• 【异位子宫内膜和子宫内膜异位病变中微血管密度,增殖活性与血管内皮生长因子-A及其受体表达的关系。】 复制标题 收藏 收藏
    DOI:10.1530/rep.1.01110 复制DOI
    作者列表:Bourlev V,Volkov N,Pavlovitch S,Lets N,Larsson A,Olovsson M
    BACKGROUND & AIMS: :Studies were performed to elucidate the possible relationship between microvessel density, proliferative activity and angiogenesis in eutopic endometrium from women with and without endometriosis and peritoneal endometriotic lesions. The question whether changes in these parameters in endometriotic lesions were reflected by the level of vascular endothelial growth factor-A (VEGF-A) in serum and peritoneal fluid was also studied. Biopsy specimens of both eutopic endometrium and peritoneal endometriotic lesions from women with endometriosis (n = 25) as well as eutopic endometrium from women without endometriosis (n = 14) were analysed immunohistochemically regarding microvessel density, proliferative activity, and expression of VEGF-A and its receptors vascular endothelial growth factor receptors 1 and 2 (VEGFR-1 and VEGFR-2) in stroma, glands and blood vessels. The VEGF-A concentration was measured in peritoneal fluid and serum. Secretory phase eutopic endometrium from women with endometriosis had significantly higher microvessel density, expression of VEGF-A in glandular epithelium and VEGFR-2 in endometrial blood vessels than those from women without endometriosis. Endometriotic lesions with high proliferative activity had a higher microvessel density and showed higher vascular expression of VEGFR-2 as well as being accompanied by higher levels of VEGF-A in peritoneal fluid and serum, compared with lesions with low proliferative activity. In conclusion, there seems to be a dysregulation of angiogenic activity in the eutopic endometrium of women with endometriosis and endometriotic lesions with high proliferative activity were accompanied by higher local angiogenic activity and higher levels of VEGF in serum and peritoneal fluid.
    背景与目标: :进行了研究以阐明患有和不患有子宫内膜异位和腹膜子宫内膜异位病变的女性在位子宫内膜的微血管密度,增殖活性和血管生成之间的可能关系。还研究了是否通过血清和腹膜液中血管内皮生长因子-A(VEGF-A)的水平反映子宫内膜异位病变中这些参数的变化的问题。对子宫内膜异位症妇女(n = 25)和非子宫内膜异位症妇女(n = 14)的对位子宫内膜和腹膜子宫内膜异位病变的活检标本进行了免疫组织化学分析,涉及微血管密度,增殖活性,VEGF-A和其受体位于基质,腺体和血管中的血管内皮生长因子受体1和2(VEGFR-1和VEGFR-2)。测定腹膜液和血清中的VEGF-A浓度。子宫内膜异位症女性的分泌期异位子宫内膜比无子宫内膜异位症女性的子宫内膜微血管密度,腺上皮中的VEGF-A表达和子宫内膜血管中的VEGFR-2显着更高。与具有低增殖活性的病变相比,具有高增殖活性的子宫内膜异位病变具有更高的微血管密度,并在腹膜液和血清中具有较高的VEGFR-2血管表达以及较高的VEGF-A水平。总之,子宫内膜异位症妇女的异位子宫内膜血管新生活性似乎异常,具有高增殖活性的子宫内膜异位病变伴有较高的局部血管新生活性和血清和腹膜液中较高的VEGF水平。
  • 【澳洲肺金枪鱼中肺鱼中胰岛素样生长因子-I mRNA表达的营养调控。】 复制标题 收藏 收藏
    DOI:10.1677/jme.0.0180273 复制DOI
    作者列表:Matthews SJ,Kinhult AK,Hoeben P,Sara VR,Anderson TA
    BACKGROUND & AIMS: The effect of nutritional status on IGF-I mRNA expression in the liver and brain of juvenile barramundi (Lates calcarifer) was investigated. Fish were either fed a satiety ration (SAT) or starved (STV) for 6 weeks. Starved fish demonstrated significantly lower condition factor and hepatic IGF-I mRNA expression at 3 and 6 weeks, when compared with the SAT group. IGF-I mRNA expression in the brain was 10 fold lower than the liver and was not affected by ration size. These results suggest the liver is the major site of IGF-I mRNA synthesis and hepatic but not brain IGF-I mRNA expression is regulated by food availability in juvenile barramundi.

    背景与目标: 研究了营养状况对少年肺鱼(Lates calcarifer)肝脏和脑中IGF-I mRNA表达的影响。给鱼喂饱口粮(SAT)或饿死(STV)6周。与SAT组相比,在3周和6周时,饥饿的鱼表现出明显较低的条件因子和肝脏IGF-I mRNA表达。脑中IGF-I mRNA表达比肝脏低10倍,并且不受口粮大小的影响。这些结果表明,肝脏是IGF-I mRNA合成的主要部位,肝而不是脑IGF-I mRNA的表达受幼鱼的食物供应量的调节。

  • 【抗氧化剂对核因子-κB的抑制作用增强了紫杉醇在卵巢癌细胞系中的敏感性。】 复制标题 收藏 收藏
    DOI:10.1111/j.1525-1438.2006.00652.x 复制DOI
    作者列表:Liu GH,Wang SR,Wang B,Kong BH
    BACKGROUND & AIMS: :The objective of this study was to determine whether paclitaxel and a strong antioxidant, pyrrolidinedithiocarbamate (PDTC), can affect the activation of nuclear factor-kappa B (NF-kappaB) in SKOV-3 human ovarian cancer cell line and the effect of these two agents on the growth and apoptosis of the cancer cells. The cells were treated with various concentrations of paclitaxel and/or PDTC at various time intervals. Following treatments, cell growth and apoptosis were determined by 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulphonyl)-2H-tetrazolium (WST-8) (WST) assay and flow cytometry, respectively. Western blot assay was used to determine the nuclear p65 protein and cytoplasmic IkappaB-alpha protein. High doses of PDTC significantly inhibited the growth of SKOV-3 cells and caused apoptosis. Paclitaxel and lower doses of PDTC combined demonstrated additive inhibition of cell growth and increased levels of apoptosis. Treatment of paclitaxel alone showed increased nuclear p65 protein and decreased cytoplasmic IkappaB-alpha protein expression, while pretreatment of PDTC reversed this function. PDTC blocks the paclitaxel-induced activation of NF-kappaB leading to increased chemosensitivity to paclitaxel and enhanced apoptosis. Combining antioxidants and paclitaxel has significant potential to overcome the risk of paclitaxel resistance.
    背景与目标: :这项研究的目的是确定紫杉醇和强抗氧化剂吡咯烷二硫代氨基甲酸酯(PDTC)是否会影响SKOV-3人卵巢癌细胞系中核因子-κB(NF-kappaB)的活化及其作用两种药剂对癌细胞的生长和凋亡都有影响。在不同的时间间隔用不同浓度的紫杉醇和/或PDTC处理细胞。处理后,通过2-(2-甲氧基-4-硝基苯基)-3-(4-硝基苯基)-5-(2,4-二磺酰基)-2H-四唑鎓(WST-8)(WST)测定细胞生长和凋亡)分析和流式细胞术。蛋白质印迹法用于确定核p65蛋白和细胞质IkappaB-alpha蛋白。高剂量的PDTC显着抑制SKOV-3细胞的生长并引起细胞凋亡。紫杉醇和较低剂量的PDTC联合显示可抑制细胞生长和增加细胞凋亡水平。单独使用紫杉醇的治疗显示核p65蛋白增加,而细胞质IkappaB-α蛋白表达降低,而PDTC的预处理逆转了该功能。 PDTC阻止紫杉醇诱导的NF-κB活化,从而导致对紫杉醇的化学敏感性增加和细胞凋亡增强。抗氧化剂和紫杉醇的组合具有克服紫杉醇耐药性的巨大潜力。
  • 【氨基末端脑钠肽:一种诊断,预后和管理心力衰竭的生物标志物。】 复制标题 收藏 收藏
    DOI:10.1586/14737159.6.5.649 复制DOI
    作者列表:Morello AM,Januzzi JL
    BACKGROUND & AIMS: :There is a substantial need for a diagnostic tool to aid in the early diagnosis of heart failure and in the recognition of those at risk for its development, as well as in guidance of therapy. Testing for amino-terminal pro-brain natriuretic peptide (NT-proBNP) has been recognized to have utility in the diagnosis, prognosis and management of heart failure. In addition, numerous other applications for NT-proBNP testing are now recognized, such as evaluation of patients with heart disease in the absence of heart failure, as well as the diagnostic and prognostic evaluation of patients with acute coronary syndromes or pulmonary thromboembolism.
    背景与目标: :非常需要一种诊断工具来辅助心力衰竭的早期诊断,并认识到可能发展为心力衰竭的人,以及指导治疗。氨基末端脑钠肽(NT-proBNP)的检测已被认为可用于心力衰竭的诊断,预后和管理。此外,现在还认可了NT-proBNP测试的许多其他应用,例如在没有心力衰竭的情况下对心脏病患者的评估以及对急性冠状动脉综合征或肺血栓栓塞患者的诊断和预后评估。
  • 【显然健康的男性和女性的组织因子血清水平和未来冠状动脉疾病的风险:EPIC-Norfolk前瞻性人群研究。】 复制标题 收藏 收藏
    DOI:10.1111/j.1538-7836.2006.02190.x 复制DOI
    作者列表:Keller TT,Choi D,Nagel C,Te Velthuis H,Gerdes VE,Wareham NJ,Bingham SA,Luben R,Hack CE,Reitsma PH,Levi M,Khaw KT,Boekholdt SM
    BACKGROUND & AIMS: INTRODUCTION:Tissue factor (TF) has been implicated in coronary artery disease (CAD). High levels of circulating TF are found in patients with acute atherothrombotic events. Whether high serum TF levels predict risk of future CAD independent of known risk factors remains unknown. METHODS:We conducted a prospective case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk population study. Cases (n=1037) were apparently healthy men and women, aged 45-79 years, who developed fatal or non-fatal CAD during follow-up. Controls (n=2005) were matched by age, sex, and enrolment time. Serum TF levels were measured using high-affinity antibodies. RESULTS:In men, median TF levels were not significant higher in cases than in controls (59.0 pg mL-1, range: 16.7-370.4 vs. 54.9 pg mL-1, range: 16.2-452.4). In women, median TF levels were not significant higher in controls than in cases (73.4 pg mL-1, range: 16.7-492.3 vs. 50.5 pg mL-1, range: 16.5-376.7). The incidence of smoking was about double in the lowest compared with the highest TF quartile. Correcting for sex, age, body mass index, smoking, diabetes, systolic blood pressure, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol and C-reactive protein levels, the risk of future CAD was 1.05 (95% CI: 0.81-1.36) for people in the highest TF quartile, compared with those in the lowest (P-value for linearity=0.8). CONCLUSION:High levels of serum TF were not independently associated with an increased risk of future CAD in apparently healthy individuals.
    背景与目标: 简介:组织因子(TF)与冠心病(CAD)有关。在患有急性动脉粥样硬化血栓形成事件的患者中发现高水平的循环TF。血清TF高水平是否能独立于已知的危险因素来预测未来CAD的风险仍然未知。
    方法:我们进行了一项前瞻性病例对照研究,该研究嵌套在欧洲癌症与营养前瞻性调查(EPIC)-诺福克人群研究中。病例(n = 1037)显然是健康的男性和女性,年龄在45-79岁之间,在随访期间发生了致命或非致命的CAD。对照组(n = 2005)按年龄,性别和入组时间进行匹配。使用高亲和力抗体测量血清TF水平。
    结果:在男性中,病例中的TF中位数没有显着高于对照组(59.0 pg / mL-1,范围:16.7-370.4 vs. 54.9 pg / mL-1,范围:16.2-452.4)。在女性中,对照的中位TF水平没有比病例高(73.4 pg / mL-1,范围:16.7-492.3 vs. 50.5 pg / mL-1,范围:16.5-376.7)。与最高四分位数的吸烟者相比,最低吸烟率的吸烟者约为两倍。校正性别,年龄,体重指数,吸烟,糖尿病,收缩压,低密度脂蛋白胆固醇,高密度脂蛋白胆固醇和C反应蛋白水平后,未来CAD的风险为1.05(95%CI: TF最高四分位数的人与最低TF四分位数的人(线性P值= 0.8)相比。
    结论:血清TF水平升高与明显健康的个体未来冠心病风险增加并没有独立的关系。
  • 【静止T细胞的有丝分裂刺激导致转录因子LSF迅速磷酸化,并增加了DNA结合活性。】 复制标题 收藏 收藏
    DOI:10.1101/gad.11.11.1435 复制DOI
    作者列表:Volker JL,Rameh LE,Zhu Q,DeCaprio J,Hansen U
    BACKGROUND & AIMS: The mammalian transcription factor LSF (CP2/LBP-1c) binds cellular promoters modulated by cell growth signals. We demonstrate here that LSF-DNA-binding activity is strikingly regulated by induction of cell growth in human peripheral T lymphocytes. Within 15 min of mitogenic stimulation of these cells, the level of LSF-DNA-binding activity increased by a factor of five. The level of LSF protein in the nucleus remained constant throughout this interval. However, a rapid decrease in the electrophoretic mobility of LSF, attributable to phosphorylation, correlated with the increase in DNA-binding activity. pp44 (ERK1) phosphorylated LSF in vitro on the same residue that was phosphorylated in vivo, specifically at amino acid position 291, as indicated by mutant analysis. As direct verification of the causal relationship between phosphorylation and DNA-binding activity, treatment in vitro of LSF with phosphatase both increased the electrophoretic mobility of the protein and decreased LSF-DNA-binding activity. This modulation of LSF-DNA-binding activity as T cells progress from a resting to a replicating state reveals that LSF activity is regulated during cell growth and suggests that LSF regulates growth-responsive promoters.

    背景与目标: 哺乳动物转录因子LSF(CP2 / LBP-1c)结合受细胞生长信号调节的细胞启动子。我们在这里证明,LSF-DNA结合活性是由人类外周血T淋巴细胞的细胞生长诱导来显着调节的。在这些细胞的促有丝分裂刺激的15分钟内,LSF-DNA结合活性的水平提高了五倍。在整个间隔期间,核中LSF蛋白的水平保持恒定。但是,可归因于磷酸化的LSF电泳迁移率的快速下降与DNA结合活性的增加有关。突变分析表明,pp44(ERK1)在体外磷酸化的同一残基上,特别是在氨基酸位置291处磷酸化LSF。作为磷酸化与DNA结合活性之间因果关系的直接验证,体外用磷酸酶处理LSF既增加了蛋白质的电泳迁移率,又降低了LSF-DNA结合活性。当T细胞从静止状态发展到复制状态时,对LSF-DNA结合活性的这种调节揭示了LSF活性在细胞生长过程中受到调节,并暗示LSF调节生长响应性启动子。

  • 【重组人可溶性肿瘤坏死因子受体融合蛋白作为同种异体造血干细胞移植后类固醇难治性移植物抗宿主病的治疗方法。】 复制标题 收藏 收藏
    DOI:10.1002/ajh.20752 复制DOI
    作者列表:Busca A,Locatelli F,Marmont F,Ceretto C,Falda M
    BACKGROUND & AIMS: :Etanercept is a recombinant human soluble tumor necrosis factor (TNF-alpha) receptor fusion protein that inhibits TNF-alpha, a major mediator in the pathogenesis of graft-versus-host disease (GVHD). The purpose of our study was to evaluate the safety and efficacy of etanercept therapy in 21 patients with steroid-refractory acute GVHD (aGVHD) (n = 13) and chronic GVHD (cGVHD) (n = 8). Etanercept 25 mg was given subcutaneously twice weekly for 4 weeks followed by 25 mg weekly for 4 weeks. At the time of initiation of etanercept, 14 patients had skin, 13 had gastro-intestinal, 5 had liver, 5 had pulmonary, and 4 had oral involvement. Twelve patients (57%) completed 12 doses of therapy. Overall, 11 of 21 patients (52%) responded to the treatment with etanercept, including 6 patients (46%) with aGVHD [n = 4 complete response (CR), n = 2 partial response (PR)] and 5 patients (62%) with cGVHD (n = 1 CR, n = 4 PR). Clinical responses were most commonly seen in patients with refractory gut aGVHD with 55% of the patients having a CR and 9% having a PR. CMV reactivation occurred in 48% of patients, bacterial infections in 14% of patients, and fungal infections in 19% of patients. Fourteen patients (67%) were alive after a median follow-up of 429 days (range 71-1007 days) since initiation of etanercept. Seven patients died, 3 of infections, 2 of refractory aGVHD, and 2 of disease progression. In conclusion, our preliminary data indicate that etanercept is well tolerated and can induce a high response rate in patients with steroid-refractory aGVHD and cGVHD, particularly in the setting of GI involvement.
    背景与目标: :Etanercept是一种重组人类可溶性肿瘤坏死因子(TNF-alpha)受体融合蛋白,可抑制TNF-alpha(一种在移植物抗宿主病(GVHD)发病机理中的主要介体)。本研究的目的是评估依那西普治疗21例激素抵抗性急性GVHD(aGVHD)(n = 13)和慢性GVHD(cGVHD)(n = 8)患者的安全性和有效性。每周两次皮下给予Etanercept 25 mg,持续4周,然后每周25 mg,持续4周。依那西普开始治疗时,有14例皮肤,13例胃肠,5例肝,5例肺,4例经口受累。 12名患者(57%)完成了12剂治疗。总体上,在21名患者中有11名患者(52%)对依那西普治疗有反应,包括6名患者(46%)患有aGVHD [n = 4完全缓解(CR),n = 2部分缓解(PR)]和5例(62 %)和cGVHD(n = 1 CR,n = 4 PR)。临床反应最常见于顽固性肠aGVHD患者,其中55%的患者为CR,9%的患者为PR。 CMV重新激活发生在48%的患者中,细菌感染发生在14%的患者中,而真菌感染发生在19%的患者中。自依那西普开始接受中位随访429天(71-1007天)后,有14名患者(67%)还活着。 7例患者死亡,3例感染,2例难治性aGVHD死亡,2例疾病进展。总之,我们的初步数据表明,依那西普耐受性好,在类固醇难治性aGVHD和cGVHD患者中可引起较高的应答率,尤其是在胃肠道受累的情况下。
  • 【使用源自人脐带血的干细胞的潜在临床应用。】 复制标题 收藏 收藏
    DOI:10.1016/s1472-6483(10)60646-3 复制DOI
    作者列表:Ghen MJ,Roshan R,Roshan RO,Blyweiss DJ,Corso N,Khalili B,Zenga WT
    BACKGROUND & AIMS: :There is an abundance of clinical applications using human umbilical cord blood (HUCB) as a source for stem cell populations. Other than haematopoietic progenitors, there are mesenchymal, endothelial stem cells and neuronal precursors, in varying quantities, that are found in human umbilical cord blood. These may be useful in diseases such as immune deficiency and autoimmune disorders. Considering issues of safety, availability, transplant methodology, rejection and side effects, it is contended that a therapeutic stem cell transplant, utilizing stem cells from HUCB, provides a reliable repository of early precursor cells that can be useful in a great number of diverse conditions. Drawbacks of relatively smaller quantities of mononucleated cells in one unit of cord blood can be mitigated by in-vitro expansion procedures, improved in-vivo signalling, and augmentation of the cellular milieu, while simultaneously choosing the appropriate transplantation site and technique for introduction of the stem cell graft.
    背景与目标: :有大量的临床应用使用人类脐带血(HUCB)作为干细胞群体的来源。除造血祖细胞外,人类脐带血中还存在不同数量的间充质,内皮干细胞和神经元前体。这些可能对诸如免疫缺陷和自身免疫性疾病等疾病有用。考虑到安全性,可用性,移植方法,排斥反应和副作用等问题,可以认为,利用HUCB干细胞进行的治疗性干细胞移植可提供可靠的早期前体细胞库,该库可在多种条件下使用。可以通过体外扩增程序,改进的体内信号传导和细胞环境增强来缓解一单位脐带血中相对较少数量的单核细胞的缺点,同时选择合适的移植部位和技术引入干细胞移植。
  • 【人脑中的微透析:其应用综述。】 复制标题 收藏 收藏
    DOI:10.1080/01616412.1997.11740814 复制DOI
    作者列表:Hamani C,Luer MS,Dujovny M
    BACKGROUND & AIMS: The analysis of brain extracellular fluid can provide essential information about both the physiology and the pathology of the human nervous system. The introduction of microdialysis into the clinical sciences has provided a new opportunity to study this environment. Using microdialysis, endogenous substances can be obtained and drugs can be delivered in very close proximity to the receptors and ion channels on neuronal membranes. In this sense, microdialysis can be regarded as a novel technique since it can continuously measure interstitial brain activity in living tissue while causing minimal adverse effects. Although it has been well established as an experimental technique for neurochemistry, the true utility of microdialysis as a clinical tool is still being defined. The potential clinical applications of microdialysis to characterize the human brain extracellular environment in patients with pathologic conditions has grown rapidly. The number of publications in which microdialysis has been performed in clinical studies has been increasing during recent years and this article gives a summary of those reports where microdialysis was applied in the study of human brain disorders.

    背景与目标: 对大脑细胞外液的分析可以提供有关人类神经系统生理和病理的基本信息。将微透析技术引入临床科学为研究这种环境提供了新的机会。使用微透析,可以获得内源性物质,并且药物可以非常靠近神经元膜上的受体和离子通道递送。从这个意义上讲,微透析可以被视为一种新颖的技术,因为它可以连续测量活组织中的间质性大脑活动,同时将不良影响降到最低。尽管已经将其很好地确立为神经化学的实验技术,但微透析作为临床工具的真正用途仍在定义中。微透析在表征病理状况患者中表征人脑细胞外环境的潜在临床应用迅速增长。近年来,在临床研究中进行微透析的出版物数量不断增加,本文总结了在人类脑部疾病研究中应用微透析的那些报道。

  • 【结肠扩张激活蓝藻:促肾上腺皮质激素释放因子和兴奋性氨基酸的作用。】 复制标题 收藏 收藏
    DOI:10.1016/s0006-8993(97)00116-9 复制DOI
    作者列表:Lechner SM,Curtis AL,Brons R,Valentino RJ
    BACKGROUND & AIMS: The present study was designed to elucidate the neurotransmitters involved in activation of the noradrenergic nucleus, locus coeruleus, by distention of the distal colon. Locus coeruleus spontaneous discharge rate was recorded from halothane-anesthetized rats before, during and after distention of the colon produced by inflation of a balloon catheter with varying volumes of water. Locus coeruleus activation by colon distention was volume-dependent and reversible. Activation of cortical electroencephalographic activity was temporally correlated with locus coeruleus activation during colon distention and prolonged distention (greater than 2 min) resulted in tachyphalaxis to both locus coeruleus and cortical electroencephalographic activation. The corticotropin-releasing factor antagonist, DPheCRF(12-41), administered intracerebroventricularly (3 microg) or microinfused into the locus coeruleus (10 ng) significantly attenuated locus coeruleus activation produced by lower, but not higher magnitudes of colon distention, implicating corticotropin-releasing factor afferents to the locus coeruleus in this response. Consistent with this, prior exposure to 30 min of footshock stress, which desensitizes locus coeruleus neurons to corticotropin-releasing factor, produced a similar attenuation of locus coeruleus activation by low, but not high magnitudes of distention. Kynurenic acid, administered intracerebroventricularly (5 micromol), significantly antagonized locus coeruleus activation by all magnitudes of colon distention. However, this excitatory amino acid antagonist was ineffective when administered directly into the locus coeruleus (0.3 nmol). Together, these findings suggest that low magnitudes of colon distention activate the locus coeruleus-noradrenergic system via corticotropin-releasing factor release within the locus coeruleus and that excitatory amino acid neurotransmission at a site distal to the locus coeruleus is necessary for this response. Activation of the locus coeruleus-noradrenergic system during colon distention may serve as a cognitive limb of the peripheral parasympathetic response. This activation may also play a role in disorders characterized by comorbidity of colonic and psychiatric symptoms, such as irritable bowel syndrome.

    背景与目标: 本研究旨在阐明远端结肠扩张引起的去甲肾上腺素能核激活的神经递质。记录了氟烷麻醉大鼠在用不同体积的水充入球囊导管使结肠扩张之前,期间和之后自发排出蓝藻的频率。结肠扩张引起的蓝斑轨迹激活是体积依赖性的和可逆的。皮质脑电图活动的激活在时间上与结肠扩张期间脑蓝素的激活相关,而长期扩张(大于2分钟)会导致脑脊髓蓝素和皮质脑电图的速动性。皮质激素释放因子拮抗剂DPheCRF(12-41),经脑室内(3微克)或微输注到蓝斑(10 ng)时,可显着减弱由较低但不是较高程度的结肠扩张产生的蓝斑激活,这暗示促肾上腺皮质激素-在这种反应中,释放因子传入蓝斑。与此相一致,事先暴露于30分钟的足底震荡中,使蓝斑蓝皮病的神经元对促肾上腺皮质激素释放因子不敏感,通过低但不高的扩张程度,蓝斑蓝皮病的激活也有类似的减弱。脑室内(5微摩尔)施用的犬尿酸通过各种程度的结肠扩张显着拮抗蓝斑轨迹激活。但是,这种兴奋性氨基酸拮抗剂当直接施用于蓝斑(0.3 nmol)时无效。在一起,这些发现表明低程度的结肠扩张通过蓝藻中的促肾上腺皮质激素释放因子释放来激活蓝藻-去甲肾上腺素能系统,并且在蓝藻远侧的部位,兴奋性氨基酸神经传递对于该反应是必需的。结肠扩张期间蓝斑-去甲肾上腺素能系统的激活可能充当外周副交感反应的认知肢体。这种活化作用还可能在以结肠和精神症状合并症为特征的疾病中起作用,例如肠易激综合症。

  • 【苯巴比妥依赖和戒断大鼠脑中谷氨酸受体,c-fos mRNA表达和激活蛋白-1(AP-1)DNA结合活性的变化。】 复制标题 收藏 收藏
    DOI:10.1016/s0006-8993(97)00134-0 复制DOI
    作者列表:Tanaka S,Kiuchi Y,Numazawa S,Oguchi K,Yoshida T,Kuroiwa Y
    BACKGROUND & AIMS: We studied changes in glutamate receptors, expression of immediate early genes, and AP-1 DNA binding activity in the brains of phenobarbital (PB)-dependent and -withdrawn rats to investigate the possible involvement of activation of glutamate receptors in PB withdrawal syndrome. PB-dependent rats were prepared by feeding drug-admixed food for 5 weeks. Autoradiographic analysis showed that binding of [3H(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imin e (MK-801), an antagonist of N-methyl-D-aspartic acid (NMDA) receptors, increased significantly in the cerebral cortices of PB-dependent and 24-h-withdrawn rats. However, [3H]MK-801 binding in the hippocampus and [3H]6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and [3H]kainic acid binding in the hippocampus and cerebral cortex were essentially unchanged in both groups. PB withdrawal seizures were followed by increased expression of c-fos mRNA in the hippocampus and cerebral cortex and of c-jun mRNA in the cerebral cortex. The induction of c-fos and c-jun mRNA was suppressed by administration of MK-801. Furthermore, PB withdrawal enhanced AP-1 DNA binding activity in the brain. The present findings suggest functional enhancement of glutamatergic neurotransmission during the development of PB withdrawal syndrome.

    背景与目标: 我们研究了苯巴比妥(PB)依赖和戒断大鼠大脑中谷氨酸受体的变化,立即早期基因的表达以及AP-1 DNA结合活性,以研究谷氨酸受体激活在PB戒断综合征中的可能。通过喂食药物混合的食物5周来制备PB依赖的大鼠。放射自显影分析表明,[3H()-5-甲基-10,11-二氢-5H-二苯并[a,d]环庚烯-5,10-亚胺e(MK-801)与N-甲基- D-天冬氨酸(NMDA)受体,在PB依赖和24小时戒断大鼠的大脑皮层中显着增加。然而,在海马中的[3H] MK-801结合以及在海马和大脑皮层中的[3H] 6-氰基-7-硝基喹喔啉-2,3-二酮(CNQX)和[3H]海藻酸结合基本上没有变化。组。 PB抽搐发作后,海马和大脑皮层中c-fos mRNA的表达增加,大脑皮层中c-jun mRNA的表达增加。通过施用MK-801抑制了c-fos和c-jun mRNA的诱导。此外,PB撤离可增强大脑中AP-1 DNA的结合活性。目前的发现表明,在PB戒断综合征的发展过程中,谷氨酸能神经传递的功能增强。

  • 【ROS形成对依赖NADH的底物支持的孤立的脑线粒体中DeltaPsim的中等依赖性。】 复制标题 收藏 收藏
    DOI:10.1007/s11064-006-9130-y 复制DOI
    作者列表:Tretter L,Adam-Vizi V
    BACKGROUND & AIMS: :The membrane potential (DeltaPsim) dependence of the generation of reactive oxygen species (ROS) in isolated guinea-pig brain mitochondria respiring on NADH-linked substrates (glutamate plus malate) was addressed. Depolarization by FCCP was without effect on H(2)O(2) formation in the absence of bovine serum albumin (BSA). Addition of BSA (0.025%) to the assay medium hyperpolarized mitochondria by 6.1 +/- 0.9 mV (from 169 +/- 3 to 175.1 +/- 2.1 mV) and increased the rate of H(2)O(2) formation from 207 +/- 4.5 to 312 +/- 12 pmol/min/mg protein. Depolarization by FCCP (5-250 nM) in the presence of BSA decreased H(2)O(2) formation but only to the level observed in the absence of BSA. Rotenone stimulated the formation of H(2)O(2) both in the absence and presence of BSA. It is suggested that H(2)O(2) formation in mitochondria supported by NADH-linked substrates is sensitive to changes in DeltaPsim only when mitochondria are highly polarized and even then, 60% of ROS generation is independent of DeltaPsim. This is in contrast to earlier reports on the highly DeltaPsim sensitive ROS formation related to reverse electron flow observed in well-coupled succinate-supported mitochondria.
    背景与目标: :膜电位(DeltaPsim)依赖于在NADH相连的底物(谷氨酸加苹果酸)上呼吸的豚鼠脑线粒体中分离的活性氧(ROS)的产生。在没有牛血清白蛋白(BSA)的情况下,通过FCCP去极化对H(2)O(2)的形成没有影响。将BSA(0.025%)添加到测定介质超极化线粒体的6.1 /-0.9 mV(从169 /-3到175.1 /-2.1 mV),并将H(2)O(2)的形成速率从207 /-增加4.5至312 /-12 pmol / min / mg蛋白质。在BSA存在下由FCCP(5-250 nM)进行的去极化降低了H(2)O(2)的形成,但仅达到了在没有BSA的情况下观察到的水平。鱼藤酮在没有和存在BSA的情况下刺激H(2)O(2)的形成。建议仅在线粒体高度极化并且即使那时,60%的ROS生成独立于DeltaPsim时,由NADH链接的底物支持的线粒体中的H(2)O(2)形成对DeltaPsim的变化敏感。这与早先报道的关于高度DeltaPsim敏感的ROS形成相反,后者与在耦合良好的琥珀酸负载的线粒体中观察到的反向电子流有关。
  • 【Dlx同源框基因在branch弓近端模式中的作用:Dlx-1,Dlx-2和Dlx-1和-2的突变改变了衍生自第一和第二弓的近端骨骼和软组织结构的形态。】 复制标题 收藏 收藏
    DOI:10.1006/dbio.1997.8556 复制DOI
    作者列表:Qiu M,Bulfone A,Ghattas I,Meneses JJ,Christensen L,Sharpe PT,Presley R,Pedersen RA,Rubenstein JL
    BACKGROUND & AIMS: The Dlx homeobox gene family is expressed in a complex pattern within the embryonic craniofacial ectoderm and ectomesenchyme. A previous study established that Dlx-2 is essential for development of proximal regions of the murine first and second branchial arches. Here we describe the craniofacial phenotype of mice with mutations in Dlx-1 and Dlx-1 and -2. The skeletal and soft tissue analyses of mice with Dlx-1 and Dlx-1 and -2 mutations provide additional evidence that the Dlx genes regulate proximodistal patterning of the branchial arches. This analysis also elucidates distinct and overlapping roles for Dlx-1 and Dlx-2 in craniofacial development. Furthermore, mice lacking both Dlx-1 and -2 have unique abnormalities, including the absence of maxillary molars. Dlx-1 and -2 are expressed in the proximal and distal first and second arches, yet only the proximal regions are abnormal. The nested expression patterns of Dlx-1, -2, -3, -5, and -6 provide evidence for a model that predicts the region-specific requirements for each gene. Finally, the Dlx-2 and Dlx-1 and -2 mutants have ectopic skull components that resemble bones and cartilages found in phylogenetically more primitive vertebrates.

    背景与目标: Dlx同源盒基因家族以复杂的模式在胚胎颅面外胚层和外间质内表达。先前的研究表明,Dlx-2对于鼠的第一和第二分支弓近端区域的发育至关重要。在这里,我们描述了具有Dlx-1和Dlx-1和-2突变的小鼠的颅面表型。具有Dlx-1和Dlx-1和-2突变的小鼠的骨骼和软组织分析提供了其他证据,证明Dlx基因调节branch弓的近现代模式。该分析还阐明了Dlx-1和Dlx-2在颅面发育中的独特作用和重叠作用。此外,缺乏Dlx-1和-2的小鼠具有独特的异常,包括不存在上颌磨牙。 Dlx-1和-2在近端和远端第一和第二弓形中表达,但仅近端区域异常。 Dlx-1,-2,-3,-5和-6的嵌套表达模式为预测每个基因的区域特定要求的模型提供了证据。最后,Dlx-2,Dlx-1和-2突变体具有异位的头骨成分,类似于在系统发育上较原始的脊椎动物中发现的骨骼和软骨。

  • 【正常成年大鼠的血脑屏障缺陷区域的免疫环境增强。】 复制标题 收藏 收藏
    DOI:10.1016/s0165-5728(97)00038-6 复制DOI
    作者列表:Pedersen EB,McNulty JA,Castro AJ,Fox LM,Zimmer J,Finsen B
    BACKGROUND & AIMS: The circumventricular organs (CVOs) in the brain are without a blood-brain barrier (BBB) and as such directly exposed to blood plasma constituents and blood-borne pathogens. In light of previous studies showing discrepancies regarding the immunocompetence of these organs, we initiated the present study to provide a comprehensive immunohistochemical analysis of the cellular expression of immune-associated antigens within the pineal gland, area postrema and the subfornical organ. In all CVOs, subpopulations of cells morphologically similar to complement receptor type 3 immunoreactive microglial/macrophage cells expressed major histocompatibility complex (MHC) class II antigen, leucocyte common antigen (LCA/CD45), as well as CD4 and ED1 antigen. Based on morphological criteria the MHC class II antigen expressing cells could be grouped into a major population of classical parenchymal and perivascular ramified microglial cells and a minor population presenting itself as scattered or small groups of rounded macrophage-like cells. CD4 and ED1 antigen were expressed by both cell types. CD45 was preferentially expressed by macrophage-like cells. MHC class I antigen was expressed by the vascular endothelium in both BBB-protected and BBB-deficient areas and was additionally present as a lattice-like network throughout the BBB-deficient parenchyma in all CVOs. The results suggest that the BBB-free areas of the brain besides being constantly surveyed by blood-borne macrophages, possess an intrinsic immune surveillance system based on resting and activated microglial cells, which may function as a non-endothelial, cellular barrier against blood-borne pathogens.

    背景与目标: 大脑中的室间隔器官(CVO)没有血脑屏障(BBB),因此直接暴露于血浆成分和血源性病原体。鉴于先前的研究表明这些器官的免疫能力存在差异,我们启动了本研究,以提供对松果体,视网膜后区域和分支下器官内免疫相关抗原的细胞表达的全面免疫组织化学分析。在所有CVO中,与补体受体3型免疫反应性小胶质细胞/巨噬细胞细胞形态相似的细胞亚群表达了主要的组织相容性复合物(MHC)II类抗原,白细胞常见抗原(LCA / CD45)以及CD4和ED1抗原。根据形态学标准,可以将表达MHC II类抗原的细胞分为经典的实质和血管周围分枝的小神经胶质细胞的主要群体,以及表现为散在的或成团的圆形巨噬细胞样细胞的少数群体。 CD4和ED1抗原通过两种细胞类型表达。 CD45优先由巨噬细胞样细胞表达。 MHC I类抗原在BBB保护区和BBB缺失区均由血管内皮表达,并在所有CVO中的整个BBB缺失实质中均呈格子状网络存在。结果表明,除了大脑中无血脑屏障的区域不断被血源性巨噬细胞检查外,还具有基于静止和活化的小胶质细胞的内在免疫监视系统,该系统可能起非内皮细胞屏障的作用。传播的病原体。

  • 【肝细胞癌患者中识别野生型p53衍生表位的CD8 T淋巴细胞频率增加与表位缺失肿瘤变体的存在相关。】 复制标题 收藏 收藏
    DOI:10.1002/ijc.22251 复制DOI
    作者列表:Cicinnati VR,Zhang X,Yu Z,Ferencik S,Schmitz KJ,Dworacki G,Kaczmarek E,Oldhafer K,Frilling A,Baba HA,Schmid KW,Grosse-Wilde H,Broelsch CE,DeLeo AB,Gerken G,Beckebaum S
    BACKGROUND & AIMS: :Wild-type (WT) sequence p53 peptides are attractive candidates for broadly applicable cancer vaccines. The aim of this study was to evaluate the potential of a WT p53-based immunotherapeutic approach for patients with hepatocellular carcinoma (HCC). Circulating CD8+ T cells specific for WT p53(149-157) and WT p53(264-272) HLA-A*0201 restricted epitopes were directly identified in the peripheral blood by the use of peptide/HLA-A2.1 tetramers in 24 HCC patients. Cytotoxic T lymphocyte (CTL) activity after WT p53 peptide-specific stimulation was assessed by analysis of granzyme B and interferon-gamma mRNA transcription, using a quantitative real-time polymerase chain reaction assay. Tumor immunophenotyping was performed to evaluate the p53 status, the expression of major histocompatibility complex (MHC) and costimulatory molecules in freshly isolated tumor cells. HCC patients exhibited significantly higher frequencies of WT p53-specific memory CD8+ T cells and stronger WT p53-specific CTL activity, when compared with healthy controls. Increased frequencies of p53-specific CD8+ T cells and their activity correlated with selective HLA-A2 allele loss and reduced costimulatory molecule expression of tumor cells. Moreover, augmented numbers of p53-specific T cells coincided with high MHC class II expression in tumor cells but were inversely related to the T status of the tumor node metastasis staging system. Our results indicate the existence of natural immunosurveillance and tumor immune evasion, involving a T cell response against WT p53 tumor antigen in patients with HCC. These findings may have important implications for the future development of cancer vaccines.
    背景与目标: :野生型(WT)序列p53肽是广泛应用的癌症疫苗的诱人候选物。这项研究的目的是评估肝细胞癌(HCC)患者基于WT p53的免疫治疗方法的潜力。通过在24 HCC中使用肽/HLA-A2.1四聚体直接在外周血中鉴定出对WT p53(149-157)和WT p53(264-272)HLA-A * 0201限制性表位具有特异性的循环CD8 T细胞耐心。 WT p53肽特异性刺激后的细胞毒性T淋巴细胞(CTL)活性通过使用实时定量聚合酶链反应测定的颗粒酶B和干扰素-γmRNA转录分析来评估。进行肿瘤免疫表型分析以评估新鲜分离的肿瘤细胞中p53的状态,主要组织相容性复合体(MHC)的表达和共刺激分子。与健康对照相比,HCC患者表现出明显更高的WT p53特异性记忆CD8 T细胞频率和更强的WT p53特异性CTL活性。 p53特异性CD8 T细胞的频率增加及其活性与选择性HLA-A2等位基因缺失和肿瘤细胞共刺激分子表达降低有关。此外,p53特异性T细胞数量的增加与肿瘤细胞中II类MHC的高表达相吻合,但与肿瘤淋巴结转移分期系统的T状态呈负相关。我们的结果表明,在肝癌患者中存在自然免疫监视和肿瘤免疫逃避,涉及针对WT p53肿瘤抗原的T细胞应答。这些发现可能对癌症疫苗的未来发展具有重要意义。

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