• 【人ADP-核糖基化因子5 (ARF5) 基因的定位和表征。】 复制标题 收藏 收藏
    DOI:10.1006/geno.1997.4689 复制DOI
    作者列表:McGuire RE,Daiger SP,Green ED
    BACKGROUND & AIMS: ADP-ribosylation factor 5 (ARF5) is a member of the ARF gene family. The ARF proteins stimulate the in vitro ADP-ribosyltransferase activity of cholera toxin and appear to play a role in vesicular trafficking in vivo. We have mapped ARF5, one of the six known mammalian ARF genes, to a well-defined yeast artificial chromosome contig on human chromosome 7q31.3. In addition, we have isolated and sequenced an approximately 3.2-kb genomic segment that contains the entire ARF5 coding region, revealing the complete intron-exon structure of the gene. With six coding exons and five introns, the genomic structure of ARF5 is unique among the mammalian ARF genes and provides insight about the evolutionary history of this ancient gene family.

    背景与目标: ADP-核糖基化因子5 (ARF5) 是ARF基因家族的成员之一。ARF蛋白刺激霍乱毒素的体外ADP-核糖基转移酶活性,并似乎在体内囊泡运输中起作用。我们已经将ARF5 (六个已知的哺乳动物ARF基因之一) 映射到人类7q31.3染色体上定义明确的酵母人工染色体重叠群。此外,我们已经分离并测序了包含整个ARF5编码区的约3.2 kb基因组片段,揭示了该基因的完整内含子-外显子结构。具有六个编码外显子和五个内含子,ARF5的基因组结构在哺乳动物ARF基因中是独特的,并提供了有关该古老基因家族进化历史的见解。
  • 【人类前额叶皮层和海马死后6型血清素受体 (5-HT6): 免疫组织化学和免疫荧光研究。】 复制标题 收藏 收藏
    DOI:10.1016/j.neuint.2012.11.013 复制DOI
    作者列表:Marazziti D,Baroni S,Pirone A,Giannaccini G,Betti L,Testa G,Schmid L,Palego L,Borsini F,Bordi F,Piano I,Gargini C,Castagna M,Catena-Dell'osso M,Lucacchini A
    BACKGROUND & AIMS: :Given the paucity of data on the distribution of serotonin (5-HT) receptors of type 6 (5-HT(6)) in the human brain, the aim of this study was to investigate their distribution in postmortem human prefrontal cortex, striatum and hippocampus by either immunohistochemical or immunofluorescence techniques. The brain samples were obtained from 6 subjects who had died for causes not involving primarily or secondarily the CNS. The 5-HT(6) receptor distribution was explored by the [(125)I]SB-258585 binding to brain membranes followed by immunohistochemical and immunofluorescence evaluations. A specific [(125)I]SB-258585 binding was detected in all the regions under investigation, whilst the content in the hippocampus and cortex being about 10-30 times lower than in the striatum. Immunohistochemistry and double-label immunofluorescence microscopy experiments, carried out in the prefrontal cortex and hippocampus only, since data in the striatum were already published, showed the presence of 5-HT(6) receptors in both pyramidal and glial cells of prefrontal cortex, while positive cells were mainly pyramidal neurons in the hippocampus. The heterogeneous distribution of 5-HT(6) receptors provides a preliminary explanation of how they might regulate different functions in different brain areas, such as, perhaps, brain trophism in the cortex and neuronal firing in the hippocampus. This study, taking into account all the limitations due to the postmortem model used, represents the starting point to explore the 5-HT(6) receptor functionality and its sub-cellular distribution.
    背景与目标: : 鉴于人脑中6型5-羟色胺 (5-HT(6)) 受体分布的数据很少,本研究的目的是通过免疫组织化学或免疫荧光技术研究其在死后人类前额叶皮层,纹状体和海马中的分布。大脑样本来自6名因不主要或次要涉及CNS的原因而死亡的受试者。5-羟色胺 (6) 受体分布通过 [(125)I]SB-258585与脑膜结合,然后进行免疫组织化学和免疫荧光评估来探索。在所研究的所有区域中检测到特定的 [(125)I]SB-258585结合,而海马和皮层的含量比纹状体低约10-30倍。免疫组织化学和双标记免疫荧光显微镜实验,仅在前额叶皮层和海马中进行,因为纹状体中的数据已经发表,显示在前额叶皮层的锥体和神经胶质细胞中都存在5-HT(6) 受体,而阳性细胞主要是海马中的锥体神经元。5-HT(6) 受体的异质分布提供了它们如何调节不同大脑区域的不同功能的初步解释,例如,也许,皮质中的脑营养和海马中的神经元放电。这项研究考虑到使用的死后模型所造成的所有局限性,代表了探索5-HT(6) 受体功能及其亚细胞分布的起点。
  • 【7,12-二甲基苯并 [a] 蒽 (DMBA) 的化学预防5-脂氧合酶抑制剂,藤黄酚引起的仓鼠颊袋致癌作用。】 复制标题 收藏 收藏
    DOI:10.1080/01635581.2012.718032 复制DOI
    作者列表:Chen X,Zhang X,Lu Y,Shim JY,Sang S,Sun Z,Chen X
    BACKGROUND & AIMS: :Our previous studies have shown that aberrant arachidonic acid metabolism, especially the 5-lipoxygenase (5-Lox) pathway, is involved in oral carcinogenesis and can be targeted for cancer prevention. To develop potent topical agents for oral cancer chemoprevention, 5 known 5-Lox inhibitors from dietary and synthetic sources (Zileuton, ABT-761, licofelone, curcumin, and garcinol) were evaluated in silico for their potential efficacy. Garcinol, a polyisoprenylated benzophenone from the fruit rind of Garcinia spp., was found to be a promising agent based on the calculation of a theoretical activity index. Computer modeling showed that garcinol well fit the active site of 5-Lox, and potentially inhibited enzyme activity through interactions between the phenolic hydroxyl groups and the non-heme catalytic iron. In a short-term study on 7,12-dimethylbenz[a]anthracene (DMBA)-treated hamster cheek pouch, topical garcinol suppressed leukotriene B4 (LTB4) biosynthesis and inhibited inflammation and cell proliferation in the oral epithelium. In a long-term carcinogenesis study, topical garcinol significantly reduced the size of visible tumors, the number of cancer lesions, cell proliferation, and LTB4 biosynthesis. These results demonstrated that topical application of a 5-Lox inhibitor, garcinol, had chemopreventive effect on DMBA-induced hamster cheek pouch carcinogenesis.
    背景与目标: : 我们以前的研究表明,异常的花生四烯酸代谢,尤其是5-脂氧合酶 (5-Lox) 途径,与口腔癌的发生有关,可以作为预防癌症的靶标。为了开发用于口腔癌化学预防的有效局部药物,在计算机上评估了饮食和合成来源的5种已知的5-Lox抑制剂 (Zileuton,ABT-761,licofelone,姜黄素和藤黄酚) 的潜在功效。根据理论活性指数的计算,发现藤黄酚是一种来自藤黄属果皮的聚异戊二烯化二苯甲酮,是一种有前途的试剂。计算机建模表明,藤酚非常适合5-Lox的活性位点,并通过酚羟基和非血红素催化铁之间的相互作用潜在地抑制了酶活性。在对7,12-二甲基苯并 [a] 蒽 (DMBA) 处理的仓鼠颊袋进行的短期研究中,外用藤黄酚抑制了白三烯B4 (LTB4) 的生物合成并抑制了口腔上皮的炎症和细胞增殖。在一项长期的致癌研究中,外用藤黄酚可显着减少可见肿瘤的大小,癌症病变的数量,细胞增殖和LTB4生物合成。这些结果表明,局部应用5-Lox抑制剂藤黄酚对DMBA诱导的仓鼠颊袋致癌具有化学预防作用。
  • 【在5-芳基乙内酰脲的胺衍生物中寻找对抗革兰氏阴性细菌的新工具。】 复制标题 收藏 收藏
    DOI:10.1016/j.bmc.2012.10.053 复制DOI
    作者列表:Handzlik J,Szymańska E,Alibert S,Chevalier J,Otrębska E,Pękala E,Pagès JM,Kieć-Kononowicz K
    BACKGROUND & AIMS: :A series of amine-alkyl derivatives of 5-arylidenehydantoin 3-21 was evaluated for their ability to improve antibiotic effectiveness in two strains of Gram-negative Enterobacter aerogenes: the reference strain (ATCC-13048) and the chloramphenicol-resistant derivative over-producing the AcrAB-TolC efflux pump (CM-64). Three antibiotics, chloramphenicol, nalidixic acid and sparfloxacin were used as markers of efflux pump activity. New compounds (5-16) were obtained within 3-4 step synthesis using Knoevenagel condensation, Mitsunobu reaction and microwave aided N-alkylation. Molecular modeling based structure-activity relationship (SAR) studies were performed. The most active compounds: (Z)-5-(4-(diethylamino)benzylidene)-3-(2-hydroxy-3-(4-(2-hydroxyethyl)piperazin-1-yl)propyl)imidazolidine-2,4-dione (14) and (Z)-5-(2,4-dimethoxybenzylidene)-3-(2-hydroxy-3-(isopropylamino)propyl)imidazolidine-2,4-dione (15) induced fourfold decrease of minimal inhibition concentration (MIC) of all tested antibiotics in the strain CM-64 overexpressing the AcrAB-TolC pump.
    背景与目标: : 评估了一系列5-亚芳基乙内酰脲3-21的胺-烷基衍生物在两种革兰氏阴性产气肠杆菌菌株中提高抗生素有效性的能力: 参考菌株 (ATCC-13048) 和耐氯霉素的衍生物过量生产AcrAB-TolC外排泵 (CM-64)。氯霉素,萘啶酸和司帕沙星三种抗生素被用作外排泵活性的标志物。使用Knoevenagel缩合,Mitsunobu反应和微波辅助N-烷基化在3-4步合成中获得了新化合物 (5-16)。进行了基于分子建模的构效关系 (SAR) 研究。最具活性的化合物 :( Z)-5-(4-(二乙氨基) 亚苄基)-3-(2-羟基-3-(4-(2-羟乙基) piperazin-1-yl) 丙基) imidazolidine-2,4-二酮 (14) 和 (Z)-5-(2,4-二甲氧基亚苄基)-3-(2-羟基-3-(异丙基氨基) 丙基) imidazolidine-2,4-二酮 (15) 导致CM-64过表达AcrAB-TolC泵的菌株中所有测试抗生素的最小抑制浓度 (MIC) 降低四倍。
  • 【使用5选择系列反应时间任务研究不同单胺递质和冲动控制的作用。】 复制标题 收藏 收藏
    DOI:10.1177/0269881112466182 复制DOI
    作者列表:Humpston CS,Wood CM,Robinson ES
    BACKGROUND & AIMS: :Previous studies have shown that drugs which block the reuptake of catecholamine neurotransmitters improve impulse control in diseases such as attention deficit hyperactivity disorder (ADHD). Serotonin-specific reuptake inhibitors (SSRI) lack efficacy in ADHD and have been linked to increased suicide risk. The present study investigated drugs with affinity for one or more of the monoamine reuptake transporters using the 5-choice serial reaction time task, a model of attention and impulsivity in rodents. We also tested the effects of the alpha(2)-adreoceptor antagonist, idazoxan and novel antidepressant, agomelatine, which both increase cortical noradrenaline concentrations through non-reuptake mechanisms. Improvements in impulse control were observed with venlafaxine, a serotonin and noradrenaline re-uptake inhibitor (SNRI) but not bupropion (dopamine and noradrenaline re-uptake inhibitor). Sibutramine (SNRI) reduced premature responses by ~50% at the highest dose tested but this was not significant. All three of the SSRIs tested reduced premature responding in a dose-dependent manner, although also slowed response and collection latencies. Neither idazoxan nor agomelatine significantly reduced premature responding, suggesting a lack of efficacy at the doses tested. None of the drugs tested improved attention in this task but sibutramine (SNRI), fluoxetine (SSRI) and paroxetine (SSRI) all increased omissions at the highest dose tested. These data suggest that the SNRIs and SSRIs reduce premature responding but tend to be less specific than noradrenaline specific reuptake inhibitors in this model. SSRIs did not induce any specific impairment in impulse control in this model.
    背景与目标: : 先前的研究表明,阻断儿茶酚胺神经递质再摄取的药物可改善注意力缺陷多动障碍 (ADHD) 等疾病的冲动控制。血清素特异性再摄取抑制剂 (SSRI) 在ADHD中缺乏疗效,并与自杀风险增加有关。本研究使用5选择系列反应时间任务 (啮齿动物的注意力和冲动性模型) 研究了对一种或多种单胺再摄取转运蛋白具有亲和力的药物。我们还测试了 α (2)-受体拮抗剂咪唑嗪和新型抗抑郁药阿戈米拉汀的作用,它们均通过非再摄取机制增加皮质去甲肾上腺素浓度。使用文拉法辛 (一种5-羟色胺和去甲肾上腺素再摄取抑制剂 (SNRI)) 但未使用安非他酮 (多巴胺和去甲肾上腺素再摄取抑制剂) 观察到冲动控制的改善。在测试的最高剂量下,西布曲明 (SNRI) 将过早反应降低约50%,但这并不显著。测试的所有三个ssri均以剂量依赖性方式减少了过早反应,尽管也减慢了反应和收集延迟。依达唑烷和阿戈米拉汀均未显着降低过早反应,表明在测试剂量下缺乏疗效。测试的药物均未提高此任务中的注意力,但西布曲明 (SNRI),氟西汀 (SSRI) 和帕罗西汀 (SSRI) 在测试的最高剂量下均增加了遗漏。这些数据表明,在该模型中,snri和SSRIs减少了过早反应,但特异性不如去甲肾上腺素特异性再摄取抑制剂。在该模型中,SSRIs不会在冲动控制中引起任何特定的损害。
  • 【具有AAAG重复序列的寡脱氧核苷酸通过抑制干扰素调节因子5途径显着减轻烧伤诱导的全身性炎症反应。】 复制标题 收藏 收藏
    DOI:10.2119/molmed.2016.00243 复制DOI
    作者列表:Xiao Y,Lu W,Li X,Zhao P,Yao Y,Wang X,Wang Y,Lin Z,Yu Y,Hua S,Wang L
    BACKGROUND & AIMS: :Previously, we showed that an oligodeoxynucleotide with AAAG repeats (AAAG ODN) rescued mice from fatal acute lung injury (ALI) induced by influenza virus and inhibited production of tumor necrosis factor-α (TNF-α) in the injured lungs. However, the underlying mechanisms remain to be elucidated. Upon the bioinformatic analysis revealing that the AAAG ODN is consensus to interferon regulatory factor 5 (IRF5) binding site in the cis-regulatory elements of proinflammatory cytokines, we tried to explore whether the AAAG ODN could attenuate burn injury induced systemic inflammatory responses via inhibiting IRF5 pathway. Using the mouse model with sterile systemic inflammation induced by burn injury, we found that AAAG ODN prolonged the life span of the mice, decreased the expression of IRF5 at injured skin, reduced the production of TNF-α and IL-6 in blood and injured skin, and attenuated the ALI. Furthermore, AAAG ODN could bind IRF5 and inhibit the nuclear translocation of IRF5 in THP-1 cells. The data suggested that the AAAG ODN could act as a cytoplasmic decoy capable of interfering the function of IRF5, and be developed as a drug candidate for the treatment of inflammatory diseases.
    背景与目标: : 以前,我们显示了具有AAAG重复序列 (AAAG ODN) 的寡脱氧核苷酸将小鼠从流感病毒诱导的致命急性肺损伤 (ALI) 中拯救出来,并抑制了受伤肺中肿瘤坏死因子-α (TNF-α) 的产生。然而,潜在的机制仍有待阐明。通过生物信息学分析揭示AAAG ODN与促炎细胞因子顺式调节元件中干扰素调节因子5 (IRF5) 结合位点是共识,我们试图探索AAAG ODN是否可以通过抑制IRF5途径减轻烧伤引起的全身炎症反应。利用烧伤诱导的无菌全身炎症小鼠模型,我们发现AAAG ODN延长了小鼠的寿命,降低了损伤皮肤处IRF5的表达,减少了血液和损伤皮肤中TNF-α 和IL-6的产生,并减弱了ALI。此外,AAAG ODN可以结合IRF5并抑制IRF5在THP-1细胞中的核易位。数据表明,AAAG ODN可以充当能够干扰IRF5功能的细胞质诱饵,并被开发为治疗炎症性疾病的候选药物。
  • 【设计和发现新的 (3S,5R)-5-[4-(2-氯苯基)-2,2-二甲基-5-氧代哌嗪-1-基] piperidine-3-carboxamides作为有效的肾素抑制剂。】 复制标题 收藏 收藏
    DOI:10.1016/j.bmcl.2012.09.103 复制DOI
    作者列表:Mori Y,Ogawa Y,Mochizuki A,Nakamura Y,Sugita C,Miyazaki S,Tamaki K,Matsui Y,Takahashi M,Nagayama T,Nagai Y,Inoue S,Nishi T
    BACKGROUND & AIMS: :Utilizing X-ray crystal structure analysis, (3S,5R)-5-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]piperidine-3-carboxamides were designed and identified as renin inhibitors. The most potent compound 15 demonstrated favorable pharmacokinetic and pharmacodynamic profiles in rat.
    背景与目标: : 利用x射线晶体结构分析,设计了 (3S,5R)-5-[4-(2-氯苯基)-2,2-二甲基-5-氧代哌嗪-1-基] piperidine-3-carboxamides,并鉴定为肾素抑制剂。最有效的化合物15在大鼠中显示出良好的药代动力学和药效学特征。
  • 【2-取代-4-(3 ',4',5 '-三甲氧基苯基)-5-芳基噻唑类抗癌剂的合成及生物学评价。】 复制标题 收藏 收藏
    DOI:10.1016/j.bmc.2012.10.001 复制DOI
    作者列表:Romagnoli R,Baraldi PG,Salvador MK,Camacho ME,Preti D,Tabrizi MA,Bassetto M,Brancale A,Hamel E,Bortolozzi R,Basso G,Viola G
    BACKGROUND & AIMS: :Antitumor agents that bind to tubulin and disrupt microtubule dynamics have attracted considerable attention in the last few years. To extend our knowledge of the thiazole ring as a suitable mimic for the cis-olefin present in combretastatin A-4, we fixed the 3,4,5-trimethoxyphenyl at the C4-position of the thiazole core. We found that the substituents at the C2- and C5-positions had a profound effect on antiproliferative activity. Comparing compounds with the same substituents at the C5-position of the thiazole ring, the moiety at the C2-position influenced antiproliferative activities, with the order of potency being NHCH(3) > Me > N(CH(3))(2). The N-methylamino substituent significantly improved antiproliferative activity on MCF-7 cells with respect to C2-amino counterparts. Increasing steric bulk at the C2-position from N-methylamino to N,N-dimethylamino caused a 1-2 log decrease in activity. The 2-N-methylamino thiazole derivatives 3b, 3d and 3e were the most active compounds as antiproliferative agents, with IC(50) values from low micromolar to single digit nanomolar, and, in addition, they are also active on multidrug-resistant cell lines over-expressing P-glycoprotein. Antiproliferative activity was probably caused by the compounds binding to the colchicines site of tubulin polymerization and disrupting microtubule dynamics. Moreover, the most active compound 3e induced apoptosis through the activation of caspase-2, -3 and -8, but 3e did not cause mitochondrial depolarization.
    背景与目标: : 与微管蛋白结合并破坏微管动力学的抗肿瘤剂在过去几年中引起了极大的关注。为了扩展我们对噻唑环作为combretastatin A-4中存在的顺式烯烃的合适模拟物的了解,我们将3,4,5-三甲氧基苯基固定在噻唑核的C4-position。我们发现C2-和C5-positions的取代基对抗增殖活性具有深远的影响。比较噻唑环C5-position具有相同取代基的化合物,C2-position部分影响抗增殖活性,效力顺序为NHCH(3)> Me> N(CH(3))(2)。相对于C2-amino对应物,N-甲基氨基取代基显着提高了MCF-7细胞的抗增殖活性。从N-甲基氨基到N,N-二甲基氨基C2-position的空间体积增加导致活性降低1-2对数。2-n-甲基氨基噻唑衍生物3b,3d和3e是作为抗增殖剂的最具活性的化合物,其IC(50) 值从低微摩尔到个位数纳摩尔,此外,它们在多药耐药细胞系中也具有活性过表达P-糖蛋白。抗增殖活性可能是由化合物与微管蛋白聚合的秋水仙碱位点结合并破坏微管动力学引起的。此外,活性最高的化合物3e通过激活caspase-2,-3和-8诱导细胞凋亡,但3e并未引起线粒体去极化。
  • 【N-{4-[5-(4-氟苯基)-3-methyl-2-methylsulfanyl-3H-imidazol-4-yl]-pyridin-2-yl}-乙酰胺 (CBS-3595),一种对tnf α 相关疾病具有活性的p38α MAPK/PDE-4双重抑制剂.】 复制标题 收藏 收藏
    DOI:10.1021/acs.jmedchem.6b01647 复制DOI
    作者列表:Albrecht W,Unger A,Bauer SM,Laufer SA
    BACKGROUND & AIMS: :The anti-inflammatory potential of p38 mitogen-activated protein kinase (MAPK) inhibitors was coincidentally expanded to a dual inhibition of p38α MAPK and phosphodiesterase 4 (PDE4), and the potential benefits arising from the blockage of both inflammation-related enzymes were thoroughly investigated. The most promising compound, CBS-3595 (1), was successively evaluated in in vitro experiments as well as in ex vivo and in vivo preclinical studies after administration of 1 to rodents, dogs, and monkeys. The resulting data clearly indicated a potent suppression of tumor necrosis factor alpha release. For reconfirming the findings of the animal studies when administering 1 to healthy human volunteers, a phase I clinical trial was conducted. Apart from further information regarding the pharmacokinetic and pharmacodynamic characteristics of 1, it was demonstrated that dual inhibition of p38α MAPK and PDE4 is able to synergistically attenuate the excessive anti-inflammatory response.
    背景与目标: : p38丝裂原活化蛋白激酶 (MAPK) 抑制剂的抗炎潜力被巧合地扩展为对p38α MAPK和磷酸二酯酶4 (PDE4) 的双重抑制,并且两种炎症相关酶的阻断所产生的潜在益处被彻底研究。在对啮齿动物,狗和猴子施用1之后,在体外实验以及体外和体内临床前研究中相继评估了最有希望的化合物CBS-3595 (1)。所得数据清楚地表明有效抑制了肿瘤坏死因子 α 的释放。为了在向健康的人类志愿者施用1时再次确认动物研究的结果,进行了I期临床试验。除了有关1的药代动力学和药效学特征的进一步信息外,还证明了p38α MAPK和PDE4的双重抑制能够协同减弱过度的抗炎反应。
  • 【5-HT(1B/D) 激动剂对CGRP诱导的野生型小鼠的光厌恶的调节。】 复制标题 收藏 收藏
    DOI:10.1523/JNEUROSCI.3265-12.2012 复制DOI
    作者列表:Kaiser EA,Kuburas A,Recober A,Russo AF
    BACKGROUND & AIMS: :The neuropeptide calcitonin gene-related peptide (CGRP) plays a critical role in the pathophysiology of migraine. We have focused on the role of CGRP in photophobia, which is a common migraine symptom. We previously used an operant-based assay to show that CGRP-sensitized transgenic (nestin/hRAMP1), but not control, mice exhibited light aversion in response to an intracerebroventricular CGRP injection. A key question was whether the transgenic phenotype was due to overexpression of the CGRP receptor at endogenous or novel expression sites. We reasoned that if endogenous receptor sites were sufficient for light-aversive behavior, then wild-type mice should also show the phenotype when given a sufficiently strong stimulus. In this study, we report that mice with normal levels of endogenous CGRP receptors demonstrate light avoidance following CGRP administration. This phenotype required the combination of two factors: higher light intensity and habituation to the testing chamber. Control tests confirmed that light aversion was dependent on coincident exposure to CGRP and light and cannot be fully explained by increased anxiety. Furthermore, CGRP reduced locomotion only in the dark, not in the light. Coadministration of rizatriptan, a 5-HT(1B/D) agonist anti-migraine drug, attenuated the effects of exogenous CGRP on light aversion and motility. This suggests that triptans can act by mechanisms that are distinct from inhibition of CGRP release. Thus, we demonstrate that activation of endogenous CGRP receptors is sufficient to elicit light aversion in mice, which can be modulated by a drug commonly used to treat migraine.
    背景与目标: : 神经肽降钙素基因相关肽 (CGRP) 在偏头痛的病理生理中起关键作用。我们关注CGRP在畏光中的作用,这是一种常见的偏头痛症状。我们以前使用基于操作的测定法来显示CGRP致敏的转基因 (nestin/hRAMP1),但不是对照,小鼠对脑室内CGRP注射表现出光厌恶。一个关键问题是转基因表型是否归因于CGRP受体在内源性或新型表达位点的过表达。我们认为,如果内源性受体位点足以引起光厌恶行为,那么当给予足够强的刺激时,野生型小鼠也应显示出表型。在这项研究中,我们报告了具有正常水平的内源性CGRP受体的小鼠在CGRP给药后表现出避免光的作用。这种表型需要两个因素的结合: 更高的光强度和测试室的习惯。对照测试证实,光厌恶取决于同时暴露于CGRP和光,不能用焦虑增加来完全解释。此外,CGRP仅在黑暗中而不是在光线中减少运动。利扎曲普坦是一种5-HT(1B/D) 激动剂抗偏头痛药物,可减轻外源性CGRP对光厌恶和运动的影响。这表明曲坦类药物可以通过不同于抑制CGRP释放的机制起作用。因此,我们证明内源性CGRP受体的激活足以引起小鼠的光厌恶,这可以通过通常用于治疗偏头痛的药物来调节。
  • 【从苏里南筛选药用植物的5-HT(1A) 配体: 从番荔叶果实中筛选具有生物活性的异喹啉生物碱。】 复制标题 收藏 收藏
    DOI:10.1016/S0944-7113(97)80059-1 复制DOI
    作者列表:Hasrat JA,Pieters L,De Backer JP,Vauquelin G,Vlietinck AJ
    BACKGROUND & AIMS: :Plants from Suriname (South-America) and several Annona species, including A. muricata, A. ckerimolia, A. montana and A. glabra were screened for 5-HT(1A) receptor binding activity by ligand-binding-studies (LBS). Crude extracts of all Annona species and from Hibiscus bifurcatus, Irlbarchia purpurascens and Scoparia dulcis showed high activity. The isoquinoline alkaloids asimilobine (1), nornuciferine (2), and annonaine (3) were isolated as the active principles from the fruit of Annona muricata. These results may partially explain the use of Hibiscus bifurcatus and Annona muricata in traditional medicine in Suriname.
    背景与目标: : 通过配体结合研究 (LBS) 筛选了苏里南 (南美) 的植物和几种番荔叶物种,包括A. muricata,A. ckerimolia,A. montana和A. glabra的5-HT(1A) 受体结合活性。所有番荔叶物种的粗提物以及木槿,紫菜和紫菜的粗提物均显示出很高的活性。从番荔叶果实中分离出异喹啉生物碱asimilobine (1),去甲钙碱 (2) 和番荔碱 (3) 作为活性成分。这些结果可能部分解释了苏里南传统医学中芙蓉和番荔叶的使用。
  • 【环氧合酶/5-脂氧合酶双重抑制剂tepoxalin对NSAID诱导的胃肠道炎症相关事件的影响。】 复制标题 收藏 收藏
    DOI:10.1016/s0952-3278(97)90593-7 复制DOI
    作者列表:Kirchner T,Aparicio B,Argentieri DC,Lau CY,Ritchie DM
    BACKGROUND & AIMS: Prostaglandins and thromboxanes are products of arachidonic acid metabolism via the cyclooxygenase (CO) enzyme and are responsible for the pain and swelling common to sites of inflammation. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the production of these substances and are used in the treatment of inflammatory diseases such as arthritis. However, one of the major side-effects of NSAID therapy is gastric ulceration. It is possible that inhibition of prostaglandin production and a related increase in the formation of leukotrienes via the 5-lipoxygenase (5-LO) enzymatic pathway are responsible for attracting inflammatory cells, causing local sites of inflammation and producing ulceration. To determine the effects of 5-LO inhibition on this hypothesis, studies were performed in rats to evaluate the effects of tepoxalin, a dual CO/LO inhibitor on leukotriene B4 levels in gastric mucosa and neutrophil adhesion in mesenteric venules. In rats, chronic oral administration of an NSAID, indomethacin (2 mg/kg daily over 4 days), resulted in 40% mortality, accompanied by intestinal adhesions and perforations when evaluated 24 h after the fourth dose of drug. Additionally, neutrophil adhesion was increased in the mesenteric venules and cell infiltration was evident in the mesenteric interstitium. These gastrointestinal side-effects were inhibited in a separate group of rats administered tepoxalin (20 mg/kg, p.o) 30 min prior to each daily indomethacin treatment. Further studies were performed to determine tepoxalin's effects on early events associated with NSAID-induced gastrointestinal inflammation, including neutrophil adhesion, lipid peroxide generation and LTB4 production. Indomethacin (100 mg/kg, p.o.) produced elevated levels of LTB4 in rat gastric mucosa 90 min after administration. Additionally, neutrophil adhesion in mesenteric venules was increased at this dose and with the administration of another NSAID, naproxen. No generation of lipid peroxides was evident in the gastric mucosa at this timepoint. Tepoxalin (up to 400 mg/kg, p.o.) did not have an effects on gastric mucosal LTB4 generation and lipid peroxide levels. A decrease in neutrophil adhesion was observed at the highest dose. In another study, pretreatment with tepoxalin (ED50=7.5 mg/kg, p.o.) or the selective 5-LO inhibitor zileuton (100 mg/kg, p.o.) prevented the increases in gastric mucosal LTB4 levels and neutrophil adhesion induced by indomethacin (100 mg/kg, p.o.). These data suggest that LO inhibition may play a vital role in the prevention of NSAID-induced gastric inflammation, providing insight into the lack of ulcerogenicity with tepoxalin and new approaches to anti-inflammatory therapy which may prevent gastric side effects.

    背景与目标: 前列腺素和血栓烷是花生四烯酸通过环氧合酶 (CO) 酶代谢的产物,并负责炎症部位常见的疼痛和肿胀。非甾体抗炎药 (NSAIDs) 抑制这些物质的产生,并用于治疗炎症性疾病,例如关节炎。然而,NSAID治疗的主要副作用之一是胃溃疡。通过5-脂氧合酶 (5-LO) 酶途径抑制前列腺素的产生和白三烯形成的相关增加可能导致吸引炎症细胞,引起局部炎症部位并产生溃疡。为了确定5-LO抑制对该假设的影响,在大鼠中进行了研究,以评估tepoxalin (一种双重CO/LO抑制剂) 对胃粘膜中白三烯B4水平和肠系膜小静脉中性粒细胞粘附的影响。在大鼠中,长期口服NSAID吲哚美辛 (在4天内每天2 mg/kg) 导致40% 死亡率,并在第四剂药物后24小时评估时伴有肠粘连和穿孔。此外,肠系膜小静脉中的中性粒细胞粘附增加,肠系膜间质中的细胞浸润明显。在每天吲哚美辛治疗前30分钟,在单独的大鼠组中抑制了这些胃肠道副作用。进行了进一步的研究以确定tepoxalin对与NSAID诱导的胃肠道炎症相关的早期事件的影响,包括中性粒细胞粘附,脂质过氧化物生成和LTB4生成。给药90分钟后,吲哚美辛 (100 mg/kg,p.o.) 在大鼠胃粘膜中产生升高的LTB4水平。此外,在该剂量下以及使用另一种NSAID萘普生时,肠系膜小静脉中的中性粒细胞粘附增加。此时,胃粘膜中没有明显的脂质过氧化物生成。Tepoxalin (最高400 mg/kg,p.o.) 对胃粘膜LTB4的生成和脂质过氧化物水平没有影响。在最高剂量下观察到中性粒细胞粘附减少。在另一项研究中,用tepoxalin (ED50 = 7.5 mg/kg,p.o.) 或选择性5-LO抑制剂zileuton (100 mg/kg,p.o.) 进行预处理可防止胃粘膜LTB4水平升高和中性粒细胞粘附由吲哚美辛 (100 mg/kg,p、o.)。这些数据表明,LO抑制作用可能在预防NSAID诱导的胃部炎症中起着至关重要的作用,从而深入了解tepoxalin缺乏溃疡性以及可能预防胃副作用的抗炎治疗的新方法。
  • 【5-羟色胺5-HT(2A) 受体激活通过磷脂酶c依赖性机制诱导2-花生四烯基甘油释放。】 复制标题 收藏 收藏
    DOI:10.1111/j.1471-4159.2006.04173.x 复制DOI
    作者列表:Parrish JC,Nichols DE
    BACKGROUND & AIMS: :To date, several studies have demonstrated that phospholipase C-coupled receptors stimulate the production of endocannabinoids, particularly 2-arachidonoylglycerol. There is now evidence that endocannabinoids are involved in phospholipase C-coupled serotonin 5-HT(2A) receptor-mediated behavioral effects in both rats and mice. The main objective of this study was to determine whether activation of the 5-HT(2A) receptor leads to the production and release of the endocannabinoid 2-arachidonoylglycerol. NIH3T3 cells stably expressing the rat 5-HT(2A) receptor were first incubated with [(3)H]-arachidonic acid for 24 h. Following stimulation with 10 mum serotonin, lipids were extracted from the assay medium, separated by thin layer chromatography, and analyzed by liquid scintillation counting. Our results indicate that 5-HT(2A) receptor activation stimulates the formation and release of 2-arachidonoylglycerol. The 5-HT(2A) receptor-dependent release of 2-arachidonoylglycerol was partially dependent on phosphatidylinositol-specific phospholipase C activation. Diacylglycerol produced downstream of 5-HT(2A) receptor-mediated phospholipase D or phosphatidylcholine-specific phospholipase C activation did not appear to contribute to 2-arachidonoylglycerol formation in NIH3T3-5HT(2A) cells. In conclusion, our results support a functional model where neuromodulatory neurotransmitters such as serotonin may act as regulators of endocannabinoid tone at excitatory synapses through the activation of phospholipase C-coupled G-protein coupled receptors.
    背景与目标: : 迄今为止,一些研究表明磷脂酶C偶联受体刺激内源性大麻素的产生,特别是2-花生四烯基甘油。现在有证据表明,内源性大麻素在大鼠和小鼠中均参与磷脂酶C偶联5-羟色胺 (2A) 受体介导的行为作用。这项研究的主要目的是确定5-HT(2A) 受体的激活是否导致内源性大麻素2-花生四烯基甘油的产生和释放。首先将稳定表达大鼠5-HT(2A) 受体的NIH3T3细胞与 [(3)H]-花生四烯酸孵育24小时。用10 mum 5-羟色胺刺激后,从测定培养基中提取脂质,通过薄层色谱分离,并通过液体闪烁计数进行分析。我们的结果表明,5-HT(2A) 受体激活刺激2-花生四烯基甘油的形成和释放。2-花生四烯基甘油的5-HT(2A) 受体依赖性释放部分依赖于磷脂酰肌醇特异性磷脂酶C活化。在5-HT(2A) 受体介导的磷脂酶D或磷脂酰胆碱特异性磷脂酶C激活下游产生的二酰基甘油似乎没有促进NIH3T3-5HT(2A) 细胞中2-花生四烯基甘油的形成。总之,我们的结果支持了一种功能模型,其中神经调节神经递质 (例如5-羟色胺) 可以通过激活磷脂酶C偶联g蛋白偶联受体在兴奋性突触中充当内源性大麻素调的调节剂。
  • 【选择性5-HT再摄取抑制剂与5-HT1A和5-HT1B受体拮抗剂联合使用对体内大鼠额叶皮层细胞外5-HT的影响。】 复制标题 收藏 收藏
    DOI:10.1038/sj.bjp.0701235 复制DOI
    作者列表:Sharp T,Umbers V,Gartside SE
    BACKGROUND & AIMS: 1. Selective 5-hydroxytryptamine (5-HT; serotonin) reuptake inhibitors (SSRIs) cause a greater increase in extracellular 5-HT in the forebrain when the somatodendritic 5-HT1A autoreceptor is blocked. Here, we investigated whether blockade of the terminal 5-HT1B autoreceptor influences a selective 5-HT reuptake inhibitor in the same way, and whether there is an additional effect of blocking both the 5-HT1A and 5-HT1B autoreceptors. 2. Extracellular 5-HT was measured in frontal cortex of the anaesthetized rat by use of brain microdialysis. In vivo extracellular recordings of 5-HT neuronal activity in the dorsal raphe nucleus (DRN) were also carried out. 3. The selective 5-HT reuptake inhibitor, paroxetine (0.8 mg kg-1, i.v.), increased extracellular 5-HT about 2 fold in rats pretreated with the 5-HT1A receptor antagonist, WAY100635. When administered alone neither paroxetine (0.8 mg kg-1, i.v.) nor WAY100635 (0.1 mg kg-1, i.v.) altered extracellular 5-HT levels. 4. Paroxetine (0.8 mg kg-1, i.v.) did not increase 5-HT in rats pretreated with the 5-HT1B/D receptor antagonist, GR127935 (1 mg kg-1, i.v.). GR127935 (1 and 5 mg kg-1, i.v.) had no effect on extracellular 5-HT when administered alone. 5. Interestingly, paroxetine (0.8 mg kg-1, i.v.) caused the greatest increase in 5-HT (up to 5 fold) when GR127935 (1 or 5 mg kg-1, i.v.) was administered in combination with WAY100635 (0.1 mg kg-1, i.v.). Administration of GR127935 (5 mg kg-1, i.v.) plus WAY100635 (0.1 mg kg-1, i.v.) without paroxetine, had no effect on extracellular 5-HT in the frontal cortex. 6. Despite the lack of effect of GR127935 on 5-HT under basal conditions, when 5-HT output was elevated about 3 fold (by adding 1 microM paroxetine to the perfusion medium), the drug caused a dose-related (1 and 5 mg kg-1, i.v.) increase in 5-HT. 7. By itself, GR127935 slightly but significantly decreased 5-HT cell firing in the DRN at higher doses (2.0-5.0 mg kg-1, i.v.), but did not prevent the inhibition of 5-HT cell firing induced by paroxetine. 8. In summary, our results suggest that selective 5-HT reuptake inhibitors may cause a large increase in 5-HT in the frontal cortex when 5-HT autoreceptors on both the somatodendrites (5-HT1A) and nerve terminals (5-HT1B) are blocked. This increase is greater than when either set of autoreceptors are blocked separately. The failure of a 5-HT1B receptor antagonist alone to enhance the effect of the selective 5-HT reuptake inhibitor in our experiments may be related to a lack of tone on the terminal 5-HT1B autoreceptor due to a continued inhibition of 5-HT cell firing. These results are discussed in relation to the use of 5-HT autoreceptor antagonists to augment the antidepressant effect of selective 5-HT reuptake inhibitors.

    背景与目标: 1.选择性5-羟色胺 (5-HT; 5-羟色胺) 再摄取抑制剂 (SSRIs) 在体细胞肌腱5-HT1A自身受体受阻时,会导致前脑细胞外5-HT的增加。在这里,我们研究了末端5-HT1B自身受体的阻断是否以相同的方式影响选择性5-HT再摄取抑制剂,以及是否存在阻断5-HT1A和5-HT1B自身受体的附加作用。2.使用脑微透析在麻醉的大鼠额叶皮层中测量细胞外5-HT。还进行了中缝背核 (DRN) 中5-HT神经元活性的体内细胞外记录。3.在用5-HT1A受体拮抗剂way100635预处理的大鼠中,选择性5-HT再摄取抑制剂帕罗西汀 (0.8 mg kg-1,i.v.) 使细胞外5-HT增加约2倍。当单独给药时,帕罗西汀 (0.8 mg kg-1,静脉注射) 和WAY100635 (0.1 mg kg-1,静脉注射) 都不会改变细胞外5-HT水平。4.在用5-HT1B/D受体拮抗剂GR127935 (1 mg kg-1,i.v.) 预处理的大鼠中,帕罗西汀 (0.8 mg kg-1,i.v.) 不增加5-HT。GR127935 (1和5 mg kg-1,静脉注射) 单独给药时对细胞外5-HT没有影响。5.有趣的是,当GR127935 (1或5 mg kg-1,静脉注射) 与WAY100635 (0.1 mg kg-1,静脉注射) 联合给药时,帕罗西汀 (0.8 mg kg-1,静脉注射) 引起5-HT的最大增加 (高达5倍)。i.v.)。施用GR127935 (5 mg kg-1,i.v.) 加WAY100635 (0.1 mg kg-1,i.v.) 而不使用帕罗西汀,对额叶皮层的细胞外5-HT没有影响。6.尽管在基础条件下GR127935对5-HT缺乏作用,但当5-HT输出量增加约3倍 (通过向灌注培养基中添加1 microM帕罗西汀) 时,药物导致5-HT剂量相关 (1和5 mg kg-1,静脉注射) 增加。7.就其本身而言,GR127935在较高剂量 (2.0-5.0 mg kg-1,i.v.) 下略微但显著降低DRN中的5-HT细胞放电,但没有阻止帕罗西汀诱导的5-HT细胞放电的抑制。8.总之,我们的结果表明,选择性5-HT再摄取抑制剂可能会导致额叶皮层5-HT大量增加,当体突肌 (5-HT1A) 和神经末梢 (5-HT1B) 上的5-HT自身受体被阻断。此增加大于单独阻塞任一组自身感受器时的增加。在我们的实验中,单独的5-HT1B受体拮抗剂未能增强选择性5-HT再摄取抑制剂的作用,这可能与由于持续抑制5-HT1B自身受体而导致末端5-HT1B自身受体缺乏音调有关。ht细胞放电。讨论了这些结果,这些结果与使用5-HT自身受体拮抗剂来增强选择性5-HT再摄取抑制剂的抗抑郁作用有关。
  • 【多巴和5-s-半胱氨酸多巴在色素细胞中的细胞内分布,色素形成最小。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Agrup G,Hansson C,Rorsman H,Rosengren AM,Rosengren E
    BACKGROUND & AIMS: The hypothesis that only melanosomal catecholic amino acids contribute to melanin formation was tested by studying adult bovine eyes in which pigment synthesis is considered to be low or absent. Dopa and 5-S-cysteinyldopa were investigated in different cell fractions of the choroid and retinal pigment epithelium of cattle. Most of the dopa and 5-S-cysteinyldopa was found in the cytoplasm and very little in the large granule fraction. The presence of cysteinyldopa in the adult eye is evidence of tyrosinase activity, but the catechol amino acids in the cytoplasm probably do not give rise to melanin formation. It is assumed that they instead are excreted from the cells.

    背景与目标: 通过研究认为色素合成低或缺乏的成年牛眼,检验了只有黑色素体儿茶酸氨基酸有助于黑色素形成的假说。在牛的脉络膜和视网膜色素上皮的不同细胞部分中研究了多巴和5-s-半胱氨酰多巴。大多数多巴和5-s-半胱氨酰多巴在细胞质中发现,而在大颗粒部分中很少发现。成年眼睛中半胱氨酰多巴的存在是酪氨酸酶活性的证据,但是细胞质中的邻苯二酚氨基酸可能不会引起黑色素的形成。假设它们是从细胞中排泄出来的。

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