ABSTRACT Background Accurately predicting environmental dangers is a fundamental ability for animal and human survival. Fear memory could be disrupted by various stimuli, including inflammation, which can be mimicked by lipopolysaccharide (LPS) injection. LPS, which can activate microglia and disrupt the blood‐brain barrier (BBB), can impair contextual fear memory consolidation when injected immediately after fear conditioning. However, the mechanism is not clear. Minocycline, a tetracycline derivative, can reduce inflammation and microglial activation. This study aims to explore the role of microglial activation in LPS‐induced contextual fear memory consolidation impairment and BBB disruption. Methods Immediately after the fear conditioning training, 0.5 or 1 mg/kg LPS was injected i.p., and the contextual fear memory was tested 24 h later, followed by biochemical and histological test. Results The results showed that LPS impaired contextual fear memory consolidation, which was accompanied by a significant leakage of immunoglobulin G (IgG) in the hippocampus 24 h after LPS treatment. In addition, significantly decreased levels of claudin‐5 and occludin, and significantly upregulated levels of caveolin‐1, microglial activation, and the levels of pro‐inflammatory factors interleukin‐1β (IL‐1β) and tumor necrosis factor‐α (TNF‐α) were found in the hippocampus. In contrast, minocycline, which could inhibit microglial activation, reduce LPS‐induced memory impairment and BBB damage. Conclusions In summary, the study provides preliminary evidence that LPS can impair the consolidation of contextual fear memory by causing microglial activation, releasing pro‐inflammatory factors IL‐1β and TNF‐α, and leading to BBB disruption in the hippocampus of mice.

Neural network connections require adequate blood flow to deliver sufficient oxygen and glucose. Acute ischemic stroke (AIS) significantly impairs neural function due to insufficient blood flow, leading to diffuse microvascular dysfunction and compromised white matter integrity, both indicators of poor prognosis. Post-stroke neural recovery hinges on promoting neovascularization around the infarct and restoring white matter integrity. Therefore, strategies to enhance angiogenesis and white matter repair are crucial for post-stroke neuro-rehabilitation. Emerging research highlights the pivotal roles of activated microglia, astrocytes, and oligodendrocyte precursor cells in facilitating neurogenesis, angiogenesis, and neural functional recovery following cerebral ischemia. In this review, we explore the mechanisms by which these neuroglial cells contribute to angiogenesis and white matter repair after AIS. We also propose potential therapeutic strategies that target the intricate interactions at the glial cell-endothelial cell interface. A deeper understanding of oligovascular signaling in ischemic conditions could unveil novel therapeutic targets for improving outcomes after AIS.

Neuroinflammation and immune responses mediated by glial cells and immune cells play dual roles in the neural injury and repair of ischemic stroke (IS): glial cells and immune cells primarily have a detrimental role in the acute phase of IS, while they mainly serve a reparative function in the chronic phase. Thus, suppressing neuroinflammation and immune responses driven by glial and immune cells represents a major strategy in the treatment of IS. In this review, we provide an overview of the molecular mechanisms of neuroinflammation and immune responses mediated by glial cells and immune cells at different stages after IS and highlight the roles of different glial cells and immune cells in post-IS neural injury and repair. We also summarize the relevant molecular targets and clinical application challenges for reducing neuroinflammation and immune responses to promote IS repair. Current evidence supports that PD-1/PD-L1, DAPK1, HDAC3-p65-cGAS-STING could be the targets. In addition, we discuss some treatment strategies for reducing neuroinflammation and immune responses such as traditional Chinese medicine (TCM) and natural product therapy, stem cell-based therapy and biomaterials, as well as current clinical trial progress and prospects.

Blood-brain barrier (BBB) damage is a major pathological change after intracerebral hemorrhage (ICH) and is both the cause and result of brain edema and the inflammatory response post-ICH. Cerebral immune cells (CICs), including microglia, pericytes, and astrocytes play a crucial role in the damage and protection of the BBB after ICH. Recent evidence suggests that peripheral immune cells (PICs) also play an important role in BBB damage and protection, brain edema, and neurological function impairment. Therefore, regulating interactions between glial cells and immune cells is expected to alleviate ICH-induced BBB damage. In this review, we first introduce the role of CICs, endothelial cells (ECs), oligodendrocytes (OLs), and PICs in BBB damage and protection after ICH, focusing on their polarization and inflammatory response. Next, we specifically discuss the crosstalk between CICs and PICs, such as the brain-spleen axis and brain-gut axis after ICH. Finally, we suggest that glial cells, PICs and, meningeal lymphatic system may be potential targets for alleviating BBB damage after ICH, and discuss some molecular targets and potential strategies for alleviating BBB damage after ICH by modulating CICs, ECs, and PICs.

Increased blood-brain barrier (BBB) permeability can lead to cerebral vasogenic edema and hemorrhagic transformation (HT) after reperfusion with tissue plasminogen activator (tPA), the only United States Food and Drug Administration (FDA)-approved treatment for acute ischemia stroke (AIS). The therapeutic benefits of tPA after AIS are partially outweighed by a more than a six-fold increase in the risk of symptomatic intracerebral hemorrhage. Therefore, strategies to protect the integrity of BBB are urgently needed to reduce HT and vasogenic edema after tPA thrombolysis or endovascular thrombectomy. Interestingly, an NIH study showed that smokers treated with tPA had a significantly lower prevalence of brain hemorrhage than nonsmokers, suggesting that cigarette smoking may protect patients treated with tPA from the side effects of cerebral hemorrhage. Importantly, we recently showed that treatment with nicotine reduces AIS-induced BBB damage and that modulating α7nAChR by modulation could reduce ischemia/reperfusion-induced BBB damage, suggesting that α7nAChR could be a potential target to reduce BBB after AIS. In this review, we first provide an overview of stroke and the impact of α7nAChR activation on BBB damage. Next, we discuss the features and mechanism of BBB destruction after AIS. We then discuss the effect of nicotine effect on BBB integrity as well as the mechanism underlying those effects. Finally, we discuss the side effects and potential strategies for modulating α7nAChR to reduce AIS-induced BBB damage.

Objective To analyze the value of combination of red blood cell distribution width（RDW） to platelet（PLT） ratio（RPR）, lactic acid level and APACHE Ⅱ score in predicting the progression of septic shock. Methods A total of 131 patients with sepsis admitted to Shanxi Provincial People’s Hospital from January 2019 to December 2021 were enrolled,including 62 septic shock cases and 69 non-shock cases. PLT, RDW, lactic acid, RPR, APACHE Ⅱ score and other indexes were compared between the two groups within 24 h after admission. ROC curve was used to analyze the efficiency of RPR,lactic acid, APACHE Ⅱ score and combination of three incicators to predict septic shock in septic patients. Binary logistic regression was used to analyze the independent risk factors of septic shock in sepsis patients. Results Compared with non-shock group, APACHE Ⅱ score, RPR and lactic acid levels were increased in sepsis shock group, while PLT was decreased（all P＜0.05）. ROC curve analysis showed that AUCs of RPR, lactic acid, APACH Ⅱ score and the combination of three indicators for predicting septic shock were 0.664, 0.687, 0.654 and 0.810, respectively（all P＜0.05）. Binary logistic regression analysis showed that RPR＞0.088, lactic acid＞1.550 mmol/L, APACHE Ⅱ score ≥10.0 were risk factors for septic shock in septic patients（all P＜0.05）. Conclusion RPR, lactic acid level and APACHE Ⅱ score can be used as predictors of septic shock in septic patients, while the combination of three indicators can improve the predicting value.

脓毒症是急诊科、重症医学科常见病,中心静脉-动脉二氧化碳分压差与动脉-中心静脉氧含量比值(Pcv-aCO2/Ca-cvO2)可反映机体氧供需状态,以氧供应不足及氧摄取利用受限为特征的氧代谢障碍是脓毒症主要的病理生理机制之一,并成为危重症患者病情发展至多器官功能衰竭的共同基础.本文从Pcv-aCO2/Ca-cvO2评估脓毒症患者氧代谢方面进行总结,以期为脓毒症患者的诊疗提供帮助.

目的 分析尿液胰岛素样生长因子结合蛋白-7(IGFBP-7)和金属蛋白酶组织抑制剂-2(TIMP-2)在脓毒症急性肾损伤(AKI)中的早期预测价值.方法 选取2020 年1 月—2021 年12 月山西省人民医院急诊科监护室收治的脓毒症患者 58 例,并根据KDIGO的诊断标准分成脓毒症AKI组 22 例和非AKI组 36 例.分别在入组后 0h、24 h、48 h、72 h采集患者尿液及血液标本,并检测血肌酐(SCr)与尿IGFBP-7、TIMP-2 水平.分析SCr、尿IGFBP-7、TIMP-2 与脓毒症AKI的相关性.受试者工作特征曲线(ROC)分析SCr、尿IGFBP-7 及TIMP-2 在脓毒症早期急性肾损伤中的诊断价值.结果 与非AKI组比较,AKI组各时点SCr、尿IGFBP-7、尿TIMP-2 水平均升高,差异具有统计学意义(F/P =147.848/<0.001、330.849/<0.001、136.777/<0.001).SCr与尿IGFBP-7、尿TIMP-2 均呈正相关(r/P = 0.680/<0.001,0.392/0.002),尿IGFBP-7 与尿TIMP-2 呈正相关(r/P =0.618/<0.001).ROC曲线分析显示,SCr、尿IGFBP-7、尿TIMP-2 及尿IGFBP-7 联合TIMP-2 预测脓毒症AKI的曲线下面积(AUC)分别为 0.586、0.907、0.738、0.914,尿IGFBP-7、尿IGFBP-7 联合TIMP-2 优于SCr(Z/P =4.117/<0.001,4.196/<0.001);尿IGFBP-7、尿IGFBP-7联合TIMP-2 优于尿TIMP-2(Z/P =2.663/0.008,3.378/0.008).结论 尿 IGFBP-7、尿 TIMP-2 与尿 IGFBP-7 联合TIMP-2 均可以作为早期预测脓毒症急性肾损伤发生的指标,且尿IGFBP-7、尿IGFBP-7 联合TIMP-2 的预测价值优于尿TIMP-2.

脓毒症相关急性肾损伤(sepsis-associated acute kidney injury,S-AKI)是急诊科和重症监护病房中脓毒症患者最常见的并发症之一,其病死率极高.S-AKI的早期诊断和可靠监测对预防脓毒症患者进展为多器官功能衰竭甚至死亡至关重要.目前虽然对 S-AKI的发病机制、诊断和治疗进行了广泛研究,但仍未找到理想的指标来早期诊断和监测该疾病,这是当前面临的具有重大挑战性的问题.本文对近年来早期预测S-AKI的标志物进行总结,分析新型生物学标志物在S-AKI等危重症患者救治过程中的作用,旨在为临床 S-AKI患者提供帮助.

目的 探讨血小板压积(plateletcrit,PCT)联合收缩压(systolic blood pressure,SBP)和急性生理与慢性健康评分(Acute Physiology and Chronic Health Evaluation,APACHE Ⅱ评分)对脓毒性休克的预测价值.方法 入选2018年1月～2021年12月山西省人民医院收治的131例脓毒症患者作为研究对象,记录患者基线资料和临床数据.根据是否发生脓毒性休克,将131例患者分为脓毒症组(n=68)和脓毒性休克组(n=63).比较两组临床资料,采用二元Logistic回归模型分析发生脓毒性休克的独立危险因素.采用受试者工作特征(receiver operating characteristic,ROC)曲线评价PCT、SBP和APACHE Ⅱ评分及三者联合对脓毒性休克的预测价值.结果 两组患者年龄、性别、C反应蛋白、血小板分布宽度和白细胞计数等比较,差异无统计学意义(P＞0.05).与脓毒症组比较,脓毒性休克组收缩压、舒张压、血小板计数、血小板压积和嗜酸性粒细胞计数显著降低;心率、D二聚体、降钙素原、序贯器官衰竭评估(sequential organ failure assessment,SOFA)评分和APACHE Ⅱ评分升高,差异有统计学意义(P＜0.05).Logistic回归分析显示,低PCT、低SBP和APACHE Ⅱ评分是脓毒症休克的独立危险因素.ROC曲线分析显示,PCT、SBP和APACHE Ⅱ预测脓毒症发生的曲线下面积(area under the curve,AUC)分别为0.653、0.665和0.692,而三者联合后,曲线下面积为0.794.结论 血小板压积可作为预测脓毒性休克的指标,与收缩压及APACHE Ⅱ评分联合能够提高预测脓毒性休克的准确性.

Blood-brain barrier (BBB) damage is the main pathological basis for acute ischemic stroke (AIS)-induced cerebral vasogenic edema and hemorrhagic transformation (HT). Glial cells, including microglia, astrocytes, and oligodendrocyte precursor cells (OPCs)/oligodendrocytes (OLs) play critical roles in BBB damage and protection. Recent evidence indicates that immune cells also have an important role in BBB damage, vasogenic edema and HT. Therefore, regulating the crosstalk between glial cells and immune cells would hold the promise to alleviate AIS-induced BBB damage. In this review, we first introduce the roles of glia cells, pericytes, and crosstalk between glial cells in the damage and protection of BBB after AIS, emphasizing the polarization, inflammatory response and crosstalk between microglia, astrocytes, and other glia cells. We then describe the role of glial cell-derived exosomes in the damage and protection of BBB after AIS. Next, we specifically discuss the crosstalk between glial cells and immune cells after AIS. Finally, we propose that glial cells could be a potential target for alleviating BBB damage after AIS and we discuss some molecular targets and potential strategies to alleviate BBB damage by regulating glial cells after AIS.

过敏性休克是一种发生于对某些特定变应原有超敏反应的个体的突发且危及生命的急诊重症,特征是血管屏障破坏及血浆外渗.过敏反应及过敏性休克的治疗策略主要包括清除过敏原、动态监测生命体征、抗休克治疗(肾上腺素、液体复苏、控制血压)、抗过敏治疗.在人体内全身性过敏反应发生后10 min内血浆外渗可使全身循环血容量损失35％左右,直接导致低血容量性休克的发生,并可进一步损害全身器官功能.近年来对于血管渗漏相关病理生理机制的研究越来越广泛,通过研究以期未来能够为过敏性休克治疗提供新的思路.

Objective:To explore the effect of small private online course (SPOC) in clinical skill integration training.Methods:Experimental control method was used in this study. From September 2016 to June 2018, 248 five-year program students majoring in clinical medicine enrolled in 2013 and 2014 in Shanxi Medical University were selected as the research objects. The students in each grade were randomly divided into experimental group and the control group. The experimental group adopted the SPOC of clinical skills integration training mode, while the control group adopted the traditional single skill theory education combined with on-site demonstration training mode. The training outcomes of the two model groups were evaluated by the pass rate in the first stage of clinical fundamental skills stage I test of National Medical Licensing Examination and by the pass rate of the skill test of National Medical Licensing Examination and by the questionnaire survey results.Results:The passing rates of the first stage I of National Medical Licensing Examination in the experimental groups of 2013 and 2014 [95.0% (57/60), 93.5% (58/62)] were significantly higher than those in the control group [83.9% (52/62), 81.3% (52/64)] (all P<0.05); the passing rate of the skill test of National Medical Licensing Examination in the experimental group of 2013 [98.3% (59/60)] was also significantly higher than that in the control group [87.1% (54/62)] ( P< 0.05); the satisfaction rates of the students about their training mode in the experimental and control group were 90.6% (774/854) and 81.6% (720/882) respectively, and the differences were statistically significant ( P<0.05). Conclusions:The teaching model of clinical skill integration based on SPOC is helpful to improve students' clinical skill level and clinical thinking ability, which is recognized by students.

Stroke is the leading cause of adult disability. Spontaneous functional recovery occurs after ischemic stroke, but it is very limited. Therefore, it is urgent to find a strategy to promote functional recovery after stroke in clinical setting. Gray matter damage has received extensive attention owing to the important roles of the gray matter in synaptic plasticity, cognitive, and motor function. However, stroke also causes white matter damage, which accounts for half of the infarct volume and can be aggravated by blood brain barrier damage. Disruption of white matter integrity, which is characterized by death of oligodendrocytes (OLs), loss of myelin, and axonal injury, greatly contributes to impaired neurological function. Impaired proliferation and differentiation of OL precursor cell (OPC, NG2-glia cells) play an important role in limited functional recovery after ischemic stroke and inhibitor of differentiation 2 (ID2) is a key factor controlling NG2-glia cells differentiation. It has been reported that the number of NG2-glia cells in the peri-infarction area significantly increases after ischemic stroke and glial growth factor (GGF2) administration promotes the proliferation and differentiation of NG2-glia cells as well as functional recovery after spinal cord injury. On the basis of the important roles of GGF2 in functional recovery and those of ID2 in NG2-glia cell proliferation and differentiation, we propose that after binding with the ErBb receptor on the surface of NG2-glia cells, GGF2 promotes NG2-glia cell proliferation and differentiation, thereby repairing BBB and white matter integrity and promoting neural functional recovery after ischemic stroke.

二甲基砜(MSM)的抗炎抗氧化作用近年来逐渐被医学界所关注. 百草枯是活性氧(ROS)的有效诱导物,百草枯中毒对肺组织的损伤作用, 主要通过促进细胞内产生ROS,导致支气管或肺泡出血、肺间质水肿、低氧血症和白细胞浸润等严重的肺损伤. NF-E2相关因子2(nuclear factor E2-relat-ed factor2,NRF2)则是ROS介导的病理生理过程中的关键抗氧化转录因子. 已经证实,NRF2具有调节氧化应激的能力,并能保护细胞对抗氧化剂刺激. 本实验拟将MSM作用于急性百草枯中毒大鼠, 观察MSM是否对百草枯诱导的氧化应激具有细胞保护作用.

Ischemic stroke often causes motor and cognitive deficits. Deregulated glia gap junction communication, which is reflected by increased protein levels of glial fibrillary acidic protein (GFAP) and connexin 43 (Cx43), has been observed in ischemic hippocampus and has been associated with cognitive impairment in animal stroke models. Here, we tested the hypothesis that reactive astrocytes-mediated loss of synaptophysin (SYP) and CREB-regulated transcription coactivator 1 (CRTC1) contribute to dysfunction in glia gap junction communication and memory impairment after ischemic stroke. Male Sprague–Dawley rats were subjected to a 90-min middle cerebral artery occlusion (MCAO) with 7-day reperfusion. Fluorocitrate (1 nmol), the reversible inhibitor of the astrocytic tricarboxylic acid cycle, was injected into the right lateral ventricle of MCAO rats once every 2 days starting immediately before reperfusion. The Morris water maze was used to assess memory in conjunction with western blotting and immunostaining to detect protein expression and distribution in the hippocampus. Our results showed that ischemic stroke caused significant memory impairment accompanied by increased protein levels of GFAP and Cx43 in hippocampal tissue. In addition, the levels of several key memory-related important proteins including SYP, CRTC1, myelin basic protein and high-mobility group-box-1 were significantly reduced in the hippocampal tissue. Of note, inhibition of reactive astrocytes with fluorocitrate was shown to significantly reverse the above noted changes induced by ischemic stroke. Taken together, our findings demonstrate that inhibiting reactive astrocytes with fluorocitrate immediately before reperfusion may protect against ischemic stroke-induced memory impairment through the upregulation of CRTC1 and SYP.

Disruption of the blood brain barrier (BBB) within the thrombolytic time window is an antecedent event to intracerebral hemorrhage in ischemic stroke. Our recent studies showed that 2-h cerebral ischemia induced BBB damage in non-infarcted area and secreted matrix metalloproteinase-2 (MMP-2) accounted for this disruption. However, the factors that affect MMP-2 secretion and regulate BBB damage remains unknown. Since hypoxia-inducible factor-1 alpha (HIF-1α) was discovered as a mater regulator in hypoxia, we sought to investigate the roles of HIF-1α in BBB damage as well as the factors regulating HIF-1α expression in the ischemic brain. in vivo rat middle cerebral artery occlusion (MCAO) and in vitro oxygen glucose deprivation (OGD) models were used to mimic ischemia. Pretreatment with HIF-1α inhibitor YC-1 significantly inhibited 2-h MCAO-induced BBB damage, which was accompanied by suppressed occludin degradation and vascular endothelial growth factor (VEGF) mRNA upregulation. Interestingly, β2-adrenergic receptor (β2-AR) antagonist ICI 118551 attenuated ischemia-induced BBB damage by regulating HIF-1α expression. Double immunostaining showed that HIF-1α was upregulated in ischemic neurons but not in astrocytes andendothelial cells. Of note, HIF-1α inhibition with inhibitor YC-1 or siRNA significantly prevented OGD-induced VEGF upregulation as well as the secretion of VEGF and MMP-2 in neurons. More importantly, blocking β2-AR with ICI 118551 suppressedHIF-1α upregulation in ischemic neurons and attenuated occludin degradation induced by the conditioned media of OGD-treatedneurons. Taken together, blockade of β2-AR-mediated HIF-1α upregulation mediates BBB damage during acute cerebral ischemia. These findings provide new mechanistic understanding of early BBB damage in ischemic stroke and may help reduce thrombolysis-related hemorrhagic complications.

Blood-brain barrier (BBB) dysfunction is considered to be an early event in the pathogenesis of a variety of neurological diseases in old patients, and this could occur in old people even when facing common stress. However, the mechanism remains to be defined. In this study, we tested the hypothesis that decreased melatonin levels may account for the BBB disruption in old mice challenged with lipopolysaccharide (LPS), which mimicked the common stress of sepsis. Mice (24-28months of age) received melatonin (10mgkg(-1)day(-1), intraperitoneally, i.p.) or saline for one week before exposing to LPS (1mgkg(-1), i.p.). Evan's blue dye (EB) and immunoglobulin G (IgG) leakage were used to assess BBB permeability. Immunostaining and Western blot were used to detect protein expression and distribution. Our results showed that LPS significantly increased BBB permeability in old mice accompanied by the degradation of tight junction proteins occludin and claudin-5, suppressed AMP-activated protein kinase (AMPK) activation, and elevated gp91(phox) protein expression. Interestingly, administration of melatonin for one week significantly decreased LPS-induced BBB disruption, AMPK suppression, and gp91(phox) upregualtion. Moreover, activation of AMPK with metformin significantly inhibited LPS-induced gp91(phox) upregualtion in endothelial cells. Taken together, our findings demonstrate that melatonin alleviates LPS-induced BBB disruption through activating AMPK and inhibiting gp91(phox) upregulation in old mice.

Blood brain barrier (BBB) plays a crucial role in maintaining homeostasis of microenvironment that is essential to neural function of the central nervous system (CNS). When facing various extrinsic or intrinsic stimuli, BBB is damaged which is an early event in pathogenesis of a variety of neurological diseases in old patients including acute and chronic cerebral ischemia, Alzheimer's disease and etc. Treatments that could maintain the integrity of BBB may prevent neurological diseases following various stimuli. Old people often face a common stress of sepsis, during which lipopolysaccharide (LPS) is released into circulation and the integrity of BBB is damaged. Of note, there is a significant decrease of melatonin level in old people and animal. Melatonin has been shown to preserves BBB integrity and permeability via a variety of pathways: inhibition of matrix metalloproteinase-9 (MMP-9), inhibition of NADPH oxidase-2, and impact on silent information regulator 1 (SIRT1) and nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. More important, a recent study showed that melatonin supplementation alleviates LPS-induced BBB damage in old mice through activating AMP-activated protein kinase (AMPK) and inhibiting gp91phox, suggesting that melatonin supplementation may help prevent neurological diseases through maintaining the integrity of BBB in old people.