• 【鸡GATA-2和GATA-3的N端指是独立的序列特异性DNA结合结构域。】 复制标题 收藏 收藏
    DOI:10.1093/emboj/16.10.2874 复制DOI
    作者列表:Pedone PV,Omichinski JG,Nony P,Trainor C,Gronenborn AM,Clore GM,Felsenfeld G
    BACKGROUND & AIMS: The GATA family of vertebrate DNA binding regulatory proteins are expressed in diverse tissues and at different times of development. However, the DNA binding regions of these proteins possess considerable homology and recognize a rather similar range of DNA sequence motifs. DNA binding is mediated through two domains, each containing a zinc finger. Previous results have led to the conclusion that although in some cases the N-terminal finger can contribute to specificity and strength of binding, it does not bind independently, whereas the C-terminal finger is both necessary and sufficient for binding. Here we show that although this is true for the N-terminal finger of GATA-1, those of GATA-2 and GATA-3 are capable of strong independent binding with a preference for the motif GATC. Binding requires the presence of two basic regions located on either side of the N-terminal finger. The absence of one of these near the GATA-1 N-terminal finger probably accounts for its inability to bind. The combination of a single finger and two basic regions is a new variant of a motif that has been previously found in the binding domains of other finger proteins. Our results suggest that the DNA binding properties of the N-terminal finger may help distinguish GATA-2 and GATA-3 from GATA-1 and the other GATA family members in their selective regulatory roles in vivo.

    背景与目标: 脊椎动物DNA结合调节蛋白的GATA家族在不同的组织和发育的不同时间表达。但是,这些蛋白质的DNA结合区域具有相当大的同源性,并且可以识别相当相似范围的DNA序列基序。DNA结合通过两个结构域介导,每个结构域都包含一个锌指。先前的结果得出的结论是,尽管在某些情况下,N末端手指可以促进特异性和结合强度,但它不会独立结合,而C末端手指对于结合既必要又足够。在这里,我们表明,尽管对于GATA-1的N末端手指是正确的,但GATA-2和GATA-3的手指能够强烈独立结合,并且偏爱基序GATC。结合需要存在位于N末端手指两侧的两个基本区域。在GATA-1的N末端手指附近没有这些手指之一可能是其无法结合的原因。单个手指和两个基本区域的组合是基序的新变体,以前已在其他手指蛋白的结合域中发现。我们的结果表明,N末端手指的DNA结合特性可能有助于将GATA-2和GATA-3与GATA-1和其他GATA家族成员在体内的选择性调节作用区分开。
  • 【内源性BDNF和NT-3在调节皮质树突生长中的相反作用。】 复制标题 收藏 收藏
    DOI:10.1016/s0896-6273(00)80316-5 复制DOI
    作者列表:McAllister AK,Katz LC,Lo DC
    BACKGROUND & AIMS: :Neurons within each layer of cerebral cortex express multiple members of the neurotrophin family and their corresponding receptors. This multiplicity could provide functional redundancy; alternatively, different neurotrophins may direct distinct aspects of cortical neuronal growth and differentiation. By neutralizing endogenous neurotrophins in organotypic slices of developing cortex with Trk receptor bodies (Trk-IgGs), we found that BDNF and NT-3 oppose one another in regulating the dendritic growth of pyramidal neurons. In layer 4, both endogenous and exogenous NT-3 inhibited the dendritic growth stimulated by BDNF. In contrast, in layer 6 both endogenous and exogenous BDNF inhibited dendritic growth stimulated by NT-3. These antagonistic actions of endogenous BDNF and NT-3 provide a mechanism by which dendritic growth and retraction can be dynamically regulated during cortical development, and suggest that the multiple neurotrophins expressed in developing cortex represent distinct components of an extracellular signaling system for regulating dendritic growth.
    背景与目标: : 大脑皮层各层内的神经元表达神经营养蛋白家族的多个成员及其相应的受体。这种多样性可以提供功能冗余; 或者,不同的神经营养蛋白可能会指导皮质神经元生长和分化的不同方面。通过用Trk受体体 (Trk-igg) 中和发育中的皮层器官型切片中的内源性神经营养蛋白,我们发现BDNF和NT-3在调节锥体神经元的树突状生长方面相互对抗。在第4层中,内源性和外源性NT-3均抑制BDNF刺激的树突状生长。相反,在第6层中,内源性和外源性BDNF均抑制NT-3刺激的树突生长。内源性BDNF和NT-3的这些拮抗作用提供了一种机制,通过该机制可以在皮质发育过程中动态调节树突生长和收缩,并表明在发育中的皮质中表达的多种神经营养蛋白代表了调节树突生长的细胞外信号系统的不同成分。
  • 【设计为MMP-3抑制剂的2-邻苯二甲酰亚胺戊二酸类似物的硅铅系列初步研究。】 复制标题 收藏 收藏
    DOI:10.1021/ci0601362 复制DOI
    作者列表:Amin EA,Welsh WJ
    BACKGROUND & AIMS: :Matrix metalloproteinases (MMPs) have been the subject of intense research because of their roles in tumor metastasis and in the rise and spread of degenerative diseases such as osteo- and rheumatoid arthritis. A preliminary class of 140 druglike, small-molecule matrix metalloproteinase-3 inhibitors, intended as starting scaffolds for optimization and synthesis, has been designed in silico using a series of highly predictive three-dimensional quantitative structure-activity relationship models, including comparative molecular field analysis and comparative molecular similarity indices analysis, with docking and scoring. Thalidomide was chosen as the skeleton on which to base the new lead series, as it moderately inhibits MMP-3, is antiangiogenic, and lends itself easily to structural modifications. Most of the new compounds demonstrate medium to high predicted biological activity and good bioavailability as estimated by the octanol-water partition coefficient ClogP. Compound 102 in particular exhibits extremely favorable predicted activity against MMP-3; is moderately bioavailable; satisfies Lipinski's Rule of Five; and shows promise for further optimization, synthesis, and experimental evaluation as a potential adjunct anticancer or antirheumatic therapeutic.
    背景与目标: : 基质金属蛋白酶 (MMPs) 由于其在肿瘤转移以及退行性疾病 (如骨关节炎和类风湿性关节炎) 的兴起和传播中的作用而成为深入研究的主题。初步设计了140类药物小分子基质metalloproteinase-3抑制剂,作为优化和合成的起始支架,使用一系列高度预测性的三维定量构效关系模型,包括比较分子场分析和比较分子相似性指数分析,对接和得分。沙利度胺被选为新铅系列的骨架,因为它适度抑制MMP-3,具有抗血管生成作用,并且易于进行结构修饰。根据辛醇-水分配系数ClogP估计,大多数新化合物表现出中等至高的预测生物活性和良好的生物利用度。化合物102尤其表现出对MMP-3极其有利的预测活性; 具有适度的生物利用度; 满足Lipinski的五法则; 并显示出有望进一步优化,合成和实验评估作为潜在的辅助抗癌或抗风湿治疗剂。
  • 【嗜热的TIM桶酶的稳定性: 嗜热古细菌的吲哚-3-甘油磷酸合酶。】 复制标题 收藏 收藏
    DOI:10.1042/bj3230259 复制DOI
    作者列表:Andreotti G,Cubellis MV,Palo MD,Fessas D,Sannia G,Marino G
    BACKGROUND & AIMS: The stability and activity of indole-3-glycerol phosphate synthase from Sulfolobus solfataricus were studied as a function of pH and temperature. In this paper we focus on three points(1) the long-term stability of the protein to irreversible denaturation at high temperature; (2) the short-term stability of the protein to reversible temperature-driven unfolding; and (3) the dependence of its activity on temperature.

    Results can be summarized as follows(a) the same first-order kinetic constant (0.020+/-0.003 min-1) was determined at different pH values (6.5, 8.0 and 9.5) from long-term stability experiments at 80 degrees C; (b) short-term stability experiments revealed different behaviour in two different pH ranges (6.5-8.0, 8.5-9.5), suggesting that the melting temperature is higher at alkaline than at neutral pH; (c) the dependence of activity on temperature was investigated at pH 7.0 and 9.0, and a discontinuity was observed in the Arrhenius plot of kcat values at pH 9.0. We also investigated the stability in the presence of guanidinium chloride at 20 degrees C either at pH 7.0 or at pH 9.0, and we present data that indicate that the unfolding mechanism closely approaches a two-state model at pH 7.0 and a more complex mechanism at pH 9.0. Satisfactory fitting of the equilibrium unfolding transition obtained by fluorescence measurements at pH 9.0 required a model that involves a stable intermediate in addition to the native and unfolded forms. At 20 degrees C the folded conformation is more stable than the unfolded conformation by (14. 7+/-1.2) kJ/mol at pH 7.0 and by (25.5+/-1.8) kJ/mol at pH 9.0.

    背景与目标: 研究了硫酸亚砜中吲哚-3-甘油磷酸合酶的稳定性和活性随pH和温度的变化。在本文中,我们重点关注三点 (1) 蛋白质在高温下不可逆变性的长期稳定性; (2) 蛋白质在可逆温度驱动的去折叠的短期稳定性; (3) 其活性对温度的依赖性。
    结果可以总结如下 (a) 在不同的ph值 (6.5,8.0和9.5) 来自80 ℃ 下的长期稳定性实验; (b) 短期稳定性实验揭示了在两个不同pH范围 (6.5-8.0,8.5-9.5) 下的不同行为,表明在碱性下的熔融温度高于在中性pH下; (c) 在pH 7.0和9.0下研究了活性对温度的依赖性,在pH 9.0下的kcat值的Arrhenius图中观察到不连续性。我们还研究了氯化胍在20 ℃ 下在pH 7.0或pH 9.0下的稳定性,并且我们提供的数据表明,展开机制在pH 7.0下接近两态模型,在pH 9.0下接近更复杂的机制。在pH 9.0下通过荧光测量获得的平衡展开转变的令人满意的拟合需要一个模型,该模型除了天然和展开形式之外还涉及稳定的中间体。在20 ℃ 下,折叠构象比未折叠构象在pH 7.0下稳定 (14. 7 +/-1.2) kJ/mol,在pH 9.0下稳定 (25.5 +/-1.8) kJ/mol。
  • 【在病因不明的原发性b细胞免疫缺陷儿童中鉴定人磷酸肌醇3激酶p110delta基因的变异。】 复制标题 收藏 收藏
    DOI:10.1111/j.1744-313X.2006.00627.x 复制DOI
    作者列表:Jou ST,Chien YH,Yang YH,Wang TC,Shyur SD,Chou CC,Chang ML,Lin DT,Lin KH,Chiang BL
    BACKGROUND & AIMS: :Our recent study demonstrated that defects in p110delta result in B-cell immunodeficiency that is very similar to that observed in BTK-deficient mice. We revealed that the p110delta fit the B-cell signal transduction complex and played a non-redundant role in the development and function of B cells. In humans, most children with primary B-cell immunodeficiency have mutations in the BTK, whereas a few have defects in the components of the B-cell signal transduction complex. But little is known about the genetic variation of p110delta in children with defects in B-cell immunodeficiency of unknown aetiology. Sixteen patients from 15 unrelated families and 112 normal controls underwent sequence analysis to identify genetic variations of the p110delta. Allele frequency in each group was also analysed and compared. We identified five single base-pair polymorphic nucleotide exchanges in both patient and control groups with similar allele frequencies, which did not contribute to the immunodeficiency. Three of them are novel (m.953A>G, m.1200C>T and m.1561A>G), and the m.953A>G and m.1561A>G nucleotide exchanges are non-synonymous (N253S and T456A, respectively). The novel m.1561A>G was in complete linkage disequilibrium with the known m.873A>G in our study of Taiwanese group. In addition, one novel single base-pair missense mutation, m.3256G>A (E1021K), was identified in one boy with typical clinical features of primary B-cell immunodeficiency and could not be found in either his family or the normal control population. By atomic structural analysis of the amino acid as well as the alignment comparison between species, it resulted in the replacement of the negative-charged amino acid E with the positive-charged amino acid K at codon 1021, located in the highly conservative and important catalytic functional domain. Our findings could shed light on further understanding the polymorphisms of p110delta in B-cell immunodeficiency and different populations. Moreover, the 3256G>A missense mutation raised the attention and warranted further extensive analysis to elucidate the role of p110delta in human immunodeficiency.
    背景与目标: : 我们最近的研究表明,p110delta的缺陷导致b细胞免疫缺陷,这与BTK缺陷小鼠中观察到的非常相似。我们揭示了p110delta符合b细胞信号转导复合物,并且在b细胞的发育和功能中起着非冗余的作用。在人类中,大多数患有原发性b细胞免疫缺陷的儿童在BTK中存在突变,而少数儿童在b细胞信号转导复合物的成分中存在缺陷。但是,对于病因不明的b细胞免疫缺陷儿童中p110delta的遗传变异知之甚少。来自15个无关家庭和112个正常对照的16名患者进行了序列分析,以鉴定p110delta的遗传变异。还对各组的等位基因频率进行了分析和比较。我们在患者组和对照组中鉴定出五个具有相似等位基因频率的单碱基对多态性核苷酸交换,这对免疫缺陷没有贡献。其中三个是新颖的 (m.953A>G,m.1200C>T和m.1561A>G),而m.953A>G和m.1561A>G核苷酸交换是非同义的 (分别为N253S和T456A)。在我们对台湾组的研究中,新颖的m.1561A>G与已知的m.873A>G完全处于连锁不平衡状态。此外,在一名具有原发性b细胞免疫缺陷典型临床特征的男孩中鉴定出一个新的单碱基对错义突变m.3256G>A (E1021K),在其家人或正常对照人群中均找不到。通过氨基酸的原子结构分析以及物种之间的比对比较,它导致负电荷氨基酸E被密码子1021位的正电荷氨基酸K取代,位于高度保守和重要的催化功能域。我们的发现可能有助于进一步了解b细胞免疫缺陷和不同人群中p110delta的多态性。此外,3256G>A错义突变引起了人们的注意,并需要进一步广泛的分析来阐明p110delta在人类免疫缺陷中的作用。
  • 【膜结合eotaxin-3介导IL-4-stimulated上皮细胞嗜酸性粒细胞经上皮迁移。】 复制标题 收藏 收藏
    DOI:10.1002/eji.200636112 复制DOI
    作者列表:Yuan Q,Campanella GS,Colvin RA,Hamilos DL,Jones KJ,Mathew A,Means TK,Luster AD
    BACKGROUND & AIMS: :Epithelial cells play an important role in orchestrating mucosal immune responses. In allergic-type inflammation, epithelial cells control the recruitment of eosinophils into the mucosa. Th2-type cytokine-driven release of eosinophil-active chemokines from epithelial cells directs eosinophil migration into the mucosal epithelium. CCR3, the main eosinophil chemokine receptor, regulates this process; however, the respective contribution of individual CCR3 ligands in eosinophil transepithelial migration is less well understood. Using an in vitro transepithelial chemotaxis system, we found that eotaxin-3 produced by IL-4-stimulated airway epithelial cells and CCR3 on eosinophils exclusively mediate eosinophil transepithelial migration. Eotaxin-3 protein levels were also increased in the nasal mucosal epithelium recovered from allergic patients as compared to non-allergic patients. Surprisingly, eotaxin-3 in IL-4-stimulated airway epithelial cells was predominantly cell surface bound, and the cell surface form was critical for eosinophil transepithelial migration. Eotaxin-3 cell surface association was partially glycosaminoglycan (GAG) dependent, but was completely protein dependent, suggesting that eotaxin-3 associates with both GAG and cell surface proteins. We thus provide evidence that cell surface-associated eotaxin-3 is the critical IL-4-dependent chemotactic signal mediating eosinophil transepithelial migration in the setting of allergic inflammation.
    背景与目标: : 上皮细胞在协调粘膜免疫反应中起重要作用。在过敏型炎症中,上皮细胞控制嗜酸性粒细胞向粘膜的募集。Th2-type细胞因子驱动的嗜酸性粒细胞活性趋化因子从上皮细胞释放引导嗜酸性粒细胞迁移到粘膜上皮中。主要的嗜酸性粒细胞趋化因子受体CCR3调节这一过程; 然而,单个CCR3配体在嗜酸性粒细胞跨上皮迁移中的各自作用尚不清楚。使用体外经上皮趋化系统,我们发现IL-4-stimulated气道上皮细胞和嗜酸性粒细胞上的CCR3产生的eotaxin-3仅介导嗜酸性粒细胞经上皮迁移。与非过敏患者相比,从过敏患者恢复的鼻粘膜上皮中Eotaxin-3蛋白水平也增加。令人惊讶的是,IL-4-stimulated气道上皮细胞中的eotaxin-3主要是细胞表面结合的,细胞表面形式对于嗜酸性粒细胞经上皮迁移至关重要。Eotaxin-3细胞表面缔合部分依赖于糖胺聚糖 (GAG),但完全依赖于蛋白质,这表明eotaxin-3与GAG和细胞表面蛋白均相关。因此,我们提供的证据表明,在过敏性炎症环境中,细胞表面相关eotaxin-3是介导嗜酸性粒细胞跨上皮迁移的关键IL-4-dependent趋化信号。
  • 【选择性临床超声信号介导两种人前列腺癌细胞系的差异基因转移和表达: LnCap和PC-3。】 复制标题 收藏 收藏
    DOI:10.1006/bbrc.1997.6578 复制DOI
    作者列表:Tata DB,Dunn F,Tindall DJ
    BACKGROUND & AIMS: Low intensity ultrasound signals, similar to that employed in clinical therapy, are found to mediate differential gene transfer and expression of the Green Fluorescence Protein (GFP) reporter in two human prostate cancer cell lines, LnCap and PC-3. Cell suspensions in the presence or in the absence of GFP (44.5nM) were treated at 37 degrees C under a standing wave condition. Cells were exposed to either continuous wave, 932.7kHz ultrasound, or to several independent bursts, each burst comprising a 20% duty cycle (932.7kHz) sine wave. The burst "repetition" frequency was varied from 10Hz to 10kHz in several different experiments and each treatment received a net identical ultrasound energy exposure. Transient GFP expression levels in viable cells were monitored by flow cytometry. The findings revealed a strong ultrasound tone-burst frequency dependence on the transfection efficiencies. Interestingly, the ultrasound signal parameters which are routinely employed in clinical therapy did not yield any statistically significant enhancement in transfection efficiency relative to their sham counterparts.

    背景与目标: 发现与临床治疗中使用的低强度超声信号相似,可介导两种人前列腺癌细胞系LnCap和PC-3中的差异基因转移和绿色荧光蛋白 (GFP) 报告基因的表达。在驻波条件下,在37 ℃ 下处理存在或不存在GFP (44.5nm) 的细胞悬浮液。将细胞暴露于连续波、932.7khz超声波或几个独立的突发,每个突发包括20% 占空比 (932.7khz) 正弦波。在几个不同的实验中,突发 “重复” 频率从10Hz到10kHz不等,并且每种处理均获得净相同的超声能量暴露。通过流式细胞术监测活细胞中的瞬时GFP表达水平。研究结果表明,超声音调爆发频率对转染效率有很强的依赖性。有趣的是,与假手术相比,临床治疗中常规使用的超声信号参数在转染效率上没有任何统计学上的显着提高。
  • 【急诊医学教育奖学金作家指南: 教育创新 (第3部分)。】 复制标题 收藏 收藏
    影响因子 :
    发表时间:2018-05-01
    来源期刊:CJEM
    DOI:10.1017/cem.2017.28 复制DOI
    作者列表:Hall AK,Hagel C,Chan TM,Thoma B,Murnaghan A,Bhanji F
    BACKGROUND & AIMS: OBJECTIVE:The scholarly dissemination of innovative medical education practices helps broaden the reach of this type of work, allowing scholarship to have an impact beyond a single institution. There is little guidance in the literature for those seeking to publish program evaluation studies and innovation papers. This study aims to derive a set of evidence-based features of high-quality reports on innovations in emergency medicine (EM) education. METHODS:We conducted a scoping review and thematic analysis to determine quality markers for medical education innovation reports, with a focus on EM. A search of MEDLINE, EMBASE, ERIC, and Google Scholar was augmented by a hand search of relevant publication guidelines, guidelines for authors, and website submission portals from medical education and EM journals. Study investigators reviewed the selected articles, and a thematic analysis was conducted. RESULTS:Our search strategy identified 14 relevant articles from which 34 quality markers were extracted. These markers were grouped into seven important themes: goals and need for innovation, preparation, innovation development, innovation implementation, evaluation of innovation, evidence of reflective practice, and reporting and dissemination. In addition, multiple outlets for the publication of EM education innovations were identified and compiled. CONCLUSION:The publication and dissemination of innovations are critical for the EM education community and the training of health professionals. We anticipate that our list of innovation report quality markers will be used by EM education innovators to support the dissemination of novel educational practices.
    背景与目标:
  • 【酰基辅酶a对P2Y1-induced血管舒张的拮抗作用: 棕榈酸酯和3 '-磷酸的关键作用。】 复制标题 收藏 收藏
    DOI:10.1111/bph.12086 复制DOI
    作者列表:Alefishat E,Alexander SP,Ralevic V
    BACKGROUND & AIMS: BACKGROUND AND PURPOSE:Acyl derivatives of CoA have been shown to act as antagonists at human platelet and recombinant P2Y1 receptors, but little is known about their effects in the cardiovascular system. This study evaluated the effect of these endogenous nucleotide derivatives at P2Y1 receptors natively expressed in rat and porcine blood vessels. EXPERIMENTAL APPROACH:Isometric tension recordings were used to evaluate the effects of CoA, acetyl CoA, palmitoyl CoA (PaCoA) and 3'-dephospho-palmitoyl-CoA on concentration relaxation-response curves to ADP and uridine triphosphate (UTP). A FlexStation monitored ADP- and UTP-evoked calcium responses in HEK293 cells. KEY RESULTS:Acetyl CoA and PaCoA, but not CoA, inhibited endothelium-dependent relaxations to ADP with apparent selectivity for P2Y1 receptors (over P2Y(2/4) receptors) in rat thoracic aorta; PaCoA was more potent than acetyl CoA (331-fold vs. fivefold shift of ADP response curve evoked by 10 μM PaCoA and acetyl CoA, respectively); the apparent pA2 value for PaCoA was 6.44. 3'-dephospho-palmitoyl-CoA (10 μM) was significantly less potent than PaCoA (20-fold shift). In porcine mesenteric arteries, PaCoA and the P2Y1 receptor antagonist MRS2500 blocked ADP-mediated endothelium-dependent relaxations; in contrast, they were ineffective against ADP-mediated endothelium-independent relaxation in porcine coronary arteries (which does not involve P2Y1 receptors). Calcium responses evoked by ADP activation of endogenous P2Y1 receptors in HEK293 cells were inhibited in the presence of PaCoA, which failed to alter responses to UTP (acting at endogenous P2Y(2/4) receptors). CONCLUSIONS AND IMPLICATIONS:Acyl derivatives of CoA can act as endogenous selective antagonists of P2Y1 receptors in blood vessels, and this inhibitory effect critically depends on the palmitate and 3'-ribose phosphate substituents on CoA.
    背景与目标:
  • 【具有1,3,5-三唑并喹烷骨架的新型三重态药物的合成及其药理作用。3: 合成具有双 (环氧) 或双 (二甲基左氧) 结构的新型三重态药物 (双端三重态)。】 复制标题 收藏 收藏
    DOI:10.1016/j.bmcl.2012.10.023 复制DOI
    作者列表:Wada N,Fujii H,Koyano K,Hirayama S,Iwai T,Nemoto T,Nagase H
    BACKGROUND & AIMS: :Novel double-capped triplet drugs, which have one pharmacophore unit and two epoxymethano or dimethylepoxymethano structures (termed cap or diMe-cap structures, respectively) were synthesized. Key intermediate oxazoline 16 derived from acetone enabled the effective synthesis of double-capped triplets. SYK-134 (7a) and SYK-135 (8a) with N-cyclopropylmethyl substituent and cap structures showed selectivities for the κ opioid receptor. On the other hand, the N-Me series exhibited selectivities for the μ opioid receptor. The double-capped triplet drugs with diMe-cap structures preferred the μ receptor independently of their N-substituents. SYK-385 (19b), one of the μ-selective double-capped triplet drugs, showed the highest selectivity for the μ receptor among the reported μ-selective nonpeptide ligands.
    背景与目标: : 合成了具有一个药效单位和两个环氧甲氧基或二甲氧基甲氧基结构 (分别称为cap或derme-cap结构) 的新型双冠三联体药物。由丙酮衍生的关键中间体恶唑啉16能够有效合成双端三联体。具有N-环丙基甲基取代基和帽结构的SYK-134 (7a) 和SYK-135 (8a) 显示了 κ 阿片受体的选择性。另一方面,N-Me系列对 μ 阿片受体表现出选择性。具有一角帽结构的双盖三重态药物独立于其N取代基而偏爱 μ 受体。SYK-385 (19b) 是 μ 选择性双封端的三联体药物之一,在报道的 μ 选择性非肽配体中显示出对 μ 受体的最高选择性。
  • 【靶向Toll-IL-1R域的诱饵肽抑制LPS和TLR4-active代谢物吗啡-3葡萄糖醛酸苷对感觉神经元的敏化。】 复制标题 收藏 收藏
    DOI:10.1038/s41598-017-03447-9 复制DOI
    作者列表:Allette YM,Kim Y,Randolph AL,Smith JA,Ripsch MS,White FA
    BACKGROUND & AIMS: :Accumulating evidence indicates that Toll-like receptor (TLR) signaling adapter protein interactions with Toll/Interleukin-1 Receptor (TIR) domains present in sensory neurons may modulate neuropathic pain states. Following ligand interaction with TLRs, TIR serves to both initiate intracellular signaling and facilitate recruitment of signaling adapter proteins to the intracytoplasmic domain. Although TLR TIR is central to a number of TLR signaling cascades, its role in sensory neurons is poorly understood. In this study we investigated the degree to which TLR TIR decoy peptide modified to include a TAT sequence (Trans-Activator of Transcription gene in HIV; TAT-4BB) affected LPS-induced intracellular calcium flux and excitation in sensory neurons, and behavioral changes due to TLR4 active metabolite, morphine-3-glucuronide (M3G) exposure in vivo. TAT-4BB inhibited LPS-induced calcium changes in a majority of sensory neurons and decreased LPS-dependent neuronal excitability in small diameter neurons. Acute systemic administration of the TAT-4BB reversed M3G-induced tactile allodynia in a dose-dependent manner but did not affect motor activity, anxiety or responses to noxious thermal stimulus. These data suggest that targeting TLR TIR domains may provide novel pharmacological targets to reduce or reverse TLR4-dependent pain behavior in the rodent.
    背景与目标: : 越来越多的证据表明,Toll样受体 (TLR) 信号衔接蛋白与感觉神经元中存在的Toll/Interleukin-1受体 (TIR) 结构域的相互作用可能调节神经性疼痛状态。配体与tlr相互作用后,TIR既可启动细胞内信号传导,又可促进信号衔接蛋白向胞浆内结构域的募集。尽管TLR TIR是许多TLR信号级联的核心,但对其在感觉神经元中的作用知之甚少。在这项研究中,我们调查了修饰为包含TAT序列 (HIV中转录基因的反式激活因子; TAT-4BB) 的TLR TIR诱饵肽对LPS诱导的细胞内钙通量和感觉神经元的兴奋以及由于TLR4活性代谢物引起的行为变化的影响程度,morphine-3-glucuronide (M3G) 体内暴露。TAT-4BB抑制了大多数感觉神经元中LPS诱导的钙变化,并降低了小直径神经元中LPS依赖性神经元的兴奋性。TAT-4BB的急性全身给药以剂量依赖性方式逆转了M3G-induced的触觉异常性疼痛,但不影响运动活动,焦虑或对有害热刺激的反应。这些数据表明,靶向TLR TIR结构域可以提供新的药理学靶标,以减少或逆转啮齿动物的TLR4-dependent疼痛行为。
  • 【3个治疗靶点多沙唑嗪对映体的手性识别以及动物实验中的药物不良反应。】 复制标题 收藏 收藏
    DOI:10.1139/y2012-129 复制DOI
    作者列表:Zhao D,Duan LH,Wang FY,Wang M,Lu HG,Wu ZG,Wang X,Ren LM
    BACKGROUND & AIMS: :Doxazosin used in benign prostatic hyperplasia has the side effects of causing hypotension and the risk of heart failure. The 3 targets of α(1A)-adrenoceptors (in the prostate), α(1D)-adrenoceptors (in the aorta), and an unknown mechanism (in the heart) are involved, respectively. We hypothesized that there is a chiral recognition of doxazosin enantiomers in the 3 targets. Using isolated rat aorta (α(1D)-adrenoceptors) and rabbit prostate (α(1A)-adrenoceptors), we examined pA(2) and pK(B) values of doxazosin enantiomers. We observed chronotropic and inotropic effects of doxazosin enantiomers in isolated rat and rabbit heart tissues. (-)Doxazosin and (+)doxazosin produced a shift to the right of concentration-contraction curves for noradrenalin (aorta) and phenylephrine (prostate smooth muscle). The pA(2) value of (-)doxazosin (8.625 ± 0.053) was smaller than (+)doxazosin (9.503 ± 0.051) in rat aorta, but their pK(B) values in rabbit prostate were the same. In rat and rabbit heart tissues, (+)doxazosin (3-30 µmol·L(-1)) significantly decreased atrial rate, and produced negative inotropic effects; however, (-)doxazosin did not affect the atrial rate, and produced positive inotropic effects in the atria. Thus, the chiral carbon atom of doxazosin does not affect its activity at the therapeutic target of α(1A)-adrenoceptors in the prostate, but significantly changes its blocking activity against α(1D)-adrenoceptors in the aorta, and produces opposite inotropic effects in the atria via an α(1)-adrenoceptor-independent mechanism.
    背景与目标: : 多沙唑嗪用于良性前列腺增生具有引起低血压和心力衰竭风险的副作用。分别涉及 α(1A)-肾上腺素受体 (在前列腺中),α(1D)-肾上腺素受体 (在主动脉中) 和未知机制 (在心脏中) 的3个目标。我们假设在3个靶标中存在多沙唑嗪对映体的手性识别。使用分离的大鼠主动脉 (α(1D)-肾上腺素受体) 和兔前列腺 (α(1A)-肾上腺素受体),我们检查了多沙唑嗪对映体的pA(2) 和pK(B) 值。我们观察到多沙唑嗪对映体在分离的大鼠和兔心脏组织中的变时性和正性肌力作用。(-) 多沙唑嗪和 () 多沙唑嗪使去甲肾上腺素 (主动脉) 和去氧肾上腺素 (前列腺平滑肌) 的浓度-收缩曲线向右移动。在大鼠主动脉中 (-) 多沙唑嗪 (8.625 ± 0.053) 的pA(2) 值小于 () 多沙唑嗪 (9.503 ± 0.051),但它们在兔前列腺中的pK(B) 值相同。在大鼠和兔心脏组织中,() 多沙唑嗪 (3-30 µ mol·L(-1)) 显着降低了心房速率,并产生了负性肌力作用; 但是,(-) 多沙唑嗪不影响心房速率,并在心房中产生了正性肌力作用。因此,多沙唑嗪的手性碳原子不会影响其在前列腺中 α(1A)-肾上腺素受体的治疗靶标上的活性,但会显着改变其对主动脉中 α(1D)-肾上腺素受体的阻断活性,并通过不依赖 α(1)-肾上腺素受体的机制在心房中产生相反的正性肌力作用。
  • 【3-羟基-3-甲基戊二酰辅酶a还原酶 (HMGCR) 途径通过异戊烯化依赖的信号通路调节发育性脑血管稳定性。】 复制标题 收藏 收藏
    DOI:10.1016/j.ydbio.2012.11.024 复制DOI
    作者列表:Eisa-Beygi S,Hatch G,Noble S,Ekker M,Moon TW
    BACKGROUND & AIMS: :Spontaneous intracranial hemorrhage is a debilitating form of stroke, often leading to death or permanent cognitive impairment. Many of the causative genes and the underlying mechanisms implicated in developmental cerebral-vascular malformations are unknown. Recent in vitro and in vivo studies in mice have shown inhibition of the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) pathway to be effective in stabilizing cranial vessels. Using a combination of pharmacological and genetic approaches to specifically inhibit the HMGCR pathway in zebrafish (Danio rerio), we demonstrate a requirement for this metabolic pathway in developmental vascular stability. Here we report that inhibition of HMGCR function perturbs cerebral-vascular stability, resulting in progressive dilation of blood vessels, followed by vessel rupture, mimicking cerebral cavernous malformation (CCM)-like lesions in humans and murine models. The hemorrhages in the brain are rescued by prior exogenous supplementation with geranylgeranyl pyrophosphate (GGPP), a 20-carbon metabolite of the HMGCR pathway, required for the membrane localization and activation of Rho GTPases. Consistent with this observation, morpholino-induced depletion of the β-subunit of geranylgeranyltransferase I (GGTase I), an enzyme that facilitates the post-translational transfer of the GGPP moiety to the C-terminus of Rho family of GTPases, mimics the cerebral hemorrhaging induced by the pharmacological and genetic ablation of HMGCR. In embryos with cerebral hemorrhage, the endothelial-specific expression of cdc42, a Rho GTPase involved in the regulation of vascular permeability, was significantly reduced. Taken together, our data reveal a metabolic contribution to the stabilization of nascent cranial vessels, requiring protein geranylgeranylation acting downstream of the HMGCR pathway.
    背景与目标: 自发性颅内出血是中风的一种衰弱形式,通常导致死亡或永久性认知障碍。与发育性脑血管畸形有关的许多致病基因和潜在机制尚不清楚。最近在小鼠中进行的体外和体内研究表明,抑制3-羟基-3-甲基戊二酰-coa还原酶 (HMGCR) 途径可有效稳定颅骨血管。使用药理学和遗传学方法相结合的方法来特异性抑制斑马鱼 (Danio rerio) 中的HMGCR途径,我们证明了这种代谢途径在发育血管稳定性中的需求。在这里,我们报告了HMGCR功能的抑制会干扰脑血管的稳定性,导致血管进行性扩张,然后血管破裂,模仿人和鼠模型中的脑海绵状畸形 (CCM) 样病变。通过事先补充香叶基焦磷酸 (GGPP) (HMGCR途径的20碳代谢产物) 来挽救脑部出血,这是Rho GTPases膜定位和激活所必需的。与该观察结果一致,吗啉代诱导的香叶基转移酶I (GGTase I) 的 β 亚基耗竭,该酶促进了GGPP部分翻译后转移到Rho gtp酶家族的C末端,模拟了HMGCR的药理和遗传消融引起的脑出血。在脑出血的胚胎中,参与调节血管通透性的Rho GTPase cdc42的内皮特异性表达显着降低。总之,我们的数据揭示了对新生颅骨血管稳定的代谢贡献,需要在HMGCR途径下游起作用的蛋白质香叶基。
  • 【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。
  • 【14元9-O-(3-芳基烷基) 肟11,12-环碳酸盐酮化物的合成、抗菌活性及对接】 复制标题 收藏 收藏
    DOI:10.1016/j.ejmech.2012.10.054 复制DOI
    作者列表:Liang JH,An K,Lv W,Cushman M,Wang H,Xu YC
    BACKGROUND & AIMS: :A series of 9-O-(3-aryl-2-propargyl)oxime ketolides 8 was synthesized and evaluated for in vitro antibacterial activity. Among 8, 8b-8d, and 8h-8l displayed dramatically improved potency against inducibly MLS(B)-resistant and efflux-resistant pathogens as compared to clarithromycin and azithromycin. Especially, 8i (Ar=4-isoquinolyl) possessed an MIC of 0.064 μg/mL against constitutively MLS(B)-resistant Streptococcus pneumoniae, and MICs of 0.032-0.064 μg/mL against methicillin-resistant Staphylococcus aureus and methicillin-resistant Staphylococcus hominis. The analog 10 with a propyl linker was less effective than both the corresponding 8 and 9 containing propynyl and propenyl linkers. A docking study was performed to gain insight into the binding mode of series 8 and 9 and to rationalize the disparity found in the SAR of 8 and 9.
    背景与目标: : 合成了一系列9-O-(3-芳基-2-炔丙基) 肟酮内酯8,并评估了其体外抗菌活性。与克拉霉素和阿奇霉素相比,在8、8b-8d和8h-8l中,对诱导性MLS(B) 抗性和耐外排病原体的效力显着提高。尤其是,8i (Ar = 4-异喹啉基) 对组成型MLS(B) 耐药的肺炎链球菌的MIC为0.064 μ g/mL,对耐甲氧西林的金黄色葡萄球菌和耐甲氧西林的人型葡萄球菌的MIC为0.032-0.064 μ g/mL。具有丙基接头的类似物10的效力低于包含丙基和丙烯基接头的相应8和9的效力。进行了对接研究,以深入了解系列8和9的结合模式,并合理化在SAR 8和9中发现的差异。

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