BACKGROUND & AIMS: :A retrospective study of male breast cancer was undertaken at Ouagadougou University Teaching Hospital over a 3 year period (1993-1996). Authors report 5 cases representing 4.16% of all breast cancers. The patients' mean age was 61 years. The average duration of signs and symptoms before the diagnosis was 13 months. Clinically all the 5 cases presented advanced cancers (4 T4N2M0, 1 T4N2M1 according to UICC TNM System) with size ranging from 5.5, to 11.5 cm. Histology found: 2 medullary infiltrating carcinoma, 1 canalar infiltrating carcinoma, 1 colloid mucous carcinoma and 1 lobular infiltrating carcinoma. All patients had mastectomy associated with axillary clearance in 4 cases. Radiotherapy, chemotherapy and hormonotherapy were not associated because unavailable in Burkina Faso. Three patients died: the first, 10 days after surgical treatment and the 2 others respectively after 14 and 17 months. We have lost sight 1 patients. The last one is still alive. Authors find that to get better prognosis, it is important to improve medical and technical means, to increase information and to promote early detection.

背景与目标： : 在瓦加杜古大学教学医院进行了为期3年 (1993-1996年) 的男性乳腺癌回顾性研究。作者报告了5例代表所有乳腺癌4.16% 的病例。患者的平均年龄为61岁。诊断前症状和体征的平均持续时间为13个月。临床上所有5例均表现为晚期癌症 (根据UICC TNM系统，4个T4N2M0，1个T4N2M1)，大小从5.5到11.5厘米。组织学发现: 髓质浸润性癌2例，管内浸润性癌1例，胶体粘液性癌1例，小叶浸润性癌1例。所有患者均行乳房切除术伴腋窝清除4例。放疗，化疗和激素治疗不相关，因为在布基纳法索不可用。3例患者死亡: 手术治疗后第1、10天，另外2例分别在14和17个月后死亡。我们已经看不见1个病人了。最后一个还活着。作者发现，要获得更好的预后，必须改善医疗和技术手段，增加信息并促进早期发现。

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： : 赛庚啶是一种对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，赛庚啶衍生物在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。

BACKGROUND & AIMS: A primer extension (toeprinting) assay was used to monitor selection by ribosomes of the first versus the second AUG codon as a function of introducing mutations on the 3' side (positions +4, +5 and +6) of the first AUG codon. Six different flanking codons starting with G (GCG, GCU, GCC, GCA, GAU and GGA) strongly augmented selection of AUG#1 when compared with matched mRNAs that had A or C instead of G in position +4. Augmentation by G in position +4 failed only when it was combined with U in position +5, as in the sequence augGUA. In contrast with the usual enhancing effect of introducing G in position +4, most mutations in position +5 had no discernible effect, as shown with the series augANA (where N = C, A, G or U) and the series augCNA. AUG codon recognition was also unaffected by mutations in position +6, as shown by testing four mRNAs that had augCCN as the start site. Thus the primary sequence context that augments the recognition of AUG start codons does not appear generally to extend beyond G in position +4. When the toeprinting assay was used with mRNAs that initiate translation at CUG instead of AUG, cugGAU was not recognized better than cugGGU, contradicting the hypothesis that initiation at non-AUG codons might be favored by A instead of G in position +5.

背景与目标： 引物延伸 (toeprinting) 测定法用于监测第一个AUG密码子与第二个AUG密码子的核糖体选择，这是在第一个AUG密码子的3' 侧 (位置4、5和6) 引入突变的函数。与在4位具有A或C而不是G的匹配mrna相比，以G开头的六个不同的侧翼密码子 (GCG，GCU，GCC，GCA，GAU和GGA) 强烈增强了AUG #1的选择。仅当G在位置4与U在位置5结合时，G的增强才失败，如序列augGUA所示。与通常在4位引入G的增强作用相反，5位的大多数突变没有明显的作用，如augANA系列 (其中N = C，A，G或U) 和augCNA系列所示。AUG密码子识别也不受6位突变的影响，如测试四个以augCCN为起始位点的mrna所示。因此，增强对AUG起始密码子的识别的主要序列上下文通常不会扩展到4位中的G以外。当toeprinting测定法与在CUG而不是AUG启动翻译的mrna一起使用时，cugGAU的识别并不比cugGGU更好，这与以下假设相矛盾: A而不是G在5位可能有利于非AUG密码子启动。

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。

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。

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。

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。

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。

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。

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。

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。

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。

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。

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。

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。