促红细胞生成素对大鼠急性脊髓损伤后核因子κB及炎症因子表达的影响

目的观察促红细胞生成素(EPO)对大鼠急性脊髓损伤后脊髓组织核因子κB(NF-κB)表达及肿瘤坏死因子α(TNF-α)、白细胞介素1β(IL-1β)、IL-6水平的影响,探讨其减轻急性脊髓损伤后继发性脊髓损伤的机制。方法 18只SD大鼠随机均分为对照组、损伤组和治疗组,用动脉瘤夹从两侧夹闭脊髓30 s造成脊髓损伤模型。治疗组分别予术后1 h和1、2、3 d腹腔注射EPO 5000U/kg。术后3 d处死大鼠取材,用EMSA法检测脊髓组织中NF-κB活性,ELISA法检测TNF-α、IL-1β、IL-6表达。结果治疗组脊髓组织中NF-κB、TNF-α、IL-1β、IL-6的水平均比损伤组显著降低(P<0.05)。结论 EPO能下调急性脊髓损伤后脊髓组织中炎症因子的表达,从而抑制炎症反应,对继发性脊髓损伤有一定的保护作用。     

罗格列酮对百草枯致大鼠肺损伤的炎症抑制作用

目的：研究罗格列酮对百草枯致大鼠肺损伤过程中的炎症抑制作用机制。方法将72只SD雄性大鼠随机分成3组,每组24只。模型对照组：腹腔注射百草枯20 mg·kg-1;罗格列酮组：腹腔注射百草枯前1 h,腹腔注射罗格列酮10 mg·kg-1;空白对照组：腹腔注射0.9％氯化钠溶液1 mL。注射百草枯后4,8 h及1,3 d,收集各组大鼠血清和肺组织标本,组织切片苏木精-伊红( HE)染色进行肺损伤评分,采用酶联免疫吸附法( ELISA)检测血清白细胞介素-1β( IL-1β)和肿瘤坏死因子-α( TNF-α)含量,采用免疫组化方法检测NF-κB蛋白在肺组织的表达,利用Western blot法检测肺组织核因子-κB (NF-κB)和激活蛋白(AP-1)蛋白表达水平。结果模型对照组大鼠血清炎性细胞因子IL-1β和TNF-α含量明显增加。罗格列酮组肺组织损伤程度明显降低,血清IL-1β和TNF-α含量减少,肺组织NF-κB和AP-1蛋白的表达降低。结论罗格列酮可以抑制百草枯中毒大鼠肺组织NF-κB和AP-1蛋白表达,减少IL-1β和TNF-α分泌,对百草枯所致大鼠肺损伤炎症有抑制作用。     

加味生脉饮注射液对内毒素休克大鼠肺组织肿瘤坏死因子-α、白细胞介素-１β和核转录因子-κB 含量的影响

目的:观察加味生脉饮注射液对内毒素休克肺组织TNF-α、IL-1β和NF-κB表达的影响。方法:静脉注射脂多糖(LPS,8.00mg·kg^-1)造成内毒素休克模型,用加味生脉饮注射液作干预治疗,酶联免疫吸附法检测上述因子在假手术组、模型组、加味生脉饮组、阳性对照组等各组大鼠肺组织内的表达。结果:模型组肺损伤较重,TNF-α、IL-1β和NF-κB含量明显升高（P<0.05）;加味生脉饮组和阳性对照组肺损伤较轻,TNF-α、IL-1β和NF-κB含量明显降低（P<0.05）。结论:加味生脉饮注射液能减轻内毒素休克时肺损伤和TNF-α、IL-1β和NF-κB表达,提示该药对内毒素休克肺损伤的保护作用可能是通过调控NF-κB通路过度激活而实现。     

电针调控肿瘤坏死因子受体1/受体相互作用蛋白激酶1/核因子κB轴对骶髓损伤后神经源性膀胱尿潴留大鼠尿动力学的影响

目的 探究电针调控肿瘤坏死因子受体1/受体相互作用蛋白激酶1/核因子κB(TNFR1/RIPK1/NF-κB)轴对骶髓损伤(SCI)后神经源性膀胱(NB)尿潴留大鼠的影响及机制。方法 采用随机数字表法将SD大鼠分为空白组、模型组、电针组和电针对照组,每组10只。建立SCI后NB尿潴留模型,电针组取穴“次髎”“中极”“三阴交”,电针对照组取三穴对照点,行电针治疗7 d。各组大鼠治疗前、后行尿动力学检测;取大鼠脊髓组织,实时荧光定量逆转录聚合酶链反应(qRT-PCR)检测TNFR1、RIPK1表达;蛋白质印迹法(Western blotting)检测TNFR1、RIPK1、p-IKKβ/IKKβ、p-NF-κB p65/NF-κB p65和p-IκBα/IκBα蛋白表达;酶联免疫吸附剂测定法(ELISA)检测TNF-α、IL-1β、IL-6、IFN-γ含量。该研究起止时间为2019年1月至2021年12月。结果 与空白组比较,模型组大鼠膀胱最大容量[(4.46±0.82)mL比(1.13±0.22)mL,P<0.05]、膀胱基础压[(32.00±4.23)cmH₂     

实验性关节炎大鼠滑膜组织核因子-κB基质金属蛋白酶-9表达相关性分析

目的观察核因子κB(NF-κB)、基质金属蛋白酶(MMP)-9在实验性关节炎(CIA)和对照组大鼠滑膜组织中不同时间点的表达差异及其血浆中肿瘤坏死因子(TNF)-α、白细胞介素(IL)-1β的含量变化,探讨这些细胞因子在CIA发病中的作用机制,为类风湿关节炎(RA)今后的治疗提供理论依椐。方法将42只雄性Wistar大鼠随机分为模型组和对照组,通过免疫组织化学的方法检测各组大鼠不同时期滑膜组织NF-κB、MMP-9的表达水平,用放射免疫法(RIA)测定TNF-α、IL-1β的血浆含量,同时观察其发病时间与关节炎指数(AI)积分、病理评分及上述细胞因子之间的关系。结果随着CIA大鼠发病时间延长,AI和病理评分逐渐增加,NF-κB、MMP-9表达水平和TNF-α、IL-1β血浆含量也随之增加。CIA大鼠这些细胞因子的测定值都显著高于对照组(P<0.01),AI、病理评分与NF-κB、MMP-9呈正相关关系(P<0.05);CIA大鼠滑膜组织NF-κB、MMP-9表达水平之间呈正相关(P<0.05),而且它们的表达水平与IL-1β、TNF-α血浆含量之间亦呈正相关(P<0.05)。结论通过与TNF-α和IL-1β相互作用,滑膜组织中NF-κB、MMP-9的表达之间可能互相影响、互相促进,形成正反馈式的损坏机制,在CIA大鼠病情进展中起着重要作用,可能是RA发生发展以及骨质侵蚀的关键因子。     

氨基胍对内毒素性肺损伤炎症反应和NF-κB信号通路的影响

目的观察选择性一氧化氮合酶抑制剂氨基胍(aminogunidine,AG)对大鼠内毒素性肺损伤(acute lung injury,ALI)NF-κB相关信号通路和炎症反应的影响,探讨AG对肺损伤组织的保护作用及其机制。方法健康♂SD大鼠随机分为对照组、模型组和AG治疗组。模型组、AG治疗组静脉注射脂多糖(lipopolysaccharide,LPS)复制内毒素性肺损伤模型。各组按治疗时间又分为给LPS3h后治疗3h(3h+3h)组和给LPS6h后治疗3h(6h+3h)组,分别于给LPS3h和6h后腹腔注射生理盐水(对照组及LPS组)和AG(100mg.kg-1,AG治疗组)。每组8只动物。免疫组化染色分析肺组织中核因子-κB(NF-κB)的核移位和粘附分子-1(ICAM-1)表达;放射免疫法分别测定肺组织中肿瘤坏死因子α(TNF-α)和白介素6(IL-6)的含量;光镜、电镜观察肺组织病理变化。结果与对照组比较,大鼠肺损伤后NF-κB活化,明显从细胞质移位于细胞核,表达量也明显增加;ICAM-1蛋白表达增加;肺组织中TNF-α、IL-6含量明显升高。肺损伤3h用AG治疗3h后,NF-κB从细胞质向细胞核的移位被明显限制,NF-κB的表达量、ICAM-1蛋白表达和肺组织中TNF-α、IL-6含量明显低于相应的LPS组,肺组织病理改变减轻;肺损伤6h用AG治疗3h后,治疗效果较差。结论AG于LPS3h后给药可减轻内毒素性肺损伤,可能与减弱诱导型一氧化氮合酶(iNOS)mRNA表达、抑制核因子的活化,在一定程度上阻断NF-κB相关信号通路的传导,下调炎症因子和ICAM-1的表达有关。     

桂枝、荆芥挥发油对大鼠急性肺损伤模型核因子κB信号通路影响的比较

目的探讨桂枝、荆芥挥发油对核因子κB/IκB信号通路的影响。方法用大肠肝菌内毒素(LPS)制作大鼠急性肺损伤模型,通过桂枝挥发油和荆芥挥发油治疗后,采用ELISA法检测肺组织细胞中核蛋白NF-κB P65的含量和肺组织溶浆中磷酸化IκB-α、TNF-α和IL-1β的含量。结果正常大鼠肺组织中,NF-κB P65、磷酸化IκB-α、TNF-α和IL-1β有微量表达,LPS经尾静脉注射6 h后,各指标表达均显著增高,与空白对照组比较有显著差异(P<0.01),桂枝、荆芥挥发油组NF-κB P65、磷酸化IκB-α、TNF-α和IL-1β的含量均较模型组显著降低(P<0.01)。结论桂枝、荆芥挥发油对急性肺损伤时高度活化的核因子κB/IκB信号通路有显著的抑制或拮抗作用,提示核因子κB/IκB信号通路可能是桂枝、荆芥挥发油抗炎作用的主要机制之一。     

抑制NF-κB信号通路对顺铂致肺癌大鼠肾损伤的保护作用及其分子机制研究

摘要：目的:探索抑制核转录因子（NF）-κB信号通路对顺铂致肺癌大鼠肾损伤的保护作用及其分子机制研究。方法:将50只大鼠随机分为5组:正常对照组、肺癌组（Lewis细胞）、顺铂组(Lewis细胞+腹腔注射顺铂溶液5 mg·kg-1)、吡咯烷二硫代氨基甲酸盐（PDTC）组(Lewis细胞+腹腔注射PDTC 25 mg·kg-1)、PDTC+顺铂组（Lewis细胞+腹腔注射顺铂和PDTC）,每组10只。末次给药后,生化分析仪检测血清肌酐（SCr）、尿素氮（BUN）、胱抑素C（Cys C）、尿液肾损伤分子-1（Kim-1）水平,ELISA法测定肾组织中超氧化物歧化酶（SOD）和丙二醛（MDA）水平,RT-PCR检测肾组织肿瘤坏死因子-α（TNF-α）、白细胞介素（IL）-1β、IL-6水平,Western Blotting检测核因子2相关因子2（Nrf2）、血红素氧合酶-1（HO-1）、NF-κB p65、p-IκBα/IκBα的表达,HE染色检测肾组织损伤。结果:与肺癌组相比,顺铂组大鼠血SCr、BUN、Cys C、尿Kim-1水平及肾组织MDA、TNF-α、IL-1β、IL-6 mRNA、Nrf2、HO-1、NF-κB p65和p-IκBα/IκBα的表达明显升高（P<0.05）,肾组织SOD活性和GSH-Px活性明显降低（P<0.05）;与顺铂组相比,PDTC+顺铂组大鼠血SCr、BUN、Cys C、尿Kim-1水平及肾组织MDA、TNF-α、IL-1β、IL-6 mRNA、NF-κB p65和p-IκBα/IκBα的表达明显明显降低（P<0.05）,肾组织SOD、GSH-Px、Nrf2和HO-1的表达明显升高（P<0.05）。结论:抑制NF-κB信号通路可以降低炎症因子水平,还可以激活Nrf2的表达,降低氧化应激水平,保护顺铂致肺癌大鼠的肾组织损伤。     

PNU-282987对颞叶癫痫模型大鼠认知功能的影响及机制

目的 研究特异性α7烟碱型乙酰胆碱受体(α7nAChR)激动剂PNU-282987对颞叶癫痫(TLE)模型大鼠认知功能的影响及机制。方法 将60只大鼠随机分为对照组、模型组、PNU-282987组(3 mg/kg)和甲基牛扁亭(MLA)+PNU-282987组(6 mg/kg MLA+3 mg/kg PNU-282987),每组15只。除对照组之外,其余各组大鼠均制备TLE模型。造模成功后,各组大鼠腹腔注射相应药物或生理盐水,每天1次,连续2周。观察大鼠癫痫发作行为并进行评分,记录发作持续时间;检测大鼠认知功能;观察海马组织CA1区神经元病理学形态;检测海马组织中肿瘤坏死因子α(TNF-α)、白细胞介素6(IL-6)和IL-1β水平;检测海马组织中离子钙接头蛋白1(IBA-1)阳性表达和α7nAChR、核因子κB(NF-κB)p65、磷酸化NF-κB p65(p-NF-κB p65)蛋白表达水平。结果 与模型组比较,PNU-282987组大鼠癫痫评分和发作持续时间,海马组织中IBA-1阳性细胞数量和TNF-α、IL-6、IL-1β水平以及NF-κB p65、p-NF-κB p65蛋白表...     

重组人促红细胞生成素对大鼠急性脊髓损伤后炎症因子表达及运动功能的影响

目的研究重组人促红细胞生成素(rhEPO)对大鼠急性脊髓损伤(SCI)后肿瘤坏死因子-α(TNF-α)、白细胞介素-1β(IL-1β)、白细胞介素-6(IL-6)等炎症因子的表达及运动功能的影响,探讨其减轻脊髓损伤、保护神经功能的可能机制以及对运动功能恢复的影响。方法36只SD大鼠,采用随机数字表法分为假手术组(Sham组)、脊髓损伤组(SCI组)、治疗组(EPO组),每组12只。Sham组:不损伤脊髓,仅行椎板切除术;SCI组和EPO组:行椎板切除术后,均采用改良的Allen's撞击法造成脊髓损伤。EPO组于术后1 h、1 d、3 d、7 d、14 d腹腔注射rhEPO;Sham组及SCI组,于术后1 h、1 d、3 d、7 d、14 d腹腔内注射等量的0.9%氯化钠溶液。术后第3天,各组分别处死6只大鼠并取材,用酶联免疫吸附试验(ELISA)法检测TNF-α、IL-1β、IL-6的表达水平;并用脊髓损伤Basso-Beattie-Bresnahan(BBB)评分法评价大鼠术后第1、3、7、14天的运动功能情况。比较三组脊髓组织中各炎症因子表达情况及不同时间点BBB评分。结果术后第3天,Sham组的TNF-α、IL-1β、IL-6水平均低于SCI组及EPO组,EPO组的TNF-α、IL-1β、IL-6水平均低于SCI组,差异均具有统计学意义(P<0.05)。BBB评分最高分21分,Sham组无脊髓损伤,术后大鼠运动功能正常,BBB评分接近正常值。术后第1、3、7、14天,EPO组和SCI组大鼠的BBB评分随着时间的延长而升高,差异均具有统计学意义(P<0.05)。术后第1、3、7、14天,EPO组和SCI组大鼠的BBB评分均低于Sham组,差异均具有统计学意义(P<0.05)。术后第7、14天,EPO组大鼠的BBB评分分别为(10.04±1.01)、(12.50±1.17)分,均高于SCI组(7.92±1.04)、(9.92±1.12)分,差异均具有统计学意义(P<0.05)。结论rhEPO可减少急性脊髓损伤后炎症因子TNF-α、IL-1β、IL-6的表达,减轻炎症反应,从而发挥保护神经的作用;且rhEPO可明显改善脊髓损伤后大鼠的运动功能,有利于神经功能的恢复。     

Hedgehog and spinal cord injury

The hedgehog (Hh) pathway is a highly conserved signalling cascade involved in many developmental processes, including a key role in morphogenesis of many tissues including the limb bud, lung, gut, hair follicle and the neural tube. Hh role in adult tissue is less well-established, however, it is known that the pathway becomes activated and reutilised in situations of repair and regeneration. In the nervous system, tissue repair appears impeded in that mature neurons undergo their final cell divisions early in life and central axons do not easily regenerate. The Hh pathway has been shown to be activated in response to nerve damage, leading to the hypothesis that enhancing Hh pathway activation in damaged nerve tissue, inducing the repair process, could offer a potentially new approach to treating neurodegenerative diseases and dysfunction, including spinal cord injury.     

Hedgehog and spinal cord injury

The hedgehog (Hh) pathway is a highly conserved signalling cascade involved in many developmental processes, including a key role in morphogenesis of many tissues including the limb bud, lung, gut, hair follicle and the neural tube. Hh role in adult tissue is less well-established, however, it is known that the pathway becomes activated and reutilised in situations of repair and regeneration. In the nervous system, tissue repair appears impeded in that mature neurons undergo their final cell divisions early in life and central axons do not easily regenerate. The Hh pathway has been shown to be activated in response to nerve damage, leading to the hypothesis that enhancing Hh pathway activation in damaged nerve tissue, inducing the repair process, could offer a potentially new approach to treating neurodegenerative diseases and dysfunction, including spinal cord injury.     

强啡肽A（1－17）致大鼠脊髓损伤

为研究脊髓损伤及继发性损伤的发病机理及其治疗方法，建立了蛛网膜下腔注射强啡肽Ａ（ＤｙｎＡ）致大鼠脊髓损伤动物模型。发现内源性ＤｙｎＡ（１－１７）的氨基端酪氨酸与竣基端的氨基酸残基在致脊髓损伤中都是重要的：Ｎ－甲基－Ｄ－天冬氨酸受体拮抗剂ＤＬ－２－氨基－５－胯酰戊酸（ＡＰＶ），犬尿氨酸及ＭＫ－８０１在对抗ＤｙｎＡ的损伤中均有一定的疗效。但ＡＰＶ和ＭＫ－８０１本身有一定毒性。而犬尿酸氨是一种内源性物质，主要作用于甘氨酸Ｂ变构调节位点，对整体生理功能影响较小。钙拮抗剂维拉帕米对抗强啡肽的致脊髓损伤作用迅速而完全。在所用剂量（５０ｎｍｏｌ）下无毒副作用。     

强啡肽A（1－17）致大鼠脊髓损伤

为研究脊髓损伤及继发性损伤的发病机理及其治疗方法，建立了蛛网膜下腔注射强啡肽Ａ（ＤｙｎＡ）致大鼠脊髓损伤动物模型。发现内源性ＤｙｎＡ（１－１７）的氨基端酪氨酸与竣基端的氨基酸残基在致脊髓损伤中都是重要的：Ｎ－甲基－Ｄ－天冬氨酸受体拮抗剂ＤＬ－２－氨基－５－胯酰戊酸（ＡＰＶ），犬尿氨酸及ＭＫ－８０１在对抗ＤｙｎＡ的损伤中均有一定的疗效。但ＡＰＶ和ＭＫ－８０１本身有一定毒性。而犬尿酸氨是一种内源性物质，主要作用于甘氨酸Ｂ变构调节位点，对整体生理功能影响较小。钙拮抗剂维拉帕米对抗强啡肽的致脊髓损伤作用迅速而完全。在所用剂量（５０ｎｍｏｌ）下无毒副作用。     

Emerging drugs for spinal cord injury

Background: This review summarizes several promising pharmacological approaches for the therapeutic management of traumatic spinal cord injury (SCI), which are either in early-phase clinical trials or nearing clinical translation. Objective: This review provides the reader with an understanding of the key pathophysiological mechanisms that contribute to neurological deficits after SCI. Through discussion of the mechanism(s) of action of the selected therapeutic approaches potentially important targets to aid further drug discovery will be highlighted. Methods: Systematic literature review of the pre-clinical literature and clinical SCI trials related to neuroprotective, immunomodulatory and regenerative therapeutic approaches. Results/conclusion: The next decade will witness an unprecedented number of clinical trials which will seek to translate key biomedical research discoveries. The promising drug-based therapeutic approaches include regenerative strategies to neutralize myelin-mediated neurite outgrowth inhibition, neuroprotective strategies to reduce apoptotic triggers, the targeting of cationic/glutamatergic toxicity, anti-inflammatory strategies and the use of approaches to stabilize disrupted cell membranes.     

Cardiovascular control after spinal cord injury

Spinal cord injury (SCI) leads to profound haemodynamic changes. Constant outflows from the central autonomic pattern generators modulate the activity of the spinal sympathetic neurons. Sudden loss of communication between these centers and the sympathetic neurons in the intermediolateral thoracic and lumbar spinal cord leads to spinal shock. After high SCI, experimental data demonstrated a brief hypertensive peak followed by bradycardia with escape arrhythmias and marked hypotension. Total peripheral resistance and cardiac output decrease, while central venous pressure remains unchanged. The initial hypertensive peak is thought to result from direct sympathetic stimulation during SCI and its presence is anaesthetic agent dependent. Hypotension improves within days in most animal species because of reasons not totally understood, which may include synaptic reorganization or hyper responsiveness of alpha receptors. No convincing data has demonstrated that the deafferented spinal cord can generate significant basal sympathetic activity. However, with the spinal shock resolution, the deafferented spinal cord (in lesions above T6) will generate life-threatening hypertensive bouts with compensatory bradycardia, known as autonomic hyperreflexia (AH) after stimuli such as pain or bladder/colonic distension. AH results from the lack of supraspinal control of the sympathetic neurons and altered neurotransmission (e.g. glutamatergic) within the spinal cord. Despite significant progress in recent years, further research is necessary to fully understand the spectrum of haemodynamic changes after SCI.     

Neural plasticity after spinal cord injury

Spinal cord injury (SCI) has devastating physical and socioeconomical impact. However, some degree of functional recovery is frequently observed in patients after SCI. There is considerable evidence that functional plasticity occurs in cerebral cortical maps of the body, which may account for functional recovery after injury. Additionally, these plasticity changes also occur at multiple levels including the brainstem, spinal cord, and peripheral nervous system. Although the interaction of plasticity changes at each level has been less well studied, it is likely that changes in subcortical levels contribute to cortical reorganization. Since the permeability of the blood-brain barrier (BBB) is changed, SCI-induced factors, such as cytokines and growth factors, can be involved in the plasticity events, thus affecting the final functional recovery after SCI. The mechanism of plasticity probably differs depending on the time frame. The reorganization that is rapidly induced by acute injury is likely based on unmasking of latent synapses resulting from modulation of neurotransmitters, while the long-term changes after chronic injury involve changes of synaptic efficacy modulated by long-term potentiation and axonal regeneration and sprouting. The functional significance of neural plasticity after SCI remains unclear. It indicates that in some situations plasticity changes can result in functional improvement, while in other situations they may have harmful consequences. Thus, further understanding of the mechanisms of plasticity could lead to better ways of promoting useful reorganization and preventing undesirable consequences.