• 【谷氨酸拮抗剂在帕金森氏病动物模型中刺激基础和L-多巴诱导的运动活动。】 复制标题 收藏 收藏
    DOI:10.1016/s0149-7634(96)00039-5 复制DOI
    作者列表:Starr MS,Starr BS,Kaur S
    BACKGROUND & AIMS: In parkinsonism, glutamate pathways within the basal ganglia become overactive, leading to the suggestion that glutamate antagonists might possess antiparkinsonian qualities. This report examines the motor properties of antagonists of NMDA and AMPA-type glutamate receptors, as well as some inhibitors of glutamate release, in animal models of idiopathic Parkinson's disease. High affinity NMDA open-channel blockers (e.g. MK 801, phencyclidine), are highly potent antagonists with inconsistent antiakinetic and strong myorelaxant activity. Other compounds are better tolerated and are capable of relieving immobility and muscular rigidity by themselves (e.g. 1-aminoadamantanes, polyamine site antagonists, kappa agonists, riluzole). Yet others do not restore movements alone (e.g. dextromethorphan, ketamine), but may interact with and strengthen the antiparkinsonian action of L-DOPA (e.g. competitive NMDA and AMPA antagonists, lamotrigine). They may do this by potentiating dopaminergic behaviours mediated by D1 or D2 receptors, or by some other mechanism.

    背景与目标: 在帕金森氏症中,基底神经节内的谷氨酸途径变得过度活跃,导致暗示谷氨酸拮抗剂可能具有抗帕金森氏症的特性。本报告研究了特发性帕金森氏病动物模型中NMDA和AMPA型谷氨酸受体拮抗剂以及谷氨酸释放抑制剂的运动特性。高亲和力的NMDA开放通道阻滞剂 (例如MK 801,苯环利定) 是具有不一致的抗肌毒性和强的肌松弛活性的高效拮抗剂。其他化合物具有更好的耐受性,并且能够自行缓解不动和肌肉僵硬 (例如1-氨基金刚烷,多胺位点拮抗剂,κ 激动剂,利鲁唑)。还有其他人不能单独恢复运动 (例如右美沙芬,氯胺酮),但可能与L-DOPA的抗帕金森病作用相互作用并加强 (例如竞争性NMDA和AMPA拮抗剂,拉莫三嗪)。他们可以通过增强D1或D2受体或其他机制介导的多巴胺能行为来做到这一点。
  • 【在位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症和腹膜子宫内膜异位病变的妇女的在位子宫内膜中微血管密度,增殖活性和血管生成之间的可能关系。还研究了血清和腹膜液中血管内皮生长因子-A (vegf-a) 的水平是否反映了子宫内膜异位病变中这些参数的变化的问题。免疫组织化学分析了子宫内膜异位症妇女 (n = 25) 的在位子宫内膜和腹膜子宫内膜异位病变的活检标本以及无子宫内膜异位症妇女 (n = 14) 的在位子宫内膜的活检标本,其微血管密度,增殖活性,并在间质、腺体和血管中表达vegf-a及其受体血管内皮生长因子受体1和2 (VEGFR-1和VEGFR-2)。在腹膜液和血清中测量vegf-a浓度。子宫内膜异位症妇女的分泌期在位子宫内膜的微血管密度,腺上皮和内膜血管VEGFR-2中vegf-a的表达明显高于无子宫内膜异位症妇女。与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,并且显示出更高的VEGFR-2血管表达,并且在腹膜液和血清中伴有较高的vegf-a水平。总之,子宫内膜异位症妇女的在位子宫内膜中似乎存在血管生成活性失调,而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生成活性以及血清和腹膜液中较高的VEGF水平。
  • 【静息T细胞的促有丝分裂刺激会导致转录因子LSF的快速磷酸化并增加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) 结合由细胞生长信号调节的细胞启动子。我们在此证明,LSF-DNA结合活性通过诱导人外周血T淋巴细胞中的细胞生长而显着调节。在有丝分裂刺激这些细胞的15分钟内,lsf-dna结合活性水平增加了5倍。在整个间隔内,细胞核中LSF蛋白的水平保持恒定。然而,由于磷酸化,LSF的电泳迁移率迅速降低与DNA结合活性的增加有关。pp44 (ERK1) 在体内磷酸化的相同残基上体外磷酸化LSF,具体地在氨基酸位置291,如突变体分析所示。作为磷酸化与DNA结合活性之间因果关系的直接验证,用磷酸酶体外处理LSF既增加了蛋白质的电泳迁移率,又降低了LSF-DNA结合活性。随着T细胞从静止状态发展为复制状态,LSF-DNA结合活性的这种调节表明LSF活性在细胞生长过程中受到调节,并表明LSF调节生长反应性启动子。
  • 【苯巴比妥依赖性和退缩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) 依赖性和退缩大鼠大脑中谷氨酸受体的变化,即刻早期基因的表达以及AP-1的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参与。通过喂养混合药物的食物5周制备PB依赖性大鼠。放射自显影分析显示,N-甲基-d-天冬氨酸 (NMDA) 受体拮抗剂 [3H(+)-5-甲基-10,11-二氢-5H-二苯并 [a,D] cyclohepten-5,10-敏e (MK-801) 的结合,PB依赖性和24h撤回大鼠的大脑皮层显着增加。然而,[3h] MK-801在海马和 [3H]6-氰基-7-硝基喹喔啉-2结合,海马和大脑皮层中的3-二酮 (CNQX) 和 [3H] 海藻酸结合在两组中基本上没有变化。铅戒断发作后,海马和大脑皮层中c-fos mRNA的表达增加,大脑皮层中c-6月mRNA的表达增加。诱导c-MK-801可抑制fos和c-6月mRNA。此外,铅戒断增强了大脑中的AP-1 DNA结合活性。目前的发现表明,在铅戒断综合征的发展过程中,谷氨酸能神经传递的功能增强。
  • 【高分辨率计算机断层扫描对结节病炎症活性的非侵入性评估。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Oberstein A,von Zitzewitz H,Schweden F,Müller-Quernheim J
    BACKGROUND & AIMS: PURPOSE:The value of high resolution computed tomography (HR-CT) in the recognition of pathologic changes of the lung parenchyma, especially in the diagnosis of sarcoidosis, is well established. The importance of these findings in regard to the inflammatory activity is not sufficiently documented, also because a direct histologic correlation is seldom possible.

    METHOD:In a prospective study twenty-one patients with suspected or known sarcoidosis were evaluated. The diagnostic work up comprised the clinical examination, lung function tests, the radiological evaluation, including GH-CT, and bronchoscopy for bronchoalveolar lavage (BAL) and transbronchial biopsy.

    RESULTS:The comparison of the HR-CT findings, like pathologic appearance of the bronchovascular bundle and intraparenchymal nodules, with serologic and BAL-parameters yielded high correlation coefficients with the total cell count in BAL and sIL-2R, and moderate correlations with the lavage lymphocyte count and the activity markers, like T4/T8 ratio, IL-2R and HLA-DR expression.

    CONCLUSION:As a non invasive method, HR-CT depicts pathologic findings of the lung parenchyma which are associated with the inflammatory activity of sarcoidosis.

    背景与目标: 目的 : 高分辨率计算机断层扫描 (hr-ct) 在识别肺实质的病理变化,特别是在结节病的诊断中的价值已得到充分确立。这些发现在炎症活性方面的重要性尚未得到充分证明,这也是因为很少有直接的组织学相关性。
    方法 : 在一项前瞻性研究中,对21例疑似或已知结节病患者进行了评估。诊断工作包括临床检查,肺功能检查,放射学评估 (包括gh-ct) 以及支气管镜检查 (用于支气管肺泡灌洗 (BAL) 和经支气管活检)。
    结果 : hr-ct结果的比较,像支气管血管束和实质内结节的病理外观一样,血清学和BAL参数与BAL和sIL-2R的总细胞计数具有高相关系数,与灌洗淋巴细胞计数和活性标志物 (如T4/T8比率) 具有中等相关性,IL-2R和hla-dr表达。
    结论 : 作为一种非侵入性方法,hr-ct描述了与结节病的炎症活性相关的肺实质的病理发现。
  • 【通过微孔过滤测量的外周血中性粒细胞流变学很好地反映了白塞氏病的活动。】 复制标题 收藏 收藏
    DOI:10.1016/s0923-1811(97)00599-9 复制DOI
    作者列表:Iijima S,Otsuka F
    BACKGROUND & AIMS: Activated neutrophils take a long time to pass through a narrow lumen like a micropore, and are supposed to play a deteriorating effect on microcirculation. Although the activation of neutrophils has been demonstrated in Behçet's disease, nobody analyzes the clinical activity of the disease by means of the rheological measure of neutrophils activity. Using a micropore (pore diameter 5 microns) filtration technique, we measured the filtration time of peripheral blood neutrophils, as a rheological measure of their activity, in order to determine the clinical activity of Behçet's disease. Twenty-one patients with Behçet's disease and 14 healthy control individuals were enrolled in the study. Symptoms and signs exhibited in the patients led us to distinguish the Behçet's disease into inactive and active cases. The latter were further differentiated into cases with absent symptoms and with present symptoms. Neutrophil filtration times were 11.5 +/- 4.8 s in the active cases with present symptoms, which were significantly (P < 0.05) larger than those (7.4 +/- 1.9 s) in the active cases with absent symptoms. The latter filtration times were further significantly (P < 0.001) larger than values (3.7 +/- 1.3 s) in the inactive cases and also those (4.8 +/- 1.2 s) in control subjects. Furthermore, increases in the filtration time obtained immediately after the exposure of cells to the chemotactic peptide formyl-methionyl-leucyl-phenylalanine (FMLP10 nM) were significantly (P < 0.01) larger in the active cases with present symptoms than those in the active cases with absent symptoms. The latter were also larger, but not significantly, than those in the inactive cases, and were significantly (P < 0.01) larger than those in control subjects. The present results demonstrate that the micropore filtration method reflects well the rheological activity of neutrophils as well as the clinical status of Behçet's disease. This method is much better than the measurement of O2 production to differentiate between active cases with absent symptoms and inactive patients or even control individuals. Furthermore, it is more sensitive and useful than laboratory data like the CRP value or the number of peripheral blood neutrophils.

    背景与目标: 活化的中性粒细胞需要很长时间才能通过像微孔一样的狭窄管腔,并且应该对微循环起到恶化的作用。尽管在beh ç et病中已经证明了中性粒细胞的激活,但没有人通过中性粒细胞活性的流变学测量来分析该疾病的临床活性。使用微孔 (孔径5微米) 过滤技术,我们测量了外周血中性粒细胞的过滤时间,作为其活性的流变学指标,以确定白塞氏病的临床活性。21名beh ç et病患者和14名健康对照者参加了这项研究。患者表现出的症状和体征使我们将白塞氏病区分为不活跃和活跃的病例。后者进一步分为无症状和现有症状的病例。有症状的活动病例的中性粒细胞过滤时间为11.5 +/- 4.8 s,显著 (P < 0.05) 大于无症状的活动病例的中性粒细胞过滤时间 (7.4 +/- 1.9 s)。后者的过滤时间进一步显著 (P < 0.001) 大于非活性情况下的值 (3.7 +/- 1.3 s),也大于对照受试者中的值 (4.8 +/- 1.2 s)。此外,在细胞暴露于趋化肽甲酰基-甲硫酰基-亮氨酸-苯丙氨酸 (fmlp10nm) 后立即获得的过滤时间的增加在存在症状的活动病例中比在不存在症状的活动病例中显着 (P < 0.01) 大。后者也比不活跃的情况更大,但不显著,并且显著 (P < 0.01) 大于对照组。目前的结果表明,微孔过滤方法很好地反映了嗜中性粒细胞的流变活性以及白塞病的临床状况。此方法比O2产生的测量要好得多,可以区分无症状的活跃病例和不活跃的患者甚至对照组。此外,它比CRP值或外周血中性粒细胞数量等实验室数据更敏感和有用。
  • 【体外药物活性和药代动力学在预测抗分枝杆菌治疗有效性中的价值: 一项重要综述。】 复制标题 收藏 收藏
    DOI:10.1097/00000441-199706000-00008 复制DOI
    作者列表:Burman WJ
    BACKGROUND & AIMS: Marked increases in case rates of drug-resistant tuberculosis and nontuberculous mycobacterial infections have brought renewed urgency to the development of new treatment regimens for mycobacterial infections. Preclinical data, such as in vitro measures of drug activity and pharmacokinetics, are used in the design of new treatment regimens. This review surveys the extensive published clinical experience concerning the treatment of drug-susceptible tuberculosis to evaluate the use of these preclinical measures in predicting clinical outcomes of antimycobacterial therapy. In vitro measures of drug activity predict the potency of a drug to prevent the emergence of resistance to other antimycobacterial drugs but do not predict the sterilizing activity of a drug or the activity of drug combinations. In vitro measures of drug activity do not allow reliable predictions of the level at which an organism should be considered resistant. Assays of drug penetration in tissues and activity against intracellular bacilli add modestly to the predictive value of in vitro measures of drug activity but still do not predict sterilizing activity. In contrast, animal models of tuberculosis have predicted relative drug potency (including sterilizing activity), the efficacy of multidrug regimens, and the duration of therapy needed. Despite pharmacokinetic parameters that would suggest the need for multiple doses per day, all of the first-line antituberculous drugs are active when given as infrequently as twice weekly. It is difficult to predict the efficacy of therapy for an intracellular pathogen that has the capacity for dormancy. Better in vitro models are needed, particularly ones that predict sterilizing activity.

    背景与目标: 耐药结核病和非结核分枝杆菌感染的病例率显着增加,为开发新的分枝杆菌感染治疗方案带来了新的紧迫性。临床前数据,例如药物活性和药代动力学的体外测量,用于设计新的治疗方案。这篇综述调查了有关药物敏感结核病治疗的广泛已发表的临床经验,以评估这些临床前措施在预测抗细菌治疗临床结果中的应用。药物活性的体外测量可以预测药物的效力,以防止对其他抗细菌药物的耐药性出现,但不能预测药物的灭菌活性或药物组合的活性。药物活性的体外测量无法可靠地预测生物体应被认为具有抗性的水平。药物在组织中的渗透和对细胞内杆菌的活性的测定适度增加了药物活性的体外测量的预测值,但仍不能预测灭菌活性。相反,结核病的动物模型已经预测了相对的药物效力 (包括灭菌活性),多药疗法的功效以及所需的治疗持续时间。尽管药代动力学参数表明每天需要多次剂量,但所有一线抗结核药物在每周两次的情况下均具有活性。很难预测具有休眠能力的细胞内病原体的治疗效果。需要更好的体外模型,尤其是可以预测灭菌活性的模型。
  • 【神经元活动的同步促进单个大鼠新皮层神经元在早期发育中的存活。】 复制标题 收藏 收藏
    DOI:10.1111/j.1460-9568.1997.tb01449.x 复制DOI
    作者列表:Voigt T,Baier H,Dolabela de Lima A
    BACKGROUND & AIMS: Neural activity is thought to play a significant role during the development of the cerebral cortex. In this study, we examined the effects of global activity block or enhancement and the effects of patterned firing on the ability of cultured rat neocortical neurons to survive during the second week in vitro, beyond the beginning of synaptogenesis. Blockade of neuronal activity by adding tetrodotoxin (TTX) and increasing magnesium concentration in the medium strongly reduced the survival of cortical cells. Increasing neuronal activity by raising the external potassium concentration significantly improved the survival of cortical neurons. We postulated that in a developing neuronal network the survival of nerve cells is regulated by synaptically mediated events that involve changes in the intracellular calcium concentration. To examine this question further, we monitored the activity of the developing network by optically recording the intracellular calcium signals of many neurons simultaneously. These recordings show that in low magnesium neocortical neurons express synchronized oscillation of their intracellular calcium concentration. The ability of a network to synchronize the changes in intracellular calcium of multiple cells appeared gradually during the second week in culture, paralleled by both an increase in the synaptic density and a decline in the number of surviving neurons. By examining the fate of identified cells several days after a recording session, we found that those nerve cells that were co-activated with other neurons had a significantly higher chance to survive than cells that did not participate in synchronized events. These experiments demonstrate that during early cortical network development cortical neurons show synchronized firing activity and that the survival of neurons is at least partially dependent on this pattern of neuronal activity.

    背景与目标: 神经活动被认为在大脑皮层发育过程中起着重要作用。在这项研究中,我们研究了整体活动阻滞或增强的影响以及图案化放电对培养的大鼠新皮层神经元在体外第二周 (突触开始后) 存活的能力的影响。通过添加河豚毒素 (TTX) 和增加培养基中的镁浓度来阻断神经元活性,从而大大降低了皮质细胞的存活。通过提高外部钾浓度来增加神经元活性,显着改善了皮质神经元的存活。我们推测,在发育中的神经元网络中,神经细胞的存活受到突触介导的事件的调节,这些事件涉及细胞内钙浓度的变化。为了进一步研究这个问题,我们通过同时光学记录许多神经元的细胞内钙信号来监测发育网络的活动。这些记录表明,在低镁的新皮层神经元中,其细胞内钙浓度表达同步振荡。在培养的第二周,网络使多个细胞的细胞内钙的变化同步的能力逐渐出现,同时突触密度增加和存活神经元数量减少。通过在记录过程几天后检查已识别细胞的命运,我们发现与其他神经元共同激活的神经细胞比不参与同步事件的细胞存活的机会要高得多。这些实验表明,在早期皮质网络发育过程中,皮质神经元显示出同步的放电活动,并且神经元的存活至少部分取决于这种神经元活动模式。
  • 【一系列赛庚胺类似物的合成,对5-HT2A,5-HT2B和5-HT2C 5-羟色胺受体的亲和力和结构-活性关系。】 复制标题 收藏 收藏
    DOI:10.1248/cpb.45.842 复制DOI
    作者列表:Honrubia MA,Rodriguez J,Dominguez R,Lozoya E,Manaut F,Seijas JA,Villaverde MC,Calleja JM,Cadavid MI,Maayani S,Sanz F,Loza MI
    BACKGROUND & AIMS: :Cyproheptadine is a drug that shows high affinity for type 2 (5-HT2) receptors. We studied a series of compounds obtained by modification of the tricyclic system of Cyp (dibenzocycloheptadiene): 2f (thioxanthene), 2g (xanthene), 2h (dihydrodibenzocycloheptadiene), 2j (diphenyl), 2i (fluorene), and 3b (phenylmethyl). Their activities at the rat cerebral cortex 5-HT2A receptor were (pKi +/- S.E.M.): 8.80 +/- 0.11 (Cyp), 8.60 +/- 0.07 (2f), 8.40 +/- 0.02 (2g), 8.05 +/- 0.03 (2h), 7.87 +/- 0.12 (2j), 6.70 +/- 0.02 (2i) and 6.45 +/- 0.02 (3b); those at the rat stomach fundus 5-HT2B receptor (pA2 +/- S.E.M.) were: 9.14 +/- 0.25 (Cyp), 8.49 +/- 0.07 (2f), 7.58 +/- 0.58 (2g), 7.02 +/- 0.14 (2h), 6.07 +/- 0.20 (2j), and undetectable (2i, 3b): and those at the pig choroidal plexus 5-HT2C receptor (pKi +/- S.E.M.) were: 8.71 +/- 0.08 (Cyp), 8.68 +/- 0.01 (2f), 8.58 +/- 0.20 (2g), 7.95 +/- 0.05 (2h), 7.57 +/- 0.04 (2j), 6.98 +/- 0.04 (2i) and 6.63 +/- 0.20 (3b). The slopes did not differ significantly from unity. The compounds exhibited the same order of activities at every type of receptor, and the most active molecules presented certain steric (butterfly conformation of the tricyclic system) and electrostatic (proton affinity on the top of the central rings) patterns. It is concluded that the activity of cyproheptadine derivatives at 5-HT2 receptors is related to these molecular features, which make feasible a common disposition to interact with all three 5-HT2 subtypes.
    背景与目标: : 赛庚胺是一种对2型 (5-HT2) 受体显示高亲和力的药物。我们研究了通过修饰Cyp (二苯并环庚二烯) 的三环体系获得的一系列化合物: 2f (噻吩),2g (xanthene),2h (二氢二苯并环庚二烯),2j (二苯基),2i (芴) 和3b (苯基甲基)。它们在大鼠大脑皮层5-HT2A受体上的活性为 (pKi +/-s.e.M.): 8.80 +/- 0.11 (Cyp),8.60 +/- 0.07 (2f),8.40 +/- 0.02 (2g),8.05 +/- 0.03 (2h),7.87 +/- 0.12 (2j),6.70 +/- 0.02 (2i) 和6.45 +/- 0.02 (3b); 大鼠胃底5-HT2B受体 (pA2 +/-s.e.M.) 为: 9.14 +/- 0.25 (Cyp),8.49 +/- 0.07 (2f),7.58 +/- 0.58 (2g),7.02 +/- 0.14 (2h),6.07 +/- 0.20 (2j) 和不可检测 (2i,3b): 猪脉络丛5-HT2C受体 (pKi +/-s.e.M.) 为: 8.71 +/- 0.08 (Cyp),8.68 +/- 0.01 (2f),8.58 +/- 0.20 (2g),7.95 +/- 0.05 (2h) 、7.57 +/- 0.04 (2j) 、6.98 +/- 0.04 (2i) 和6.63 +/- 0.20 (3b)。坡度与统一没有显着差异。这些化合物在每种类型的受体上都表现出相同的活性顺序,并且最具活性的分子呈现某些空间 (三环系统的蝴蝶构象) 和静电 (中心环顶部的质子亲和力) 模式。结论是,赛庚胺衍生物在5-HT2受体上的活性与这些分子特征有关,这使得与所有三种5-HT2亚型相互作用的共同处置是可行的。
  • 【注意缺陷多动障碍可能与中枢脑源性神经营养因子活性降低有关: 临床和治疗意义。】 复制标题 收藏 收藏
    DOI:10.1016/j.mehy.2006.06.025 复制DOI
    作者列表:Tsai SJ
    BACKGROUND & AIMS: :Attention-deficit hyperactivity disorder (ADHD) is a common childhood psychiatric disorder. Despite intensive research efforts, the aetiology of ADHD remains unknown. Current evidence suggests that the aetiology of ADHD is heterogeneous, comprising of multiple factors. Recently, it has been proposed that brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, may be implicated in the pathogenesis of ADHD. This hypothesis is supported by recent genetic studies in ADHD. Drawing on findings from studies into the drugs for ADHD relating to central BDNF expression, hyperactivity in BDNF knockout mice, BDNF effects in midbrain dopaminergic function and the close association between BDNF and the dopamine transporter (an important molecule for ADHD pathogenesis), it is proposed here that decreased central BDNF, particularly in the midbrain region, may play an important role in the pathogenesis ADHD. This hypothesis may have some implications for clinical findings in ADHD (for example, the co-morbidity between ADHD and major depression), and provide a new direction for the development of medication for ADHD treatment.
    背景与目标: : 注意力缺陷多动障碍 (ADHD) 是一种常见的儿童精神疾病。尽管进行了大量研究,但ADHD的病因仍然未知。目前的证据表明,ADHD的病因是异质的,由多种因素组成。最近,有人提出,神经营养因子家族的成员脑源性神经营养因子 (BDNF) 可能与ADHD的发病机理有关。该假设得到了ADHD最近的遗传研究的支持。根据对ADHD药物的研究结果,该药物与中枢BDNF表达,BDNF基因敲除小鼠的活动过度,BDNF在中脑多巴胺能功能中的作用以及BDNF与多巴胺转运蛋白 (ADHD发病机理的重要分子) 之间的密切联系有关,在这里提出降低中枢BDNF,特别是在中脑区域,可能在ADHD的发病机理中起重要作用。该假设可能对ADHD的临床发现 (例如,ADHD与重度抑郁症之间的合并症) 具有一定的意义,并为ADHD治疗药物的发展提供了新的方向。
  • 【具有NMDA拮抗剂活性的天然衍生肽抑制神经病理性疼痛。】 复制标题 收藏 收藏
    DOI:10.1016/s0006-8993(97)00183-2 复制DOI
    作者列表:Siegan JB,Hama AT,Sagen J
    BACKGROUND & AIMS: :Chronic pain may result from hyperexcitability following activation of spinal NMDA receptors. A naturally-derived mammalian peptide, histogranin, may possess NMDA antagonist activity. This study explored the possibility that stable analog [Ser1]Histogranin (SHG) could reduce chronic pain. Neuropathic pain was induced using the chronic constriction injury model (CCI). Intrathecal injection of SHG markedly attenuated the hyperalgesia and allodynia resulting from CCI, nearly normalizing responses. These results suggest that the natural peptide histogranin may be a novel adjunct in neuropathic pain management.
    背景与目标: : 脊髓NMDA受体激活后过度兴奋可能导致慢性疼痛。天然衍生的哺乳动物肽组织蛋白可能具有NMDA拮抗剂活性。这项研究探讨了稳定的类似物 [Ser1] 组织蛋白 (SHG) 可以减轻慢性疼痛的可能性。使用慢性收缩损伤模型 (CCI) 诱发神经病理性疼痛。鞘内注射SHG可显着减轻由CCI引起的痛觉过敏和异常性疼痛,几乎使反应正常化。这些结果表明,天然肽组织粒蛋白可能是神经性疼痛管理的新型辅助手段。
  • 【牙龈卟啉单胞菌主动调节 β2整合素粘附活性并促进与巨噬细胞的结合和内化。】 复制标题 收藏 收藏
    DOI:10.1128/IAI.00784-06 复制DOI
    作者列表:Hajishengallis G,Wang M,Harokopakis E,Triantafilou M,Triantafilou K
    BACKGROUND & AIMS: :In monocytes, the fimbriae of the oral pathogen Porphyromonas gingivalis activate cross talk signaling from Toll-like receptor 2 (TLR2) to the beta2 integrin CD11b/CD18, leading to the induction of the high-affinity state of the latter receptor. CD14 plays an important role in this "inside-out" proadhesive pathway by binding fimbriae and facilitating the activation of TLR2 and phosphatidylinositol 3-kinase signaling. In its high-affinity state, CD11b/CD18 mediates monocyte adhesion to endothelial cells and transmigration to sites of infection. We have now shown that P. gingivalis fimbriae function as both an activator and a ligand of CD11b/CD18; thus, fimbriae proactively promote their own binding to monocytes. Indeed, treatments that interfered with fimbria-induced activation of CD11b/CD18 (i.e., blockade of CD14, TLR2, or phosphatidylinositol 3-kinase signaling) also suppressed the cell binding activity of fimbriae, which was largely inducible and CD11b/CD18 dependent. Development of a recombinant inside-out signaling system in Chinese hamster ovary cells confirmed the ability of fimbriae to activate CD14/TLR2 signaling and induce their own CD11b/CD18-dependent binding. Induction of this proadhesive pathway by P. gingivalis fimbriae appeared to take place in lipid rafts. Indeed, methyl-beta-cyclodextrin, a cholesterol-sequestering agent that disrupts lipid raft organization, was found to inhibit the fimbria-induced assembly of CD14/TLR2 signaling complexes and the activation of the high-affinity state of CD11b/CD18. Experiments using macrophages from mice deficient in various pattern recognition receptors indicated that the receptors involved in the inside-out proadhesive pathway (CD14, TLR2, and CD11b/CD18) are important for mediating P. gingivalis internalization within macrophages. It therefore appears that P. gingivalis proactively modulates beta2 integrin adhesive activity for intracellular uptake.
    背景与目标: : 在单核细胞中,口腔病原体牙龈卟啉单胞菌的菌毛激活从Toll样受体2 (TLR2) 到 β2整合素CD11b/CD18的串扰信号,导致诱导后者受体的高亲和力状态。CD14通过结合菌毛并促进TLR2和磷脂酰肌醇3-激酶信号的激活,在这种 “由内而外” 的前粘附途径中起重要作用。在其高亲和力状态下,CD11b/CD18介导单核细胞与内皮细胞的粘附并转移到感染部位。我们现在已经证明,牙龈卟啉单胞菌菌毛既是CD11b/CD18的激活剂又是配体。因此,菌毛会主动促进其自身与单核细胞的结合。实际上,干扰菌毛诱导的CD11b/CD18激活 (即CD14,TLR2或磷脂酰肌醇3-激酶信号传导的阻断) 的治疗也抑制了菌毛的细胞结合活性,这在很大程度上是可诱导的并且CD11b/CD18依赖性。在中国仓鼠卵巢细胞中开发了重组的由内而外信号系统,证实了菌毛激活CD14/TLR2信号并诱导其自身CD11b/CD18-dependent结合的能力。牙龈卟啉单胞菌诱导这种前粘附途径似乎发生在脂质筏中。实际上,发现甲基-β-环糊精是一种破坏脂质筏组织的胆固醇螯合剂,可抑制菌毛诱导的CD14/TLR2信号复合物的组装以及CD11b/cd18高亲和力状态的激活。使用缺乏各种模式识别受体的小鼠的巨噬细胞进行的实验表明,参与由内而外的前粘附途径 (CD14,TLR2和CD11b/CD18) 的受体对于介导巨噬细胞内牙龈卟啉单胞菌内化很重要。因此,似乎牙龈卟啉单胞菌主动调节 β2整合素粘附活性以促进细胞内摄取。
  • 【用黄色荧光蛋白变体YFP-H148Q/I152L对碘化钠同向转运体活性的细胞成像。】 复制标题 收藏 收藏
    DOI:10.1152/ajpcell.00291.2006 复制DOI
    作者列表:Rhoden KJ,Cianchetta S,Stivani V,Portulano C,Galietta LJ,Romeo G
    BACKGROUND & AIMS: :The sodium iodide symporter (NIS) mediates iodide (I(-)) transport in the thyroid gland and other tissues and is of increasing importance as a therapeutic target and nuclear imaging reporter. NIS activity in vitro is currently measured with radiotracers and electrophysiological techniques. We report on the development of a novel live cell imaging assay of NIS activity using the I(-)-sensitive and genetically encodable yellow fluorescent protein (YFP) variant YFP-H148Q/I152L. In FRTL-5 thyrocytes stably expressing YFP-H148Q/I152L, I(-) induced a rapid and reversible decrease in cellular fluorescence characterized by 1) high affinity for extracellular I(-) (35 muM), 2) inhibition by the NIS inhibitor perchlorate, 3) extracellular Na(+) dependence, and 4) TSH dependence, suggesting that fluorescence changes are due to I(-) influx via NIS. Individual cells within a population of FRTL-5 cells exhibited a 3.5-fold variation in the rate of NIS-mediated I(-) influx, illustrating the utility of YFP-H148Q/I152L to detect cell-to-cell difference in NIS activity. I(-) also caused a perchlorate-sensitive decrease in YFP-H148Q/I152L fluorescence in COS-7 cells expressing NIS but not in cells lacking NIS. These results demonstrate that YFP-H148Q/I152L is a sensitive biosensor of NIS-mediated I(-) uptake in thyroid cells and in nonthyroidal cells following gene transfer and suggest that fluorescence detection of cellular I(-) may be a useful tool by which to study the pathophysiology and pharmacology of NIS.
    背景与目标: : 碘化钠同向转运体 (NIS) 介导碘 (I(-)) 在甲状腺和其他组织中的转运,作为治疗靶标和核成像报告基因的重要性日益提高。目前使用放射性示踪剂和电生理技术测量体外的NIS活性。我们报告了使用I(-) 敏感且可遗传编码的黄色荧光蛋白 (YFP) 变体YFP-H148Q/I152L对NIS活性进行新型活细胞成像测定的开发。在稳定表达YFP-H148Q/I152L的FRTL-5甲状腺细胞中,I(-) 诱导细胞荧光的快速和可逆降低,其特征是1) 对细胞外I(-) (35 muM) 的高亲和力,2) NIS抑制剂高氯酸盐的抑制,3) 细胞外Na(+) 依赖性,和4) TSH依赖性,表明荧光变化是由于I(-) 通过NIS流入所致。FRTL-5细胞群内的单个细胞表现出NIS介导的I(-) 流入速率的3.5倍变化,说明YFP-H148Q/I152L用于检测NIS活性的细胞间差异。I(-) 还导致表达NIS的COS-7细胞中YFP-H148Q/I152L荧光的高氯酸盐敏感降低,但在缺乏NIS的细胞中不引起。这些结果表明,YFP-H148Q/I152L是基因转移后甲状腺细胞和非甲状腺细胞中NIS介导的I(-) 摄取的敏感生物传感器,并表明细胞I(-) 的荧光检测可能是研究的有用工具。NIS的病理生理学和药理学。
  • 【尿激酶型纤溶酶原激活剂和基质金属蛋白酶在大肠癌中的活性和表达。】 复制标题 收藏 收藏
    DOI:10.1186/1471-2407-6-211 复制DOI
    作者列表:Kim TD,Song KS,Li G,Choi H,Park HD,Lim K,Hwang BD,Yoon WH
    BACKGROUND & AIMS: BACKGROUND:Matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and urokinase-type plasminogen activator (uPA) are involved in colorectal cancer invasion and metastasis. There is still debate whether the activity of MMP-2 and MMP-9 differs between tumors located in the colon and rectum. We designed this study to determine any differences in the expression of MMP-2, MMP-9 and uPA system between colon and rectal cancer tissues. METHODS:Cancer tissue samples were obtained from colon carcinoma (n = 12) and rectal carcinomas (n = 10). MMP-2 and MMP-9 levels were examined using gelatin zymography and Western blotting; their endogenous inhibitors, tissue inhibitor of metalloproteinase-2 (TIMP-2) and tissue inhibitor of metalloproteinase-1 (TIMP-1), were assessed by Western blotting. uPA, uPAR and PAI-1 were examined using enzyme-linked immunosorbent assay (ELISA). The activity of uPA was assessed by casein-plasminogen zymography. RESULTS:In both colon and rectal tumors, MMP-2, MMP-9 and TIMP-1 protein levels were higher than in corresponding paired normal mucosa, while TIMP-2 level in tumors was significantly lower than in normal mucosa. The enzyme activities or protein levels of MMP-2, MMP-9 and their endogenous inhibitors did not reach a statistically significant difference between colon and rectal cancer compared with their normal mucosa. In rectal tumors, there was an increased activity of uPA compared with the activity in colon tumors (P = 0.0266), however urokinase-type plasminogen activator receptor (uPAR) and plasminogen activator inhibitor-1 (PAI-1) showed no significant difference between colon and rectal cancer tissues. CONCLUSION:These findings suggest that uPA may be expressed differentially in colon and rectal cancers, however, the activities or protein levels of MMP-2, MMP-9, TIMP-1, TIMP-2, PAI-1 and uPAR are not affected by tumor location in the colon or the rectum.
    背景与目标:
  • 【快速荧光法测量pendrin (SLC26A4) Cl-/I-转运活性。】 复制标题 收藏 收藏
    DOI:10.1159/000095164 复制DOI
    作者列表:Dossena S,Rodighiero S,Vezzoli V,Bazzini C,Sironi C,Meyer G,Fürst J,Ritter M,Garavaglia ML,Fugazzola L,Persani L,Zorowka P,Storelli C,Beck-Peccoz P,Bottá G,Paulmichl M
    BACKGROUND & AIMS: :Malfunction of the SLC26A4 protein leads to Pendred syndrome, characterized by sensorineural hearing loss, often associated with mild thyroid dysfunction and goiter. It is generally assumed that SLC26A4 acts as a chloride/anion exchanger, which in the thyroid gland transports iodide, and in the inner ear contributes to the conditioning of the endolymphatic fluid. Here we describe a fast fluorometric method able to be used to functionally scrutinize SLC26A4 and its mutants described in Pendred syndrome. The validation of the method was done by functionally characterizing the chloride/iodide transport of SLC26A4, and a mutant, i.e. SLC26A4(S28R), which we previously described in a patient with sensorineural hearing loss, hypothyroidism and goiter. Using the fluorometric method we describe here we can continuously monitor and quantify the iodide or chloride amounts transported by the cells, and we found that the transport capability of the SLC26A4(S28R) mutant protein is markedly reduced if compared to wild-type SLC26A4.
    背景与目标: : SLC26A4蛋白的故障导致Pendred综合征,其特征是感音神经性听力损失,通常与轻度甲状腺功能障碍和甲状腺肿有关。通常认为SLC26A4充当氯化物/阴离子交换剂,在甲状腺中转运碘化物,在内耳中有助于调节内淋巴液。在这里,我们描述了一种快速荧光测量方法,该方法能够用于功能检查SLC26A4及其在Pendred综合征中描述的突变体。该方法的验证是通过功能表征SLC26A4的氯化物/碘化物转运和突变体即SLC26A4(S28R) 来完成的,我们先前在患有感音神经性听力损失,甲状腺功能减退和甲状腺肿的患者中进行了描述。使用我们在这里描述的荧光法,我们可以连续监测和定量细胞转运的碘化物或氯化物量,并且我们发现与野生型SLC26A4相比,SLC26A4(S28R) 突变蛋白的转运能力显着降低。

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