Nrf2/ARE通路与糖尿病相关动脉粥样硬化

氧化应激和炎性反应是糖尿病致动脉粥样硬化的两个主要危险因素,Nrf2/ARE通路是体内调控氧化应激的关键通路.激活Nrf2/ARE通路可保护血管内皮细胞、血管平滑肌细胞及胰岛β细胞免受氧化损伤,并可增加胰岛素分泌,改善胰岛素抵抗.Nrf2/ARE通路对糖尿病动脉粥样硬化的防治具有重要意义.     

柚皮素对高糖诱导的H9c2心肌细胞凋亡及Nrf2/ARE信号通路的影响

[目的]探讨柚皮素(NAR)对高糖(HG)诱导的大鼠心肌细胞(H9c2)凋亡及核因子E2相关因子2(Nrf2)/抗氧化反应元件(ARE)信号通路的影响。[方法]将培养的H9c2细胞分为对照组(正常糖量)、HG组(35.5 mmol/L葡萄糖)、HG+NAR低、中、高浓度组(35.5 mmol/L葡萄糖+6.25、12.5、25.0μmol/L NAR)。用噻唑蓝法检测H9c2细胞增殖活性;流式细胞术检测细胞凋亡;二氯二氢荧光素二乙酸酯荧光探针染色法检测细胞内活性氧(ROS)水平;Western blot法检测Nrf2、血红素加氧酶1(HO-1)、Bax、Caspase-3、Bcl-2蛋白表达水平。[结果]经HG处理的H9c2细胞增殖活性、Nrf2、HO-1、Bcl-2蛋白表达水平显著降低,细胞凋亡率、ROS水平、Bax、Caspase-3蛋白表达水平显著升高(P<0.05)。经HG与NAR共同处理H9c2细胞后,NAR低、中、高浓度组H9c2细胞增殖活性、Nrf2、HO-1、Bcl-2蛋白表达水平显著升高,细胞凋亡率、ROS水平、Bax、Caspase-3蛋白表达水平显著降低(P...     

Melatonin successfully rescues hippocampal bioenergetics and improves cognitive function following drug intoxication by promoting Nrf2‐ARE signaling activity

Prolonged exposure to gamma‐hydroxybutyric acid (GHB) would cause drug intoxication in which impaired cognitive function results from enhanced hippocampal oxidative stress may serve as a major symptom in this deficiency. Considering melatonin possesses significant anti‐oxidative efficacy, this study aimed to determine whether melatonin would successfully promote the nuclear factor erythroid 2‐related factor 2 and antioxidant responsive element (Nrf2‐ARE) signaling, depress oxidative stress, and rescue hippocampal bioenergetics and cognitive function following drug intoxication injury. Adolescent rats subjected to 10 days of GHB were received melatonin at doses of either 10 or 100 mg/kg. Time‐of‐flight secondary ion mass spectrometry, biochemical assay, quantitative histochemistry, [¹⁴C]‐2‐deoxyglucose analysis, together with Morris water maze were employed to detect the molecular signaling, oxidative status, bioenergetic level, as well as the cognitive performances, respectively. Results indicated that in GHB‐intoxicated rats, enhanced oxidative stress, increased cholesterol level, and decreased anti‐oxidative enzymes activities were detected in hippocampal regions. Intense oxidative stress paralleled well with reduced bioenergetics and poor performance in behavioral testing. However, in rats treated with melatonin following GHB intoxication, all above parameters and cognitive function were gradually returned to nearly normal levels. Melatonin also remarkably promoted the translocation of Nrf2 from cytoplasm to nucleus in a dose‐dependent manner, thereby increased the Nrf2‐ARE signaling‐related downstream anti‐oxidative enzymes activities. As melatonin effectively rescues hippocampal bioenergetics through depressing the oxidative stress by promoting Nrf2‐ARE molecular machinery, this study thus highlights for the first time that clinical use of melatonin may serve as a therapeutic strategy to improve the cognitive function in unsuspecting victims suffered from GHB intoxication injury.     

大黄素对急性有机磷农药中毒致肺损伤大鼠肺组织Nrf-2/ARE信号通路的影响

目的探讨大黄素对急性有机磷农药中毒(AOPP)大鼠肺损伤的影响,及其对肺组织核因子相关因子2/抗氧化反应元件(Nrf-2/ARE)信号通路的作用。方法取36只健康雄性SD大鼠构建急性有机磷农药中毒致肺损伤模型,随机分为急性有机磷农药中毒模型组(AOPP组)和大黄素干预组(大黄素组),18只/组,另取18只健康雄性SD大鼠作为健康对照组。分批处死大鼠,通过HE染色观察大鼠肺组织病理改变;测量肺组织湿干质量比(W/D);采用比色法检测肺组织中丙二醛(MDA)含量及超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)活性;采用Western blot检测肺组织Nrf-2,血红素氧合酶-1(HO-1)蛋白表达。结果氧乐果染毒后AOPP组大鼠肺组织湿干质量比显著增加,大黄素组在24 h、72 h时肺组织湿干质量比显著低于AOPP组(P<0.05);AOPP组各时间点MDA水平较健康对照组明显升高(P<0.05),大黄素组各时间点MDA水平较AOPP组显著降低(P<0.05),在72 h时与健康对照组比较差异无统计学意义(P>0.05),AOPP组和大黄素组肺组织SOD、GSH-Px活力在各时间点较健康对照组显著降低(P<0.05),大黄素组各时间点SOD、GSH-Px活力明显高于AOPP组(P<0.05);AOPP组和大黄素组24 h、72 h时Nrf-2和HO-1蛋白表达上调,与AOPP组比较,大黄素组24 h、2h时Nrf-2和HO-1蛋白表达上调(P<0.05)。结论大黄素可能通过调节Nrf-2/ARE信号通路促进HO-1蛋白表达,降低有机磷中毒大鼠MDA生成,并提高SOD、GSH-Px活力发挥保护肺损伤作用。     

Assessment of traumatic brain injury degree in animal model

Objective:To establish stable and controllable brain injury with accurate degree and good repeatability in rat model.Methods:Controlled cortical impact(CCI) device was used to prepare for the rat brain injury model by the impact head of different model(Group A No.4.Group B No.5,Group C No.6) and the impact depth(Group A:1.5-2.0 mm.Group B:2.5-3.0 mm.Group C:3.5-4.0mm) with impact time of 0.1 s and impact velocity of 2.5 m/s.Twelve rats with three months of age were used in each group(the impact depth of every two rats was added 1 mm respectively).After modeling for 1 h,magnetic resonance imaging(MRI) was received and brain histopathology was observed to assess degree of injury by model parameter's of three groups.Results:After modeling of Group A,MRI showed that the cortex structure was damaged with a small amount of bleeding in center and mild edema around,and the total volume of injury was(28.69±4.94)mm~3.Pathology revealed the injury was confined to the superficial cortical with mild edema of nerve cell,which was assessed as mild cerebral contusion.While after modeling,MRI of Group B showed that the structure of cortex and medulla were damaged simultaneously and extended to cerebral nuclei zone,With 4 cases of hematoma in the center and larger edema range around,and the total volume of injury was(78.38±9.28) mm~3.Pathology revealed the injury range was reached nuclei zone,with swell of nerve cell and mitochondria,which was assessed to moderate cerebral contusion.After modeling of Group C,MRI showed that extensive tissue injury was appeared in cortex and medulla and deep nuclei,with 9 cases of hematoma and large edema signal of surrounding tissue T2W1,while in 5 cases,lateral nucleus of injury signal was increased,and the total volume of injury was(135.89±24.80)mm~3.Pathology revealed the deep cerebral nuclei was damaged,with the disappearance of neuronal structure and vacuolization of mitochondria,which was assessed as severe cerebral contusion.MRI changes were consistent with pathological changes in three groups of model,and the injury range was significantly different(P0.01).Conclusions:Application of CCI can make stable quantitative traumatic brain injury model,which overcomes the randomness in previous injury model and possesses highly unity in iconography and pathology changes.This can provide quantitative modeling reference for clinical research.     

虾青素对创伤性颅脑损伤保护作用的研究进展

创伤性颅脑损伤（TBI）致死、致残率高,严重危害人类健康,TBI后的继发级联损伤是导致患者预后不良的重要原因。有效地治疗继发性脑损伤是降低TBI致残率,改善患者预后,提高生活质量的重要环节。虾青素（ATX）是一种天然的类胡萝卜素,具有多种生物学活性。许多研究表明了ATX在对抗中枢神经系统急慢性损伤中产生的氧化应激、炎症反应以及改善颅脑灌注、保护神经等方面有良好作用。本文针对ATX对TBI的保护作用机制及研究进展综述如下。     

Evolving hypopituitarism as a consequence of traumatic brain injury (TBI) in childhood - call for attention

Hypopituitarism is a common complication of TBI in long-term survivors, more frequent than previously realized. It may be partial or complete, sometimes very subtle without visible lesions in hypothalamo-pituitary region and is diagnosed only by biochemical means. Neuroendocrine abnormalities caused by TBI may have significant implications for the recovery and rehabilitation of these patients. The subjects at risk are those who have suffered moderate to severe trauma, although mild intensity trauma may precede hypopituitarism also. Particular attention should be paid to this problem in children and adolescents. We describe a patient with hypopituitarism thought to be idiopathic due to mild head trauma which caused diabetes insipidus in childhood, gradual failure of pituitary hormones during the period of growth and development, and metabolic (dyslipidemia), physical (obesity), and cognitive impairments in the adult period.     

芹菜素通过激活Nrf2/HO-1通路改善血管性痴呆大鼠的认知功能

[目的]研究芹菜素(APG)对血管性痴呆(VD)大鼠认知功能的保护作用及机制。[方法]通过结扎双侧颈总动脉复制VD大鼠模型,设置假手术组、模型组、APG低剂量组、APG高剂量组和尼莫地平(NMP)组,每组30只。APG低剂量组、高剂量组分别1次/天腹腔注射20、40 mg/kg APG,NMP组1次/天腹腔注射2 mg/kg NMP,假手术组和模型组给予生理盐水,疗程28天。Morris水迷宫实验检测大鼠的认知功能,HE染色和TUNEL染色观察海马体CA1区神经元病理特点和凋亡状况,通过电子显微镜观察神经元超微结构变化,分光光度法检测海马体丙二醛(MDA)含量和超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)活性;RT-PCR和Western blot检测海马体核因子E2相关因子2(Nrf2)、血红素加氧酶1(HO-1)mRNA和蛋白的表达。[结果]与模型组相比,APG高剂量组和NMP组大鼠的认知功能明显改善;海马体CA1区神经元数量、形态结构病理学改变、超微结构改变和凋亡状况均明显改善,病理分级和凋亡指数(AI)降低;海马体MDA含量降低,SOD、GSH-Px活性升高,N...     

咪达唑仑在创伤性颅脑损伤患者镇静治疗中的应用及影响

目的研究静脉注射咪达唑仑对镇静治疗中创伤性颅脑损伤患者的脑血流动力学、呼吸状况及长期预后的影响。 方法纳入西安医学院第二附属医院神经外科自2014年5月至2019年12月收治的70例创伤性颅脑损伤患者,按照随机数字表法分为治疗组（35例）和对照组（35例）。治疗组患者以0.1 mg/（kg·h）的速度静脉注射咪达唑仑,同时对照组患者不采用任何镇静镇痛剂以及其他影响颅内血流动力学的药物。应用经颅多普勒超声分别测定2组患者的大脑中动脉平均血流速度,以及收集患者收缩压、心率、呼吸频率等参数。 结果治疗组患者的流速尽管有所降低,但与对照组比差异并无统计学意义（P>0.05）。此外,治疗组心率、收缩压和呼吸频率较对照组均有明显下降,其中呼吸频率的差异具有统计学意义（P=0.049）。进一步分析随访资料发现2组患者的死亡率及GOS评分差异均无统计学意义（P>0.05）。 结论静脉注射咪达唑仑可有效控制患者躁动,且可在一定程度上影响患者的颅内血流动力学以及呼吸状况,但对创伤性颅脑损伤患者的长期预后并无显著影响。     

管切开时机对老年颅脑损伤患者肺部感染影响的研究

目的探讨选择在不同气管切开时机的拔管率、肺部感染发生率和死亡率的差异。方法选取老年颅脑损伤患者41例,收集患者的年龄、性别、格拉斯哥昏迷评分（GCS）、发病至气切的时间、平均置管时间及拔管率、预后。其中颅脑损伤后72h内气切者有25例,称为A组,72h以后气切者有16例,称为B组。结果在性别（P=0．185）、年龄（P=0．078）、昏迷指数水平GCS（P=0．922）差异无统计学意义的情况下,其病死率差异无统计学意义（P=0．354）,拔管率差异无统计学意义（P=0．493）,肺部感染率差异（P=0．033）,A组小于B组。结论老年颅脑损伤患者,在具有气管切开手术指征的情况下,颅脑外伤后72h内行气管切开术可降低其肺部感染率。     

基于颅脑外伤患者认知障碍特点的临床治疗对策

目的基于颅脑外伤患者认知障碍（CI）的临床对策初探。 方法选择吴川市人民医院脑外科及广东医科大学附属廉江医院脑卒中科自2017年1月至2018年1月收治的60例颅脑外伤后CI患者作为研究对象,所有患者接受颅脑外伤综合治疗（常规治疗+高压氧治疗+脑康复治疗）,记录患者各项临床资料（基本资料、类型、诊断）,对患者治疗前后认知功能[洛文斯顿认知功能量表(LOT-CA)]进行评估和分析治疗后认知功能的改善情况。 结果60例颅脑外伤患者的CI表现：9例（15%）为逻辑推理力降低,19例（32%）为记忆功能减退,8例（13%）为注意力不集,8例（13%）为感知感觉力下降,16例（27%）为语言功能下降。双侧半球损伤、右侧半球损伤、左侧半球损伤后CI患者经治疗后LOT-CA评分均高于入院时评分,差异有统计学意义（P<0.05）。 结论颅脑外伤综合治疗对不同类型和损伤部位颅脑外伤后CI患者的疗效确切,临床工作中应重视并积极治疗颅脑外伤后患者的认知功能,以改善患者的预后。     

3D打印聚醚醚酮材料在颅脑损伤后颅骨成形术中的应用疗效分析

目的对比分析聚醚醚酮（PEEK）和钛网在颅脑损伤（TBI）后颅骨成形术中的临床疗效,并探讨PEEK材料的潜在优势。 方法选取解放军联勤保障部队第九〇一医院神经外科自2017年1月至2021年1月行颅骨成形术的48例TBI患者为研究对象,按照使用材料的不同将患者分为PEEK组（20例）和钛网组（28例）。比较2组患者手术出血、平均手术时间、住院时间、术后并发症、塑形效果及总治疗费用方面的差异。术后随访12个月,采用Karnofsky功能状态（KPS）评分评估患者的远期效果。 结果所有患者均于术后12~14 d拆除缝线,且切口为甲级愈合。2组患者手术出血、手术时间及住院时间比较,差异无统计学意义（P>0.05）。PEEK组术后总的并发症发生率（65.00%）与钛网组（60.71%）比较,差异无统计学意义（P>0.05）;2组术后颅内迟发性出血、术区硬膜下积液、术区颅内感染、癫痫及迟发性脑积水的发生率比较,差异无统计学意义（P>0.05）;钛网组患者的皮下积液发生率及治疗费用均低于PEEK组,差异具有统计学意义（P<0.05）。2组患者术后的平均满意度均较高,但PEEK组优于钛网组,差异具有统计学意义（P<0.05）。术后随访12个月,2组患者均未出现迟发性切口感染及材料外露,KPS评分比较差异无统计学意义（P>0.05）。 结论应用3D打印PEEK材料对TBI患者行颅骨成形术,总体并发症发生率与钛网材料相比无明显差异,但3D打印PEEK材料与颅骨契合更加完美,适合儿童、青少年及女性患者在经济情况好的条件下使用。     

Melatonin activates the Nrf2-ARE pathway when it protects against early brain injury in a subarachnoid hemorrhage model

Melatonin has beneficial effects against early brain injury (EBI) by modulating cerebral oxidative stress after experimental subarachnoid hemorrhage (SAH); however, few investigations relate to the precise underlying molecular mechanisms. To date, the relation between melatonin and nuclear factor erythroid 2-related factor 2 and antioxidant responsive element (Nrf2-ARE) pathway has not been studied in SAH models. This study was undertaken to evaluate the influence of melatonin on Nrf2-ARE pathway in rats after SAH. Adult male SD rats were divided into four groups: (i) control group (n=18); (ii) SAH group (n=18); (iii) SAH+vehicle group (n=18); and (iv) SAH+melatonin group (n=18). The rat SAH model was induced by injection of 0.3mL fresh arterial, nonheparinized blood into the prechiasmatic cistern in 20s. In SAH+melatonin group, melatonin was administered i.p. at 150mg/kg at 2 and 24hr after the induction of SAH. Brain samples were extracted at 48hr after SAH. Treatment with melatonin markedly increased the expressions of Nrf2-ARE pathway-related agents, such as Nrf2, heme oxygenase-1, NAD(P)H:quinone oxidoreductase 1, and glutathione S-transferase α-1. Administration of melatonin following SAH significantly ameliorated EBI, including brain edema, blood-brain barrier (BBB) impairment, cortical apoptosis, and neurological deficits. In conclusion, post-SAH melatonin administration may attenuate EBI in this SAH model, possibly through activating Nrf2-ARE pathway and modulating cerebral oxidative stress by inducing antioxidant and detoxifying enzymes.     

氧化槐定碱通过Nrf2/HO-1通路抑制大鼠急性心肌梗死后心肌细胞凋亡

目的观察氧化槐定碱(OSR)通过核因子E2相关因子2(Nrf2)/血红素氧化酶1(HO-1)通路抑制大鼠急性心肌梗死(AMI)后心肌细胞凋亡的作用。方法成年健康雄性SD大鼠分为假手术组、AMI组、OSR组、OSR+锌原卟啉9(ZPP-Ⅸ)组,后3组采用左冠状动脉前降支结扎的方式建立AMI模型,OSR组给予OSR腹腔注射,OSR+ZPP-Ⅸ组给予OSR及HO-1抑制剂ZPP-Ⅸ腹腔注射。检测血清心肌酶含量、心肌细胞凋亡率、心肌中凋亡基因及Nrf2、HO-1的表达量。结果 AMI组大鼠的血清乳酸脱氢酶(LDH)、磷酸肌酸激酶(CK)、磷酸肌酸激酶同工酶(CK-MB)含量、心肌细胞凋亡率以及心肌中Bcl-2相关X蛋白(Bax)、Cleaved-caspase-3、Nrf2、HO-1的表达量均明显高于假手术组,心肌中B淋巴细胞瘤2蛋白(Bcl-2)的表达量明显低于假手术组。OSR组大鼠的血清LDH、CK、CK-MB含量、心肌细胞凋亡率以及心肌中Bax、Cleaved-caspase-3的表达量均明显低于AMI组,心肌中Bcl-2、Nrf2、HO-1的表达量明显高于AMI组。OSR+ZPP-Ⅸ组大鼠的血清LDH、CK、CK-MB含量、心肌细胞凋亡率以及心肌中Bax、Cleaved-caspase-3的表达量均明显高于OSR组,心肌中Bcl-2的表达量明显低于OSR组。结论OSR通过激活Nrf2/HO-1通路抑制大鼠AMI后心肌细胞的凋亡。     

呼气末二氧化碳监测在颅脑外伤术后的应用

目的 研究颅脑外伤术后应用机械通气患者呼气末二氧化碳分压(partial pressure of end tidal carbon dioxide,PetCO2)与PaCO2相关性及肺泡动脉血二氧化碳分压差(alveolar-arterial carbon dioxide tension difference,a-ADCO2)变化规律,探讨PetCO2在颅脑外伤术后临床应用价值.方法 入选2012年6月至2014年6月入住ICU一科50例颅脑外伤术后应用机械通气患者,分别于设定潮气量6 ml/kg、8 ml/kg、10 ml/kg、12 ml/kg通气1h、6h、12h、24 h后抽取动脉血行血气分析并记录即刻PetCO2,同时计算a-ADCO2.结果 50例患者不同潮气量通气以及机械通气后1h、6h、12 h后PetCO2与PaCO2间相关性差异有统计学意义(P＜0.05),除12 ml/kg通气24 h外,a-ADCO2在其余潮气量不同时间段均小于5 mmHg,在8 ml/kg时为最低,通气1h、6h、12 h、24 h分别为(2.98±0.33)mmHg、(3.28±0.36) mmHg、(3.74±0.28) mmHg、(3.65±0.31) mmHg.结论 PetCO2与PaCO2具有一定的相关性,PetCO2可作为颅脑外伤术后患者机械通气早期评估PaCO2的手段之一.a-ADCO2在潮气量为8 ml/kg时最低,可作为呼吸机设置的起始参数之一.PetCO2是颅脑外伤术后患者行机械通气治疗时无创、连续的有效监测手段.     

The effect of cranioplasty in cognitive and functional improvement: Experience of post traumatic brain injury inpatient rehabilitation

To investigate the effect of cranioplasty on rehabilitation of post-traumatic brain injury (TBI) patients, 37 patients with TBI were arranged by retrospectively assessment study. Those TBI patients receiving in-hospital rehabilitation in the Department of Rehabilitation in a medical center of South Taiwan from 2010 to 2015 were assigned into two groups: A and B. All patients entered the multidisciplinary holistic in-patient rehabilitation training for about 1 month. Patients in Group A received decompressive craniectomy (DC), patients in Group B received DC and cranioplasty. All assessments were arranged right on admission and before discharge. The functional activity evaluation included muscle power and Barthel index (BI), and cognitive function evaluation, including the Rancho Los Amigo Scale, Mini Mental State Examination (MMSE), Community Mental State Examination (CMSE), and the Luria-Nebraska Neuropsychological Battery-Screening Test Short Form (LNNBS). The results showed that there were synergetic effects of cranioplasty on post-TBI patients with rehabilitation training, especially in the BI score, and cognitive improvement in CMSE and LNNBS.     

TLR介导的Nrf2抗氧化通路在对乙酰氨基酚药物性肝损伤中的保护作用

目的研究内毒素(LPS)及Toll样受体(TLR)在对乙酰氨基酚(APAP)药物性肝损伤中的保护作用及其相关机制。方法雄性C57BL/6小鼠40只,分为4组,每组10只。空白对照组腹腔注射0.9%氯化钠溶液,LPS组腹腔注射LPS 10μg/kg,APAP组腹腔注射APAP 300 mg/kg,LPS+APAP组在APAP造模前16 h给予LPS 10μg/kg预处理。通过比较各组血清ALT和AST水平,并通过HE染色评价肝组织损伤程度,观察LPS对小鼠肝损伤的保护作用。测定相应时间点的肝脏组织丙二醛(MDA)、还原型谷胱甘肽(GSH)的变化以及肝组织DHE染色,评价小鼠氧化应激水平。应用Western印迹及RT-PCR检测肝脏Nrf2,Gclc及HO-1的表达水平。结果 LPS预处理可明显减轻APAP所致的肝脏氧化应激反应及肝损伤程度。LPS预处理组的小鼠血清ALT(518.3±142.3对4542±498.4 U/L)、AST(643.3±105.6对5432.1±569.2 U/L)水平及肝组织MDA(78.0±14.5对141.7±26.4 mmoL/mg)水平与模型组相比明显降低,而GSH(6.2±1.7对3.5±1.0μmol/g)水平明显升高(P0.05),肝组织病理损伤明显减轻。同时,LPS预处理可明显促进Nrf2及其下游抗氧化基因的表达。结论 LPS在小鼠APAP肝损伤中起到保护作用,作用机制与Nrf2抗氧化通路的激活相关,可能成为药物性肝损伤的新的治疗策略。     

胰高血糖素样肽1对H9c2心肌细胞缺氧复氧损伤的保护作用及机制研究

目的 研究胰高血糖素样肽1(GLP-1)对H9c2心肌细胞缺氧复氧(H/R)损伤的保护作用及机制.方法 培养H9c2心肌细胞,随机分为常规处理的对照组、H/R组及1、5、10mol/L GLP-1组以验证GLP-1的保护作用,随机分为 si-NC 组、si-NC+H/R 组、si-NC+H/R+10 μmol/L GL...