• 【发现烯基硼酸作为神经保护剂,可影响涉及阿尔茨海默氏病的多个生物学靶标。】 复制标题 收藏 收藏
    DOI:10.1016/j.bmcl.2012.11.068 复制DOI
    作者列表:Jiménez-Aligaga K,Bermejo-Bescós P,Martín-Aragón S,Csákÿ AG
    BACKGROUND & AIMS: :Alkenylboronic acids have shown important biological activities that contribute to neuroprotection. We have determined their influence on the β-amyloid (βA) aggregation process, β-secretase and acethylcholinesterase activities on cell-free systems, on the redox and lipid peroxidation status, and on the vulnerability to apoptotic death in an APPswe neuroblastoma cell line, before and after hydrogen peroxide treatment. We have discovered that 2-arylvinylboronic acids and some of their esters possess a set of properties which makes them highly useful as neuroprotective agents affecting multiple biological targets involved in AD. These properties are not paralleled by the related 2-arylboronic acids.
    背景与目标: 烯基硼酸已显示出重要的生物活性,可促进神经保护作用。我们已经确定了它们对β-淀粉样蛋白(βA)聚集过程,β-分泌酶和乙酰胆碱酯酶活性在无细胞系统,氧化还原和脂质过氧化状态以及对APPswe神经母细胞瘤细胞系中凋亡死亡的脆弱性的影响,过氧化氢处理前后。我们已经发现2-芳基乙烯基硼酸及其某些酯具有一系列特性,这使得它们非常有用地用作影响涉及AD的多个生物学靶标的神经保护剂。这些性能是相关的2-芳基硼酸无法比拟的。
  • 【通过核酸碱基的四分之一化与芳香族氨基酸的突出堆积相互作用:X射线晶体学特征和生物学意义。】 复制标题 收藏 收藏
    DOI:10.1016/0003-9861(90)90251-s 复制DOI
    作者列表:Ishida T,Ueda H,Segawa K,Doi M,Inoue M
    BACKGROUND & AIMS: :In order to investigate the mode of interaction between the N-quarternized cytosine base and the aromatic amino acid, the crystal structure of the 3-methyl-cytidine-5'-monophosphate:tryptamine complex was analyzed by X-ray diffraction. The complex crystals were stabilized by extensive hydrogen bond formations in which eight independent water molecules per complex pair participated. A prominent stacking interaction, characterized by a parallel alignment of both rings with a separation distance of ca. 3.4 A, was observed between the cytosine base and the indole ring. Combining the present results with X-ray crystallographic data on the adenine--and guanine--aromatic amino acid interactions, we summarize the structural characteristics observed in the stacking interaction of the N-quarternized nucleic acid base with the aromatic amino acid and discuss their biological implications, especially in connection with the significance of N-protonation of nucleic acid base for selective recognition by protein.
    背景与目标: :为了研究N-季铵化的胞嘧啶碱基与芳族氨基酸之间的相互作用方式,通过X射线衍射分析了3-甲基胞苷-5'-单磷酸酯:色胺的配合物的晶体结构。复杂的晶体通过广泛的氢键形成而稳定,其中每个复杂对参与八个独立的水分子。突出的堆叠相互作用,其特征在于两个环的平行排列的间隔距离为ca。在胞嘧啶碱基和吲哚环之间观察到3.4A。将当前结果与腺嘌呤-鸟嘌呤-芳族氨基酸相互作用的X射线晶体学数据相结合,我们总结了在N-季铵化核酸碱基与芳族氨基酸的堆叠相互作用中观察到的结构特征,并讨论了它们的结构特征。生物学意义,特别是与核酸碱基的N质子化对于蛋白质选择性识别的意义有关。
  • 【Roscovitine衍生的有效CDK5抑制剂:合成,生物学评估和分子建模。】 复制标题 收藏 收藏
    DOI:10.1016/j.bmcl.2012.10.141 复制DOI
    作者列表:Demange L,Abdellah FN,Lozach O,Ferandin Y,Gresh N,Meijer L,Galons H
    BACKGROUND & AIMS: :Cyclin dependent kinase 5 (CDK5) is a serine/threonine kinase belonging to the cyclin dependent kinase (CDK) family. CDK5 is involved in numerous neuronal diseases (including Alzheimer's or Parkinson's diseases, stroke, traumatic brain injury), pain signaling and cell migration. In the present Letter, we describe syntheses and biological evaluations of new 2,6,9-trisubstituted purines, structurally related to roscovitine, a promising CDK inhibitor currently in clinical trials (CDK1/Cyclin B, IC(50)=350 nM; CDK5/p25, IC(50)=200 nM). These new molecules were synthesized using an original Buchwald-Hartwig catalytic procedure; several compounds (3j, 3k, 3l, 3e, 4k, 6b, 6c) displayed potent kinase inhibitory potencies against CDK5 (IC(50) values ranging from 17 to 50 nM) and showed significant cell death inducing activities (IC(50) values ranging from 2 to 9 μM on SH-SY5Y). The docking of the inhibitors into the ATP binding domain of the CDK5 catalytic site highlighted the discriminatory effect of a hydrogen bond involving the CDK5 Lys-89. In addition, the calculated final energy balances for complexation measured for several inhibitors is consistent with the ranking of the IC(50) values. Lastly, we observed that several compounds exhibit submicromolar activities against DYRK1A (dual specificity, tyrosine phosphorylation regulated kinase 1A), a kinase involved in Down syndrome and Alzheimer's disease (3g, 3h, 4m; IC(50) values ranging from 300 to 400 nM).
    背景与目标: :细胞周期蛋白依赖性激酶5(CDK5)是属于细胞周期蛋白依赖性激酶(CDK)家族的丝氨酸/苏氨酸激酶。 CDK5与多种神经元疾病(包括阿尔茨海默氏症或帕金森氏症,中风,脑外伤),疼痛信号和细胞迁移有关。在本信中,我们描述了新的2,6,9-三取代嘌呤的合成和生物学评估,这些嘌呤在结构上与roscovitine有关,roscovitine是一种有前途的CDK抑制剂,目前正在临床试验中(CDK1 / Cyclin B,IC(50)= 350 nM; CDK5 / p25,IC(50)= 200 nM)。这些新分子是使用原始的Buchwald-Hartwig催化程序合成的;几种化合物(3j,3k,3l,3e,4k,6b,6c)对CDK5表现出有效的激酶抑制作用(IC(50)值为17至50 nM),并显示出显着的细胞死亡诱导活性(IC(50)值) SH-SY5Y的范围为2至9μM)。抑制剂对接至CDK5催化位点的ATP结合域中,突显了涉及CDK5 Lys-89的氢键的歧视性作用。此外,针对几种抑制剂测得的复合物最终计算出的最终能量平衡与IC(50)值的排名一致。最后,我们观察到几种化合物对DYRK1A表现出亚微摩尔活性(双重特异性,酪氨酸磷酸化调节激酶1A),该激酶与唐氏综合症和阿尔茨海默氏病有关(3g,3h,4m; IC(50)值介于300至400 nM之间)。
  • 【新的吡普拉汀类似物作为有效的醛糖还原酶抑制剂(ARIs)的合成和生物学评估。】 复制标题 收藏 收藏
    DOI:10.1016/j.ejmech.2012.09.014 复制DOI
    作者列表:Rao VR,Muthenna P,Shankaraiah G,Akileshwari C,Babu KH,Suresh G,Babu KS,Chandra Kumar RS,Prasad KR,Yadav PA,Petrash JM,Reddy GB,Rao JM
    BACKGROUND & AIMS: :As a continuation of our efforts directed towards the development of anti-diabetic agents from natural sources, piplartine was isolated from Piper chaba, and was found to inhibit recombinant human ALR2 with an IC(50) of 160 μM. To improve the efficacy, a series of analogues have been synthesized by modification of the styryl/aromatic and heterocyclic ring functionalities of this natural product lead. All the derivatives were tested for their ALR2 inhibitory activity, and results indicated that adducts 3c, 3e and 2j prepared by the Michael addition of piplartine with indole derivatives displayed potent ARI activity, while the other compounds displayed varying degrees of inhibition. The active compounds were also capable of preventing sorbitol accumulation in human red blood cells.
    背景与目标: :作为我们致力于从天然来源开发抗糖尿病药的努力的继续,从哌派(Piper chaba)分离了吡哌汀,并发现其抑制重组人ALR2的IC(50)为160μM。为了提高功效,已经通过修饰该天然产物铅的苯乙烯基/芳族和杂环官能团合成了一系列类似物。测试了所有衍生物的ALR2抑制活性,结果表明,通过迈克尔加成的吡哌丁与吲哚衍生物制得的加合物3c,3e和2j表现出有效的ARI活性,而其他化合物则表现出不同程度的抑制作用。活性化合物还能够防止山梨糖醇在人红细胞中积累。
  • 【一系列新的含吩噻嗪的蛋白质法呢基转移酶抑制剂的合成和生物学评估。】 复制标题 收藏 收藏
    DOI:10.1016/j.ejmech.2012.11.008 复制DOI
    作者列表:Abuhaie CM,Ghinet A,Farce A,Dubois J,Gautret P,Rigo B,Belei D,Bîcu E
    BACKGROUND & AIMS: :Two new families of human farnesyltransferase inhibitors 13a-m and 14a-d, based on a phenothiazine scaffold, were synthesized. Compounds 14a and 14b were the most promising inhibitors of human farnesyltransferase with IC(50) values of 0.7 and 0.6 μM, respectively.
    背景与目标: :基于吩噻嗪支架,合成了两个新的人类法呢基转移酶抑制剂家族13a-m和14a-d。化合物14a和14b是人类法呢基转移酶的最有希望的抑制剂,其IC(50)值分别为0.7和0.6μM。
  • 【八氢吡嗪[2,1-a:5,4-a']二异喹啉衍生物作为有效的抗癌药的生物学评价。】 复制标题 收藏 收藏
    DOI:10.1177/1010428317701641 复制DOI
    作者列表:Gornowicz A,Pawłowska N,Czajkowska A,Czarnomysy R,Bielawska A,Bielawski K,Michalak O,Staszewska-Krajewska O,Kałuża Z
    BACKGROUND & AIMS: :In this study, we evaluated the cytotoxic activity and antiproliferative potency of novel octahydropyrazin[2,1-a:5,4-a']diisoquinoline derivatives (1-7) in MCF-7 and MDA-MB-231 breast cancer cell lines. Annexin V binding assay and disruption of the mitochondrial potential were performed to determine apoptosis. The activity of caspases 3, 8, 9, and 10 was measured after 24 h of incubation with tested compounds to explain detailed molecular mechanism of induction of apoptosis. The results from experiments were compared with effects obtained after incubation in the presence of camptothecin and etoposide. Our study demonstrated that the most active compounds in both analyzed breast cancer cell lines were compounds 3 and 4. We also observed that all compounds induced apoptosis. We demonstrated the higher activity of caspases 3, 8, 9, and 10, which confirmed that induction of apoptosis is associated with external and internal cell death pathway. Our study revealed that the novel compounds in group of diisoquinoline derivatives are promising candidates in anticancer treatment by activation of both extrinsic and intrinsic apoptotic pathways.
    背景与目标: :在这项研究中,我们评估了新型八氢吡嗪[2,1-a:5,4-a']二异喹啉衍生物(1-7)在MCF-7和MDA-MB-231乳腺癌细胞中的细胞毒活性和抗增殖能力线。进行膜联蛋白V结合测定和线粒体电位破坏以确定细胞凋亡。在与被测化合物孵育24小时后,测定了胱天蛋白酶3、8、9和10的活性,以解释诱导凋亡的详细分子机制。将实验结果与在喜树碱和依托泊苷存在下孵育后获得的效果进行比较。我们的研究表明,在两种分析过的乳腺癌细胞系中,活性最高的化合物是化合物3和4。我们还观察到所有化合物均可诱导细胞凋亡。我们证明了胱天蛋白酶3,8,9和10较高的活动,这证实凋亡的诱导与外部和内部细胞死亡途径相关。我们的研究表明,通过激活外在和内在的凋亡途径,二异喹啉衍生物类中的新化合物有望成为抗癌治疗的候选药物。
  • 【ATria:一种应用于生物网络的新型中心算法。】 复制标题 收藏 收藏
    DOI:10.1186/s12859-017-1659-z 复制DOI
    作者列表:Cickovski T,Peake E,Aguiar-Pulido V,Narasimhan G
    BACKGROUND & AIMS: BACKGROUND:The notion of centrality is used to identify "important" nodes in social networks. Importance of nodes is not well-defined, and many different notions exist in the literature. The challenge of defining centrality in meaningful ways when network edges can be positively or negatively weighted has not been adequately addressed in the literature. Existing centrality algorithms also have a second shortcoming, i.e., the list of the most central nodes are often clustered in a specific region of the network and are not well represented across the network. METHODS:We address both by proposing Ablatio Triadum (ATria), an iterative centrality algorithm that uses the concept of "payoffs" from economic theory. RESULTS:We compare our algorithm with other known centrality algorithms and demonstrate how ATria overcomes several of their shortcomings. We demonstrate the applicability of our algorithm to synthetic networks as well as biological networks including bacterial co-occurrence networks, sometimes referred to as microbial social networks. CONCLUSIONS:We show evidence that ATria identifies three different kinds of "important" nodes in microbial social networks with different potential roles in the community.
    背景与目标: 背景:中心性概念用于识别社交网络中的“重要”节点。节点的重要性尚未明确定义,并且文献中存在许多不同的概念。当网络边缘可以被正负加权时,以有意义的方式定义中心性的挑战尚未在文献中得到充分解决。现有的中心性算法还具有第二个缺点,即,最中心节点的列表通常被聚集在网络的特定区域中,并且不能在整个网络中很好地表示。
    方法:我们通过提出Ablatio Triadum(ATria)来解决这两个问题,这是一种迭代的中心性算法,它使用了经济理论中的“收益”概念。
    结果:我们将我们的算法与其他已知的中心性算法进行了比较,并演示了ATria如何克服其一些缺点。我们证明了我们的算法对合成网络以及包括细菌共生网络(有时称为微生物社交网络)在内的生物网络的适用性。
    结论:我们显示出证据表明,ATria识别了微生物社会网络中三种不同类型的“重要”节点,这些节点在社区中具有不同的潜在作用。
  • 【在晚期前列腺癌的早期药物开发中测试生物学假设的新策略。】 复制标题 收藏 收藏
    DOI:10.1373/clinchem.2012.185157 复制DOI
    作者列表:Ferraldeschi R,Attard G,de Bono JS
    BACKGROUND & AIMS: BACKGROUND:Major advances in our understanding of the underlying biology of prostate cancer have helped to herald a new era in the treatment of castration-resistant prostate cancer (CRPC), with 5 new agents having shown a survival advantage in the last 3 years and an impressive number of promising novel agents now entering the clinic. CONTENT:We discuss the challenges facing drug development for CRPC and strategies to meet these challenges, with a focus not only on the development of predictive and intermediate endpoint biomarkers, but also on novel hypothesis-testing, biomarker-driven clinical trial designs. SUMMARY:With several promising agents now entering the clinic, there is increasing pressure to rethink drug development for CRPC to ensure that novel agents are appropriately evaluated and that patients and resources are appropriately allocated. We envision that biomarker-driven, reiterative clinical trials will have a major impact on CRPC treatment through the testing of robust scientific hypotheses with rationally designed drugs and drug combinations administered to selected patients.
    背景与目标: 背景:我们对前列腺癌基础生物学的认识的重大进步帮助开创了去势抵抗性前列腺癌(CRPC)治疗的新时代,最近5年中有5种新药显示出生存优势,并且数量惊人的有希望的新型药物现已进入临床。
    内容:我们讨论了针对CRPC的药物开发面临的挑战以及应对这些挑战的策略,不仅着眼于预测性和中间终点生物标志物的开发,还着重于新的假设检验,生物标志物驱动的临床试验设计。
    摘要:随着一些有前途的药物现在进入临床,对CRPC进行药物开发的重新思考的压力越来越大,以确保正确评估新型药物以及适当分配患者和资源。我们设想,通过对合理设计的药物和给药于选定患者的药物进行可靠的科学假设测试,生物标记物驱动的重复性临床试验将对CRPC治疗产生重大影响。
  • 【用作抗癌剂的2-取代的4-(3',4',5'-三甲氧基苯基)-5-芳基噻唑的合成和生物学评估。】 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: 近年来,与微管蛋白结合并破坏微管动力学的抗肿瘤剂引起了相当大的关注。为了扩展我们对噻唑环作为康美他汀A-4中顺式烯烃的合适模拟物的认识,我们将3,4,5-三甲氧基苯基固定在噻唑核心的C4位。我们发现,在C2和C5位置的取代基对抗增殖活性具有深远的影响。比较噻唑环C5位上具有相同取代基的化合物,C2位上的部分影响抗增殖活性,效力顺序为NHCH(3)> Me> N(CH(3))(2) 。相对于C 2-氨基对应物,N-甲基氨基取代基显着提高了对MCF-7细胞的抗增殖活性。从N-甲基氨基到N,N-二甲基氨基的C2位增加的空间体积导致活性降低1-2 log。 2-N-甲基氨基噻唑衍生物3b,3d和3e是最有效的化合物作为抗增殖剂,其IC(50)值从低微摩尔到一位数纳摩尔,此外,它们还对耐多药细胞具有活性系过度表达P-糖蛋白。抗增殖活性可能是由于化合物与微管蛋白聚合的秋水仙碱位点结合并破坏了微管动力学而引起的。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不会引起线粒体去极化。
  • 【使用厌氧-好氧工艺从垃圾渗滤液中去除生物氮:通过原始渗滤液中的有机物和微生物的细胞内储存聚合物进行反硝化作用。】 复制标题 收藏 收藏
    DOI:10.1016/j.biortech.2012.10.063 复制DOI
    作者列表:Zhu R,Wang S,Li J,Wang K,Miao L,Ma B,Peng Y
    BACKGROUND & AIMS: :A system which combined ASBR with pulsed SBR (PSBR) was introduced to enhance COD and nitrogen removal from the real landfill leachate. ASBR was used to degrade the organics from raw leachate mainly. Three equal feeds mode was applied in PSBR operation. The results obtained from the joint operation period (157 days) show that the COD removal rate of ASBR was 83-88% under the specific loading rate of 0.43-0.62 gCOD gVSS(-1) day(-1). PSBR's operation can be divided into four phases according to the different influent NH(4)(+)-N which increased to 800-1000 mg L(-1) finally, and total nitrogen (TN) removal rate of more than 90% with the effluent TN of less than 40 mg L(-1) was obtained. PHB and glycogen can act as electron donor for endogenous denitritation orderly with the hypothetical function from DNGAOs. Consequently, the system achieved COD and TN removal rate of 89.61-96.73% and 97.03-98.87%, respectively, without any extra carbon source addition.
    背景与目标: :引入了结合了ASBR和脉冲SBR(PSBR)的系统,以提高从真实垃圾填埋场渗滤液中去除COD和氮的能力。 ASBR主要用于降解原渗滤液中的有机物。在PSBR操作中应用了三个均等进给模式。从联合运行期(157天)获得的结果表明,在比加载率为0.43-0.62 gCOD gVSS(-1)day(-1)的条件下,ASBR的COD去除率为83-88%。 PSBR的操作可根据进水NH(4)-N的不同而分为四个阶段,最终将其增加至800-1000 mg L(-1),而总氮(TN)去除率超过90%,获得的废水总氮少于40 mg L(-1)。 PHB和糖原可以按DNGAOs的假设功能有序地充当内源性反硝化的电子供体。因此,该系统在不添加任何碳源的情况下,分别实现了89.61-96.73%和97.03-98.87%的COD和TN去除率。
  • 【Badula barthesia和Embelia angustifolia中苯醌的生物活性。】 复制标题 收藏 收藏
    DOI:10.1016/S0944-7113(98)80028-7 复制DOI
    作者列表:Lund AK,Adsersen A,Nyman U
    BACKGROUND & AIMS: :In our screening program for antihypertensive plant constituents extracts of the leaves and bark of Badula barthesia showed strong in vitro inhibition of angiotensin converting enzyme (ACE). Rapanone (1), 2,5-dihydroxy-3-tridecyl-1,4-benzoquinone, was isolated as an active constituent of the leaves. The IC(50) values of rapanone and three 3-alkyl-2,5-dihydroxybenzoquinones, (2)-(4), (Z)-2,5-dihydroxy-3-(pentadec-8-enyl)-1,4-benzoquinone, (Z,Z)-2,5-dihydroxy-3-(heptadeca-8,11-dienyl)-1,4-benzoqui-none and (Z)-2,5-dihydroxy-3-(heptadec-8-enyl)-1,4-benzoquinone recently isolated from Embelia angustifolia were determined. The following IC(50) ± S.D. values have been obtained (1) 36 ± 4.6 μM, (2) 19 ± 6.2 μM, (3) 19 ± 8.7 μM and (4) 16 ± 3.0 μ.M. The IC(50) value for the reference compound Captopril was determined to 12 ± 2.6 nM. The antimicrobial activity of the four compounds was determined by thin layer chromatography agar overlay technique as minimum growth inhibitory amount in μg. One yeast, Candida albicans, and four bacteria, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus were used as test organisms.
    背景与目标: :在我们针对降压植物成分的筛选程序中,Badula barthesia的叶子和树皮提取物显示出对血管紧张素转化酶(ACE)的强烈抑制作用。分离出2,5-二羟基-3-十三烷基-1,4-苯醌的雷帕酮(1)作为叶片的活性成分。雷帕酮和三个3-烷基-2,5-二羟基苯醌,(2)-(4),(Z)-2,5-二羟基-3-(pentadec-8-enyl)-1, 4-苯醌,(Z,Z)-2,5-二羟基-3-(十七烷-8,11-二烯基)-1,4-苯并喹酮和(Z)-2,5-二羟基-3-(庚二酮)确定了最近从安哥拉花(Embelia angustifolia)分离的-8-烯基)-1,4-苯醌。以下IC(50)±S.D.已获得(1)36±4.6μM,(2)19±6.2μM,(3)19±8.7μM和(4)16±3.0μM。参考化合物卡托普利的IC(50)值确定为12±2.6 nM。通过薄层层析琼脂覆盖技术确定这四种化合物的抗微生物活性,以μg为单位的最小生长抑制量。将一种酵母,白色念珠菌和四种细菌(枯草芽孢杆菌,大肠杆菌,铜绿假单胞菌和金黄色葡萄球菌)用作测试生物。
  • 【一种基于动物组织作为生物容器的超精子研究处理精子样品的新方法。】 复制标题 收藏 收藏
    DOI:10.1002/jemt.20466 复制DOI
    作者列表:Junquera C,Colás C,Martínez-Ciriano C,Serrano P,Castiella T,Cebrian-Perez JA,Muiño-Blanco T
    BACKGROUND & AIMS: :The study of the ultrastructure of spematozoa by means of transmission electron microscopy often presents with problems of interpretation according to the method employed, depending on whether samples are either centrifuged previously to the fixation or immersed in viscous gels. The major problems of interpretation are: changes in the location of vesicles originated during the maturation process and modifications in the adsorption of seminal plasma proteins to the sperm membrane surface. The aim of our study is to communicate an original new method for the treatment of spermatozoa for ultrastructural study. Our method is based on the use of animal tissues as biological containers, inside which the spermatic suspensions are included. We developed this method using fresh sperm samples taken from mature Rasa aragonesa rams. As biological container, we used 2.5-cm long segments of the intestine of 1-week-old chickens (Gallus gallus) (diameter around 4 mm). To avoid any influence of digestive enzymes of the mucosa on the sperm surface, we put each intestine fragment inside out by means of microdissection forceps under bifocal optical microscope and cold light. One of the edges was tied with thin suture silk. The sperm suspension was injected in the optimal experimental condition and amount. Finally, the still open edge of the intestine segment was tied with silk in the same way as the other segment edge. By using this technique, we can perform a suitable morphological study at an ultrastructural level. In addition, the functional relationship of the ultrastructural components of the target cells is correctly preserved.
    背景与目标: :根据透射电子显微镜对血吸虫超微结构的研究通常会遇到根据所用方法进行解释的问题,这取决于样品是预先离心至固定液还是浸入粘性凝胶中。解释的主要问题是:在成熟过程中产生的囊泡位置的变化以及精浆蛋白对精子膜表面的吸附作用的改变。我们研究的目的是为了交流用于超微结构研究的治疗精子的原始新方法。我们的方法是基于将动物组织用作生物容器,其中包含了精子悬浮液。我们使用从成熟的Rasa aragonesa公羊中提取的新鲜精子样本开发了这种方法。作为生物容器,我们使用了2.5周长的1周龄鸡(鸡胆)的肠段(直径约4毫米)。为了避免粘膜消化酶对精子表面的任何影响,我们在双焦点光学显微镜和冷光下通过显微解剖钳将每个肠段内翻。边缘之一用细缝线缝合。以最佳实验条件和最佳剂量注射精子悬浮液。最后,肠段的仍然敞开的边缘与另一段段的边缘用丝绸绑在一起。通过使用这种技术,我们可以在超微结构水平上进行合适的形态学研究。另外,正确保留了靶细胞超微结构成分的功能关系。
  • 【化学遗传学:阐明具有小分子化合物的生物系统。】 复制标题 收藏 收藏
    DOI:10.1038/sj.jid.5700853 复制DOI
    作者列表:Kawasumi M,Nghiem P
    BACKGROUND & AIMS: :Chemical genetics employs diverse small-molecule compounds to elucidate biological processes in a manner analogous to the mutagenesis strategies at the core of classical genetics. Screening small-molecule libraries for compounds that induce a phenotype of interest represents the forward chemical genetic approach, whereas the reverse approach involves small molecules targeting a single protein. Here, we review key differences between the goals for small-molecule screening in industry versus academia, recent developments in high-throughput screening, and publicly available resources of compound collections, screening facilities, and databases. A particularly exciting outcome of a chemical genetic screen is the discovery of a previously unknown role for a protein in a pathway together with compounds that affect the function of that protein. In illustrative cases, such discoveries have led to progress toward therapeutic development and more commonly have increased the size of the small molecule "toolbox" available to the research community for the study of biological processes.
    背景与目标: 化学遗传学采用多种小分子化合物来阐明生物学过程,其方式类似于经典遗传学的核心诱变策略。在小分子文库中筛选诱导目标表型的化合物代表了正向化学遗传方法,而反向方法则涉及靶向单个蛋白质的小分子。在这里,我们回顾了工业界和学术界对小分子筛选的目标,高通量筛选的最新发展以及化合物集合,筛选设施和数据库的公开可用资源之间的主要区别。化学遗传筛选的一个特别令人兴奋的结果是,发现一种蛋白质在通路中的作用是未知的,而化合物会影响该蛋白质的功能。在说明性情况下,这样的发现导致了治疗发展的进步,并且更普遍地增加了可供研究团体用于生物学过程研究的小分子“工具箱”的大小。
  • 14 Biological redox systems and oxidative stress. 复制标题 收藏 收藏

    【生物氧化还原系统和氧化应激。】 复制标题 收藏 收藏
    DOI:10.1007/s00018-007-7230-8 复制DOI
    作者列表:Sies H
    BACKGROUND & AIMS: :This account revolves around fascination and excitement with science. Early curiosity and fortunate opportunities can lead to a satisfying career. The privilege of performing basic research in biochemistry and molecular biology at a university coupled with teaching motivated students and working with dedicated co-workers makes for sustained thrust in the advance of knowledge. Research fields centered around cellular redox systems, oxidants and antioxidants, and the concept of oxidative stress. A noteworthy aspect is the global network of scientists joining in these endeavors worldwide.
    背景与目标: :这个科目围绕着对科学的迷恋和兴奋。早期的好奇心和幸运的机会可以带来令人满意的职业。在一所大学从事生物化学和分子生物学基础研究的特权,再加上积极进取的学生教学以及与敬业的同事一起工作的特权,为不断发展的知识提供了动力。研究领域围绕细胞氧化还原系统,氧化剂和抗氧化剂以及氧化应激的概念。一个值得注意的方面是参与全球这些努力的全球科学家网络。
  • 【小碱-噻吩杂化物作为多功能试剂的合成及生物学评估:抑制乙酰胆碱酯酶,丁酰胆碱酯酶,Aβ聚集和抗氧化活性。】 复制标题 收藏 收藏
    DOI:10.1016/j.bmc.2013.07.011 复制DOI
    作者列表:Su T,Xie S,Wei H,Yan J,Huang L,Li X
    BACKGROUND & AIMS: :A series of berberine-thiophenyl hybrids were designed, synthesised, and evaluated as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and β-amyloid (Aβ) aggregation and as antioxidants. Among these hybrids, compounds 4f and 4i, berberine linked with o-methylthiophenyl and o-chlorothiophenyl by a 2-carbon spacer, were observed to be potent inhibitors of AChE, with IC50 values of 0.077 and 0.042 μM, respectively. Of the tested compounds, 4i was also the most potent inhibitor of BuChE, with an IC50 value of 0.662 μM. Kinetic studies and molecular modelling simulations of the AChE-inhibitor complex indicated that a mixed-competitive binding mode existed for these berberine derivatives. The biological studies also demonstrated that these hybrids displayed interesting activities, including Aβ aggregation inhibition and antioxidant properties.
    背景与目标: :设计,合成并评估了一系列小ber碱-硫代苯基杂化物,作为乙酰胆碱酯酶(AChE),丁酰胆碱酯酶(BuChE)和β-淀粉样蛋白(Aβ)聚集的抑制剂和抗氧化剂。在这些杂种中,观察到化合物4f和4i(通过2碳间隔基与邻甲基硫代苯基和邻氯硫代苯基连接的小ber碱)是有效的AChE抑制剂,IC50值分别为0.077和0.042μM。在测试的化合物中,4i也是BuChE的最强抑制剂,IC50值为0.662μM。 AChE-抑制剂复合物的动力学研究和分子建模模拟表明,这些小碱衍生物存在混合竞争结合模式。生物学研究还表明,这些杂种表现出有趣的活性,包括抑制Aβ聚集和抗氧化性能。

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