novel candidate biomarkers for PCa. This may improve the diagnosis and prognosis of PCa. This study assessed the differential methylation and messenger RNA (mRNA) expression between normal and PCa samples. Correlation between promoter methylation and mRNA expression was estimated using Pearson's correlation coefficients. Moreover, the diagnostic potential of candidate methylation markers was estimated by the receiver operating characteristic (ROC) curve using continuous beta values. Survival and Cox analysis was performed to evaluate the prognostic potential of the candidate methylation markers. A total of 359 hypermethylated sites 3435 hypomethylation sites, 483 upregulated genes, and 1341 downregulated genes were identified from The Cancer Genome Atlas database. Furthermore, 17 hypermethylated sites (covering 13 genes), including known genes associated with hypermethylation in PCa (e.g., AOX1 and C1orf114), showed high discrimination between adjacent normal tissues and PCa samples with the area under the ROC curve from 0.88 to 0.94. Notably, ANXA2, FGFR2, HAAO, and KCNE3 were identified as valuable prognostic markers of PCa through the Kaplan-Meier analysis. Using gene methylation as a continuous variable, four promoter hypermethylation was significantly associated with disease-free survival in univariate Cox regression and multivariate Cox regression. This study identified four novel diagnostic and prognostic markers for PCa. The markers provide important strategies for improving the timely diagnosis and prognosis of PCa.

目的 探讨微信随访在提高军校学员患者门诊就诊满意度的作用.方法 选择2018年04月至2018年08月武警某军校门诊学员患者300名,随机分为微信随访组(150例)及对照组(150例),微信随访组患者就诊时添加医生微信,收到相应疾病的健康指导建议,并随时通过微信与就诊医生进行图文咨询,医生给出建议;对照组就诊后仅留下手机号,2w后电话随访添加微信.2 w后两组均填写问卷调查表.结果 微信随访组门诊患者很满意率33.3％、满意率36.7％、基本满意率26.7％、不满意率3.3％及很不满意率0;对照组门诊患者很满意率8％、满意率23.3％、基本满意率39.3％、不满意率20％及很不满意率9.3％.两组间差异有统计学意义(P＜0.05).结论 军校学员门诊患者总体满意率有待改善,微信随访能够提高军校学员门诊就诊患者的满意度.

目的:探讨在食管癌细胞增殖过程中蛋白酶激活受体-2(PAR-2)影响细胞周期蛋白D1(CyclinD1)的机制.方法:方法:使用食管癌EC109细胞株,实验分为:空白对照组、PAR-2激动组(加入激动剂SLIGKV)、PAR-2反激动组(加入反激动剂VKGILS)、PAR-2 shRNA组(PAR-2shRNA成功转染)和MAPK抑制组(加入阻滞剂PD98059);取对数生长期的细胞,以6×104 cells/ml的密度接种于培养瓶中,置于孵育箱中培养24 h后使用PBS清洗3次,更换为无血清的1640培养基培养24 h,之后各实验组按实验设计分别加入所需试剂,每组设置3个复孔,于孵育箱中继续培养24 h,采用RT-PCR法检测PAR-2、ERK1、CyclinD1的mRNA的表达水平;采用Western blot法检测PAR-2、ERK1、p-ERK1、CyclinD1的蛋白表达水平.结果:与空白对照组相比,PAR-2激动组PAR-2mRNA、ERK1 mRNA、和CyclinD1 mRN表达明显升高(P<0.05),PAR-2、p-ERK1和CyclinD1蛋白表达升高(P<0.05);PAR-2 shRNA组PAR-2mRNA、ERK1 mRNA和CyclinD1 mRNA表达降低(P<0.05),PAR-2、p-ERK1和CyclinD1蛋白表达降低(P<0.05);MAPK抑制组ERK1 mRNA和CyclinD1 mRNA表达明显降低(P<0.05),p-ERK1和CyclinD1表达降低(P<0.05).

目的 研究华蟾酥毒基对食管癌细胞侵袭转移的影响.方法 分别将食管癌EC-109和Kyse-150细胞分为4组:对照组和3个浓度实验组.对照组加入含有溶媒(0.1％ DMSO)的培养基,低、中、高3个浓度实验组给予25,50,100 nmol· L-1华蟾酥毒基,处理1d.用划痕实验和Transwell小室法检测各组细胞迁移水平和侵袭能力,用免疫印迹实验检测细胞中磷酸化黏着斑激酶Tyr397[p-FAK(Tyr397)]、P53、人第10号染色体缺失的磷酸酶及张力蛋白同源基因(PTEN)、基质金属蛋白酶2(MMP-2)和基质金属蛋白酶9(MMP-9)的蛋白表达情况,用实时荧光定量PCR检测各组细胞中上述指标mRNA的相对表达水平.结果 EC-109细胞:以25～100 nmol·L-1的华蟾酥毒基处理1d后,实验组划痕愈合面积约为(9.96±1.17)％ ～ (5.02±0.92)％,侵袭细胞数约为(162.33±12.01)-(42.33±12.50)个;与对照组的(23.80±1.32)％和(254.33±14.01)个相比,差异均有统计学意义(均P＜0.01).低、中、高3个浓度实验组的MMP-2蛋白表达水平分别为0.74±0.04,0.54±0.06和0.44±0.05.中、高2个浓度实验组的MMP-9蛋白表达分别为0.69±0.08,0.52±0.04;这2组的p-FAK(Tyr397)的表达水平分别为0.90±0.08,0.62±0.06;这2组的P53蛋白表达水平分别为1.20±0.06,2.86±0.05;这2组的PTEN蛋白表达水平分别为1.31±0.06,1.53±0.05,与对照组的(1.00±0.00)比较,差异均有统计学意义(均P＜0.01);在同样的处理条件下,实验组上述指标的mRNA的表达变化与蛋白表达趋势相同.Kyse-150细胞:迁移和侵袭能力的改变以及各指标的表达变化与EC-109细胞趋势相同.结论 华蟾酥毒基可能通过上调P53和PTEN表达,下调FAK的磷酸化及其下游分子MMP-2和MMP-9的表达,进而抑制食管癌细胞的迁移和侵袭.

Protease-activated receptor 2 (PAR-2) has been demonstrated to promote invasion and metastasis of certain cancer cells. This study aimed to investigate the mechanism by which PAR-2 regulated invasion and migration of esophageal cancer (EC) cells EC109. A successfully constructed PAR-2 shRNA lentiviral vector (Lenti-PAR-2 shRNA) was stably transfected into EC109 cells, and the expression of PAR-2 in infected cells was detected by quantitative real-time PCR (qRT-PCR) and western blotting. Specific inhibitors, PD98059 (for MEK/ERK) and LY294002 (for PI3K/Akt), were used to confirm the role of MEK/ERK and PI3K/Akt signaling pathways, respectively, in PAR-2-regulated invasion and migration of EC109 cells. A significant decrease in PAR-2 mRNA and protein expression was detected in EC109 cells stably transfected with Lenti-PAR-2 shRNA. The PAR-2 agonist could dramatically promote cell invasion and migration, up-regulate the expression of MMP-9 and TM4SF3, and activate MEK/ERK and PI3K/Akt signaling pathways. However, PAR-2 gene silencing attenuated PAR-2-mediated enhancement of invasion and migration of EC109 cells, significantly down-regulated the mRNA and protein expression of MMP-9 and TM4SF3, and inhibited ERK (Try202/204) and Akt (Ser473) phosphorylation. An effect similar to PAR-2 silencing could be achieved with the two specific MEK/ERK and PI3K/Akt pathway inhibitors. Consequently, these results demonstrated that PAR-2 promoted invasion and migration of esophageal cancer cells EC109 by activating MEK/ERK and PI3K/Akt signaling pathways, which was accompanied by up-regulation of MMP-9 and TM4SF3 expression. Hence, PAR-2 may be a potential candidate for anti-metastasis treatment of EC.

<span id="ChDivSummary" name="ChDivSummary" class="abstract-text">目的探讨华蟾酥毒基抑制食管癌Kyse-520细胞迁移和侵袭的相关机制。方法 CCK-8法检测Kyse-520细胞经不同浓度华蟾酥毒基作用12、24、48 h后的增殖活性;划痕愈合实验和Transwell小室法检测细胞迁移和侵袭过程;实时荧光定量PCR（RT-qPCR）分析Kyse-520细胞中FAK、Akt、PTEN、VEGF-A、MMP-2、MMP-9 mRNA的表达;Western blot检测FAK、p-FAK（Tyr397）、Akt、p-Akt（Ser473）、PTEN、VEGF-A、MMP-2、MMP-9蛋白表达水平。结果 CCK-8结果显示,华蟾酥毒基可以抑制Kyse-520细胞增殖,呈现时间和浓度依赖性,划痕实验和Transwell小室实验结果表明,华蟾酥毒基可以抑制食管癌细胞迁移和侵袭;RT-qPCR和Western blot结果显示,华蟾酥毒基对FAK、Akt mRNA及总蛋白无明显影响,但可以下调p-FAK、p-Akt、VEGF-A、MMP-2、MMP-9表达,上调PTEN的表达。结论华蟾酥毒基通过诱导PTEN表达,下调FAK/PI3K/Akt信号通路,抑制食管癌Kyse-520细胞的迁移和侵袭。</span>