• 【干扰素-β 治疗的复发缓解型多发性硬化症患者的血清IL-17A水平。】 复制标题 收藏 收藏
    DOI:10.1177/1352458512468497 复制DOI
    作者列表:Bălaşa R,Bajko Z,Huţanu A
    BACKGROUND & AIMS: BACKGROUND:Interleukin-17 (IL-17), which is secreted by Th17 cells, is a proinflammatory cytokine that is implicated in the pathogenesis of multiple sclerosis (MS) and plays a role in nonresponse of MS patients to interferon-β (IFN-β) therapy. OBJECTIVES:The purpose of this study was to establish a correlation between nonresponders (NR) and IL-17A serum titers and binding antibodies (BAbs) to IFN-β, as well as to find a correlation between IL-17A serum levels and other features of MS patients. METHODS:Our prospective study included 72 inactive relapsing-remitting multiple sclerosis (RRMS) patients that had been treated for at least 18 months with IFN-β and 15 healthy subjects. We determined the serum levels of IL-17A and of BAbs. IL-17A levels were considered elevated (IL-17A+) if the recorded value was greater than 1.6 pg/ml. RESULTS:Twenty-seven patients (37.5%) were NR and had a significantly higher serum IL-17A level compared to the responders group. Nineteen patients (26.4%) were IL-17A+ and had had a significantly higher number of relapses in the previous year and a higher Expanded Disability Status Score. The majority of IL-17A+ patients were NR and had a shorter MS duration. CONCLUSIONS:RRMS patients with high serum IL-17A levels do not respond well to IFN-β therapy and have shorter MS duration compared to patients with low IL-17A levels. This response is not influenced by the presence of BAbs.
    背景与目标:
  • 【从两个ABl-SH3结构域肽形成淀粉样蛋白的多个 β-折叠分子动力学。】 复制标题 收藏 收藏
    DOI:10.1002/bip.22161 复制DOI
    作者列表:Lapidus D,Duka V,Stonkus V,Czaplewski C,Liwo A,Ventura S,Liepina I
    BACKGROUND & AIMS: :Molecular dynamics simulations in explicit water were carried out for two stacks, each composed of six 10-strand antiparallel β-sheets for two peptides corresponding to the diverging turn of two homologous Abl-SH3 domains. The first system, referred to as 10×6×MK contained the DLSFMKGE sequence from the Drosophila, while the second one, referred to as 10×6×KK, contained the human DLSFKKGE sequence. It was found that the 10×6×MK β-sheet stack is stable, but the 10×6×KK β-sheet stack is not. The stability of the 10×6×MK β-sheet stack results from the hydrophobic interactions of the methionine and phenylalanine residues and the leucine residues of the neighboring sheets. The Met, Phe, and Leu hydrophobic units make a hydrophobic core for the stack of β-sheets. During the MD run, the Met, Phe, and Leu residues of the neighboring β-sheets acted as a conformational switch moving the β-sheets so that the Phe residue interacted with the Met residue from the neighboring β-sheet. Replacement of Met by Lys destroys the hydrophobic core, which is the stability factor of the β-sheet stack. For the 10×6×KK system, individual β-sheets were preserved during simulations, but the interactions between the β-sheets were lost. The calculations of a six β-sheet stack confirm the conclusion drawn from our earlier studies of single β-sheet systems that the β-sheets must form stacks to be stabilized. These results suggest that the two conserved basic residues at the diverging turn of SH3 domains could act as gatekeepers to avoid aggregation.
    背景与目标: : 在显式水中对两个堆栈进行了分子动力学模拟,每个堆栈由两个肽的六个10链反平行 β-折叠组成,对应于两个同源Abl-SH3域的发散转向。第一个系统 (称为10 × 6 × mk) 包含果蝇的DLSFMKGE序列,而第二个系统 (称为10 × 6 × kk) 包含人类DLSFKKGE序列。发现10 × 6 × mk β-折叠堆叠是稳定的,而10 × 6 × kk β-折叠堆叠则不稳定。10 × 6 × mk β-薄片堆叠的稳定性是由蛋氨酸和苯丙氨酸残基与相邻薄片的亮氨酸残基的疏水相互作用引起的。Met,Phe和Leu疏水单元为 β-折叠堆叠形成疏水核心。在MD运行期间,相邻 β-sheet的Met,Phe和Leu残基充当构象开关,移动 β-sheet,以使Phe残基与相邻 β-sheet的Met残基相互作用。用Lys代替Met会破坏疏水核,这是 β-折叠堆叠的稳定性因子。对于10 × 6 × kk系统,在模拟过程中保留了单个 β-折叠,但是 β-折叠之间的相互作用丢失了。六个 β-sheet堆栈的计算证实了我们先前对单个 β-sheet系统的研究得出的结论,即 β-sheet必须形成堆栈才能稳定。这些结果表明,在SH3结构域发散的转弯处的两个保守的碱性残基可以充当网守以避免聚集。
  • 【BAG-1抑制结直肠肿瘤细胞中关键调节细胞因子转化生长因子 β (TGF-β1) 的表达。】 复制标题 收藏 收藏
    DOI:10.1038/onc.2012.480 复制DOI
    作者列表:Skeen VR,Collard TJ,Southern SL,Greenhough A,Hague A,Townsend PA,Paraskeva C,Williams AC
    BACKGROUND & AIMS: :As colorectal cancer remains the second highest cause of cancer-related deaths in much of the industrialised world, identifying novel strategies to prevent colorectal tumour development remains an important challenge. BAG-1 is a multi-functional protein, the expression of which is up-regulated at relatively early stages in colorectal tumorigenesis. Importantly, BAG-1 is thought to enhance colorectal tumour progression through promoting tumour cell survival. Here, we report for the first time a novel role for BAG-1, establishing it as a suppressor of transforming growth factor β (TGF-β1) expression in colorectal tumour cells. Microarray analysis first highlighted the possibility that BAG-1 may regulate TGF-β1 expression, a key cytokine in normal colonic tissue homoeostasis. Q-RT-PCR and ELISA demonstrated TGFB1 mRNA and protein expression to be significantly increased when BAG1 levels were reduced by small interfering RNA; additionally, induction of BAG-1L caused suppression of TGFB1 mRNA in colorectal tumour cells. Using reporter and chromatin immunoprecipitation assays, a direct association of BAG-1 with the TGFB1 gene regulatory region was identified. Immunohistochemistry and Weiser fraction data indicated that the levels of BAG-1 and TGF-β1 are inversely correlated in the normal colonic epithelium in vivo, consistent with a role for BAG-1-mediated repression of TGF-β1 production. In vitro studies showed that the change in TGF-β1 production following manipulation of BAG-1 is functionally relevant; through induction of anchorage-independent growth in TGF-β1-dependent normal rat kidney fibroblasts and regulation of SMAD2 phosphorylation in TGF-β1-sensitive adenoma cells. Taken together, this study identifies the anti-apoptotic protein BAG-1 as a suppressor of the inhibitory growth factor TGF-β1, suggesting that high expression of BAG-1 can impact on a number of the hallmarks of cancer, of potential importance in promoting the early stages of colorectal tumorigenesis. Establishing BAG-1 as a repressor of TGF-β1 has important biological implications, and highlights a new role for BAG-1 in colorectal tumorigenesis.
    背景与目标: : 由于大肠癌仍然是许多工业化国家中癌症相关死亡的第二大原因,因此确定预防大肠癌发展的新策略仍然是一项重要挑战。BAG-1是一种多功能蛋白,其表达在结直肠肿瘤发生的相对早期阶段上调。重要的是,BAG-1被认为可以通过促进肿瘤细胞存活来促进结直肠肿瘤的进展。在这里,我们首次报道了BAG-1的新作用,将其确立为大肠肿瘤细胞中转化生长因子 β (TGF-β1) 表达的抑制因子。微阵列分析首先强调了BAG-1可能调节TGF-β1表达的可能性,TGF-β1是正常结肠组织平衡中的关键细胞因子。Q-rt-pcr和ELISA证明,当小干扰RNA降低BAG1水平时,TGFB1 mRNA和蛋白表达显着增加; 此外,BAG-1L的诱导引起大肠肿瘤细胞中TGFB1 mRNA的抑制。使用报告基因和染色质免疫沉淀测定法,鉴定了BAG-1与TGFB1基因调控区的直接关联。免疫组织化学和Weiser分数数据表明,体内正常结肠上皮中BAG-1和TGF-β1的水平呈负相关,这与BAG-1介导的TGF-β1产生抑制作用一致。体外研究表明,操纵BAG-1后TGF-β1产生的变化在功能上是相关的; 通过诱导TGF-β1依赖性正常大鼠肾脏成纤维细胞中的锚定依赖性生长以及调节TGF-β1敏感性腺瘤细胞中的SMAD2磷酸化。总之,这项研究确定了抗凋亡蛋白BAG-1作为抑制性生长因子TGF-β1的抑制因子,表明BAG-1的高表达可以影响许多癌症的特征,在促进结直肠肿瘤发生的早期阶段具有潜在的重要性。建立BAG-1作为TGF-β1的阻遏物具有重要的生物学意义,并突出了BAG-1在结直肠肿瘤发生中的新作用。
  • 【TGF-β/miR-155/c-Ski调节人冠状动脉内皮细胞间充质转化的机制.】 复制标题 收藏 收藏
    DOI:10.1042/BSR20160603 复制DOI
    作者列表:Wang J,He W,Xu X,Guo L,Zhang Y,Han S,Shen D
    BACKGROUND & AIMS: :Human coronary artery endothelial cells (HCAECs) have the potential to undergo fibrogenic endothelial-mesenchymal transition (EndMT), which results in matrix-producing fibroblasts and thereby contributes to the pathogenesis of cardiac fibrosis. Recently, the profibrotic cytokine transforming growth factor-β (TGF-β) is shown to be the crucial pathogenic driver which has been verified to induce EndMT. C-Ski is an important regulator of TGF-β signaling. However, the detailed role of c-Ski and the molecular mechanisms by which c-Ski affects TGF-β-induced EndMT in HCAECs are not largely elucidated. In the present study, we treated HCAECs with TGF-β of different concentrations to induce EndMT. We found that overexpression of c-Ski in HCAECs either blocked EndMT via hindering Vimentin, Snail, Slug, and Twist expression while enhancing CD31 expression, with or without TGF-β treatment. In contrast, suppression of c-Ski further enhanced EndMT. Currently, miRNA expression disorder has been frequently reported associating with cardiac fibrosis. By using online tools, we regarded miR-155 as a candidate miRNA that could target c-Ski, which was verified using luciferase assays. C-Ski expression was negatively regulated by miR-155. TGF-β-induced EndMT was inhibited by miR-155 silence; the effect of TGF-β on Vimentin, CD31, Snail, Slug, and Twist could be partially restored by miR-155. Altogether, these findings will shed light on the role and mechanism by which miR-155 regulates TGF-β-induced HCAECs EndMT via c-Ski to affect cardiac fibrosis, and miR-155/c-Ski may represent novel biomarkers and therapeutic targets in the treatment of cardiac fibrosis.
    背景与目标: : 人冠状动脉内皮细胞 (HCAECs) 具有发生纤维化的内皮-间质转化 (EndMT) 的潜力,这导致产生基质的成纤维细胞,从而有助于心脏纤维化的发病机理。最近,纤维化细胞因子转化生长因子-β (TGF-β) 被证明是关键的致病驱动因素,已被证实可诱导EndMT。C-ski是TGF-β 信号的重要调节因子。然而,c-Ski的详细作用以及c-Ski影响HCAECs中TGF-β 诱导的EndMT的分子机制尚未得到很大的阐明。在本研究中,我们用不同浓度的TGF-β 处理HCAECs以诱导EndMT。我们发现,有或没有TGF-β 处理,HCAECs中c-Ski的过表达通过阻碍波形蛋白,蜗牛,Slug和Twist的表达来阻断EndMT,同时增强CD31的表达。相比之下,抑制c-ski进一步增强了EndMT。目前,miRNA表达紊乱经常被报道与心脏纤维化有关。通过使用在线工具,我们将miR-155视为可以靶向c-Ski的候选miRNA,使用荧光素酶分析验证了这一点。C-Ski表达受miR-155负调节。TGF-β 诱导的EndMT被miR-155沉默抑制; TGF-β 对波形蛋白,CD31,蜗牛,Slug和Twist的作用可以通过miR-155部分恢复。总之,这些发现将阐明miR-155通过c-Ski调节TGF-β 诱导的HCAECs EndMT以影响心脏纤维化的作用和机制,并且miR-155/c-Ski可能代表治疗心脏纤维化的新型生物标志物和治疗靶标。
  • 【壳聚糖-磷酸甘油/血液植入物增加钻孔软骨缺损中的细胞募集,瞬时血管化和软骨下骨重塑。】 复制标题 收藏 收藏
    DOI:10.1016/j.joca.2006.08.007 复制DOI
    作者列表:Chevrier A,Hoemann CD,Sun J,Buschmann MD
    BACKGROUND & AIMS: OBJECTIVE:Marrow-stimulation techniques are used by surgeons to repair cartilage lesions although consistent regeneration of hyaline cartilage is rare. We have shown previously that autologous blood can be mixed with a polymer solution containing chitosan in a glycerol phosphate (GP) buffer (chitosan-GP), and that implantation of this polymer/blood composite onto marrow-stimulated chondral defects in rabbit and sheep leads to the synthesis of more chondral repair tissue with greater hyaline character compared to marrow-stimulation alone. In the current study, we examined the modulation of cell recruitment and repair tissue characteristics at early post-surgical time points (from day 1 to 56) in a rabbit model to elucidate potential mechanisms behind this improved repair outcome. DESIGN:Thirty-three skeletally mature New Zealand White rabbits underwent bilateral arthrotomies, with each trochlea receiving a cartilage defect (3.5 mm x 4.5mm) bearing four microdrill holes (0.9 mm diameter, approximately 4 mm deep) into the subchondral bone. One defect per rabbit was treated with a chitosan-GP/blood implant, while the other defect was left as a microdrilled control. Repair tissues were stained by histochemistry, for collagen types I, II, and X by immunohistochemistry and analyzed using quantitative stereological tools. RESULTS:Histological analyses demonstrated that control defects followed a typical healing sequence observed previously in marrow-stimulation animal models while chitosan-GP/blood implants led to three significant modifications in the healing sequence at early stages: (1) increased inflammatory and marrow-derived stromal cell recruitment to the microdrill holes, (2) increased vascularization of the provisional repair tissue in the microdrill holes, and (3) increased intramembranous bone formation and subchondral bone remodeling (BR). CONCLUSIONS:These results suggest that the greater levels of provisional tissue vascularization and BR activity are main factors supporting improved cartilage repair when chitosan-GP/blood implants are applied to marrow-stimulated cartilage lesions.
    背景与目标:
  • 【磷酸三甲苯酯诱导的母鸡腰脊髓神经元丢失 -- 免疫组织化学和超微结构研究。】 复制标题 收藏 收藏
    DOI:10.1080/00207450500519655 复制DOI
    作者列表:Mou DL,Wang YP,Song JF,Rao ZR,Duan L,Ju G
    BACKGROUND & AIMS: :To investigate the neuronal losses of hens' spinal cords in the model of organophosphate-induced delayed neuropathy (OPIDN) and to analyze the impact of apoptosis on the pathogenesis of OPIDN. Adult hens were challenged with triorthocresyl phosphate (TOCP) at a single dose (750 mg/kg). Neuronal losses in the 3rd lumbar spinal cord (L3) were assessed by light-microscopy and electron-microscopy methods at different days post exposure, respectively. The typical OPIDN signs were seen in the TOCP-exposed hens at about 9th day. The number of large nerve cells declined gradually. And these cells were verified as neurons by immunostained with neuronal marker NeuN. The expression of FasL reached proximal at about 9th day, decreased from 14th day. Neurons in TOCP exposed groups displayed degenerative morphologies in electronic microscopy. Some neurons showed apoptotic-like ultrastructure profiles at 5th day. The nuclear membrane was complete with chromatin condensed to the margins of nuclear membrane like a crescent-shaped body. Mitochondria morphologic changes appeared early (5 d) following exposure to TOCP, and developed in a time-dependent fashion. Apoptosis might be involved in the development of OPIDN, and play a role in the pathogenesis of OPIDN.
    背景与目标: : 研究有机磷酸盐诱导的迟发性神经病 (OPIDN) 模型中母鸡脊髓的神经元丢失,并分析凋亡对OPIDN发病机理的影响。以单剂量 (750 mg/kg) 对成年母鸡进行磷酸三邻甲苯酯 (TOCP) 攻击。在暴露后的不同天,分别通过光学显微镜和电子显微镜方法评估了第三腰椎脊髓 (L3) 的神经元损失。在大约第9天,在暴露于TOCP的母鸡中可以看到典型的OPIDN迹象。大神经细胞的数量逐渐减少。通过用神经元标记NeuN免疫染色将这些细胞验证为神经元。FasL的表达在第9天左右达到近端,从第14天开始下降。TOCP暴露组的神经元在电子显微镜下显示出退化形态。某些神经元在第5天显示凋亡样超微结构。核膜是完整的,染色质浓缩到核膜的边缘,就像一个新月形的身体。暴露于TOCP后早期 (5 d) 出现线粒体形态变化,并以时间依赖性方式发展。凋亡可能参与OPIDN的发生发展,并在OPIDN的发病机制中起作用。
  • 【放射性碘的雌莫司汀磷酸盐和雌莫司汀结合蛋白抗体在小鼠的前列腺中积累。】 复制标题 收藏 收藏
    DOI:10.1002/(sici)1097-0045(19970615)32:1<1::aid-pros1 复制DOI
    作者列表:Ståhlberg K,Kairemo K,Karonen SL,Jekunen A,Taari K,Rannikko S
    BACKGROUND & AIMS: BACKGROUND:The purpose of this study was to determine the distribution of radioiodinated estramustine (RI-EMP) and a radioiodinated antibody against estramustine binding protein (RI-EMBP-AB) in mice. METHODS:RI-EMP and RI-EMBP-AB were injected in male mice intravenously, and the activities of tissue samples were measured 1-31 hr from the injection. Pure iodine-125 (RI) was used as a control. RESULTS:RI-EMP accumulated in the prostate, which contained 2.6% of injected activity (ID) per gram tissue at 7 hr. The liver had an activity of 21.4% ID/g at 1 hr, which decreased as RI-EMP was secreted in bile. The lung contained 2.3% ID/g at 7 hr, and it retained the activity longer than the prostate. RI-EMBP-AB accumulated in the prostate: The activity was 2.9% ID/g at 7 hr. The gallbladder contained 6.5% ID/g at 7 hr. CONCLUSIONS:Due to its cytotoxic and radiosensitizing properties, RI-EMP can possibly be used for treating prostate cancer and other tumors.
    背景与目标:
  • 【由琥珀酸沃林菌分离的ATP合酶催化的磷酸化和磷酸-ATP交换。】 复制标题 收藏 收藏
    DOI:10.1016/0005-2728(85)90218-x 复制DOI
    作者列表:Bokranz M,Mörschel E,Kröger A
    BACKGROUND & AIMS: :The ATP synthase, isolated from Wolinella (formerly Vibrio) succinogenes could be fully incorporated into liposomes without significant cleavage of the enzyme or loss of activity. These proteoliposomes, but not the isolated enzyme, catalyzed phosphate-ATP exchange and the phosphorylation of ADP which was driven by an artificially imposed delta mu H across the liposomal membrane. Phosphorylation driven by light was catalyzed by proteoliposomes containing also bacteriorhodopsin. The three activities were similarly sensitive to protonophores or dicyclohexylcarbodiimide. This sensitivity was similar to that of the electron-transport-driven phosphorylation catalyzed by bacterial membrane vesicles. With a delta mu H value 280 mV to drive phosphorylation the turnover number of the enzyme was in the same order of magnitude as that measured in the electron-transport-driven phosphorylation catalyzed by the bacterial membrane. When the delta mu H was below 150 mV, the phosphorylation activity of the incorporated enzyme was two orders of magnitude slower, and was about as fast as light-driven phosphorylation or as the exchange reaction.
    背景与目标: : 从Wolinella (以前称为弧菌) 琥珀生成素中分离出的ATP合酶可以完全掺入脂质体中,而不会显着裂解酶或丧失活性。这些蛋白脂质体 (而不是分离的酶) 催化了磷酸盐-ATP交换和ADP的磷酸化,而ADP的磷酸化是由在脂质体膜上人工施加的 δ mu H驱动的。光驱动的磷酸化是由也含有细菌视紫红质的蛋白脂质体催化的。这三种活性对原蛋白或二环己基碳二亚胺敏感。这种敏感性与细菌膜囊泡催化的电子传输驱动的磷酸化相似。在280 mV驱动磷酸化的 δ μ H值的情况下,酶的周转数与在由细菌膜催化的电子传输驱动的磷酸化中测量的周转数处于相同的数量级。当 δ μ H低于150 mV时,掺入的酶的磷酸化活性慢两个数量级,并且大约与光驱动磷酸化或交换反应一样快。
  • 【番木瓜脂肪酶在间歇开放反应模式下生物合成 (S)-萘普生淀粉酯。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Wang Y,Xin JY,Li QH,Sun LR,Xia CG
    BACKGROUND & AIMS: :Inorder to brought S-naproxen into small intestine, an optically pure (S)-naproxen starch ester was produced by lipase through enantio-selective trans-esterification of racemic naproxen methyl ester with pretreatment starch in solvent system. With carefully selection of the reaction medium (isooctane), lipase (Carica Papaya Lipase, CPL) and the reaction mode (intermittent opening), a high conversion rate (48.6%) and enantiomeric excess of product (99.6%) was obtained. The slow release macromolecular (S)-Naproxen had been synthesized to improve the efficacy of racemic naproxen and overcome its side effects. The enanitomeric ratio of CPL (E=52.5) was higher than CRL (E=22) and greatly influenced by the byproduct methyl alcohol. The intermittent opening reaction mode was the effective way to remove the inhibition of methyl alcohol and to improve the enantio-selectivity of CPL. S-naproxen starch was confirmed by HPLC and 1H NMR. This method may also apply to preparation the other optically pure 2-phenylpropionic acid derivatives. S-naproxen starch was a new optically pure derivatives possessing emulsifying and slow release properties would be widely applied to the food, pharmaceutical and biomedical industries.
    背景与目标: : 为了将S-萘普生带入小肠,通过脂肪酶通过外消旋萘普生甲酯与预处理淀粉在溶剂体系中的对映选择性酯化反应,制得光学纯的 (S)-萘普生淀粉酯。通过仔细选择反应介质 (异辛烷) 、脂肪酶 (番木瓜脂肪酶,CPL) 和反应模式 (间歇开放),获得高转化率 (48.6%) 和对映体过量的产物 (99.6%)。合成了缓释大分子萘普生,以提高外消旋萘普生的功效并克服其副作用。CPL的烯醇比 (E = 52.5) 高于CRL (E = 22),并且受副产物甲醇的影响很大。间歇开放反应模式是去除甲醇抑制和提高CPL对映体选择性的有效途径。通过HPLC和1H NMR证实了S-萘普生淀粉。该方法也可用于制备其他光学纯的2-苯基丙酸衍生物。S-萘普生淀粉是一种新型的光学纯衍生物,具有乳化和缓释特性,被广泛应用于食品、制药和生物医药行业。
  • 【BEL β-三叶草: 一种在牛肝菌 (牛肝菌) 蘑菇中具有抗肿瘤特性的新型凝集素。】 复制标题 收藏 收藏
    DOI:10.1093/glycob/cws164 复制DOI
    作者列表:Bovi M,Cenci L,Perduca M,Capaldi S,Carrizo ME,Civiero L,Chiarelli LR,Galliano M,Monaco HL
    BACKGROUND & AIMS: :A novel lectin was purified from the fruiting bodies of king bolete mushrooms (Boletus edulis, also called porcino, cep or penny bun). The lectin was structurally characterized i.e its amino acid sequence and three-dimensional structure were determined. The new protein is a homodimer and each protomer folds as β-trefoil domain and therefore we propose the name Boletus edulis lectin (BEL) β-trefoil to distinguish it from the other lectin that has been described in these mushrooms. The lectin has potent anti-proliferative effects on human cancer cells, which confers to it an interesting therapeutic potential as an antineoplastic agent. Several crystal forms of the apoprotein and of complexes with different carbohydrates were studied by X-ray diffraction. The structure of the apoprotein was solved at 1.12 Å resolution. The interaction of the lectin with lactose, galactose, N-acetylgalactosamine and T-antigen disaccharide, Galβ1-3GalNAc, was examined in detail. All the three potential binding sites present in the β-trefoil fold are occupied in at least one crystal form and are described in detail in this paper. No important conformational changes are observed in the lectin when comparing its co-crystals with carbohydrates with those of the ligand-free protein.
    背景与目标: : 从牛肝菌王蘑菇 (牛肝菌,也称为牛肝菌,cep或penny bun) 的子实体中纯化了一种新型凝集素。凝集素的结构表征,即确定其氨基酸序列和三维结构。新蛋白是同型二聚体,每个原聚物都折叠为 β-三叶结构域,因此我们提出了牛肝菌 (Boletus edulis) 凝集素 (BEL) β-三叶,以将其与这些蘑菇中描述的其他凝集素区分开。凝集素对人类癌细胞具有有效的抗增殖作用,这赋予它作为抗肿瘤药的有趣治疗潜力。通过x射线衍射研究了载脂蛋白和与不同碳水化合物的复合物的几种晶体形式。载脂蛋白的结构以1.12的分辨率求解。详细检查了凝集素与乳糖,半乳糖,N-乙酰半乳糖胺和T抗原二糖Galβ1-3GalNAc的相互作用。存在于 β-三叶折叠中的所有三个潜在结合位点均以至少一种晶体形式占据,并在本文中进行了详细描述。将凝集素与碳水化合物的共晶体与无配体蛋白的共晶体进行比较时,未观察到凝集素的重要构象变化。
  • 【靶向脂肪酸酰胺水解酶 (FAAH) 和瞬时受体电位 (TRP) 通道的四氢-β-carboline衍生物。】 复制标题 收藏 收藏
    DOI:10.1016/j.bmcl.2012.10.137 复制DOI
    作者列表:Ortar G,De Petrocellis L,Moriello AS,Allarà M,Morera E,Nalli M,Di Marzo V
    BACKGROUND & AIMS: :A series of twenty-five derivatives of tetrahydro-β-carbolines 1-3 was synthesized and assayed on FAAH and TRPV1 and TRPA1 channels. Four carbamates, that is, 5a,c,e, and 9b inhibited FAAH with significant potency and interacted also effectively with TRPV1 and TRPA1 nociceptive receptors, while ureas 7b,d,f, and 8a,b were endowed with specific submicromolar TRPV1 modulating activities.
    背景与目标: : 合成了一系列25种四氢-β-carbolines 1-3衍生物,并在FAAH和TRPV1和TRPA1通道上进行了测定。四种氨基甲酸酯,即5a,c,e和9b以显着的效力抑制FAAH,并且还与TRPV1和TRPA1伤害性受体有效相互作用,而ureas 7b,d,f和8a,b具有特定的亚微摩尔TRPV1调节活性。
  • 【磷酸盐粘合剂治疗对早期慢性肾脏病血管僵硬度的影响。】 复制标题 收藏 收藏
    DOI:10.1159/000353569 复制DOI
    作者列表:Seifert ME,de las Fuentes L,Rothstein M,Dietzen DJ,Bierhals AJ,Cheng SC,Ross W,Windus D,Dávila-Román VG,Hruska KA
    BACKGROUND & AIMS: BACKGROUND/AIMS:Cardiovascular disease (CVD) is increased in chronic kidney disease (CKD), and contributed to by the CKD-mineral bone disorder (CKD-MBD). CKD-MBD begins in early CKD and its vascular manifestations begin with vascular stiffness proceeding to increased carotid artery intima-media thickness (cIMT) and vascular calcification (VC). Phosphorus is associated with this progression and is considered a CVD risk factor in CKD. We hypothesized that modifying phosphorus balance with lanthanum carbonate (LaCO3) in early CKD would not produce hypophosphatemia and may affect vascular manifestations of CKD-MBD. METHODS:We randomized 38 subjects with normophosphatemic stage 3 CKD to a fixed dose of LaCO3 or matching placebo without adjusting dietary phosphorus in a 12-month randomized, double-blind, pilot and feasibility study. The primary outcome was the change in serum phosphorus. Secondary outcomes were changes in measures of phosphate homeostasis and vascular stiffness assessed by carotid-femoral pulse wave velocity (PWV), cIMT and VC over 12 months. RESULTS:There were no statistically significant differences between LaCO3 and placebo with respect to the change in serum phosphorus, urinary phosphorus, tubular reabsorption of phosphorus, PWV, cIMT, or VC. Biomarkers of the early CKD-MBD such as plasma fibroblast growth factor-23, Dickkopf-related protein 1 (DKK1), and sclerostin were increased 2- to 3-fold at baseline, but were not affected by LaCO3. CONCLUSION:Twelve months of LaCO3 had no effect on serum phosphorus and did not alter phosphate homeostasis, PWV, cIMT, VC, or biomarkers of CKD-MBD.
    背景与目标:
  • 【蜂胶保护胰岛 β 细胞免受链脲佐菌素 (STZ) 的毒性。】 复制标题 收藏 收藏
    DOI:10.1016/S0944-7113(96)80037-7 复制DOI
    作者列表:Matsushige K,Basnet P,Hase K,Kadota S,Tanaka K,Namba T
    BACKGROUND & AIMS: :Propolis is a glue, prepared by honeybees from plant materials to stick their hives on the beehive wall. It has gained popularity in Japan as a healthy drink and people believe that propolis can cure inflammation, heart diseases and even diabetes and cancer. We have evaluated the β-cell protective effect of propolis against the toxicity of streptozotocin (STZ) in rats. The water extract of propolis (PWE) completely protected β-cell destruction against STZ toxicity. The protective effect of PWE was found to be almost equal to that of nicotinamide. PWE also inhibited the interleukin-1 β (IL-1 β) generation from human leukocytes. The free radical scavenging activity together with IL-1 β and nitric oxide (NO) synthase inhibitory activities are thought to be the prime factors for the protective effect of PWE against STZ toxicity.
    背景与目标: : 蜂胶是一种胶水,由蜜蜂用植物材料制成,将蜂巢粘在蜂巢壁上。它作为一种健康的饮料在日本越来越受欢迎,人们认为蜂胶可以治愈炎症,心脏病,甚至糖尿病和癌症。我们已经评估了蜂胶对大鼠链脲佐菌素 (STZ) 毒性的 β 细胞保护作用。蜂胶 (PWE) 的水提取物完全保护了 β 细胞的破坏免受STZ毒性。发现PWE的保护作用几乎与烟酰胺相同。PWE还抑制人白细胞interleukin-1 β (IL-1 β) 的产生。自由基清除活性以及IL-1 β 和一氧化氮合酶抑制活性被认为是PWE对STZ毒性保护作用的主要因素。
  • 【用玉米淀粉珠通过无污染干磨技术一步制备球形药物颗粒。】 复制标题 收藏 收藏
    DOI:10.1016/j.ijpharm.2017.06.062 复制DOI
    作者列表:Niwa T,Yoshida M,Hayashi N,Kondo K
    BACKGROUND & AIMS: :The novel dry milling technique has been developed by using a mechanical powder processor for improving the dissolution properties of poorly water-soluble drugs. It was found that the drug crystals were well pulverized by co-processing with fine particles of corn starch (CS). The morphological observation and particle size evaluation revealed that the processed products formed the composite particles with ordered-mixed structure, having double-layered particles with a core of CS and a coating layer of phenytoin (Phe), as a model drug. This result suggested that the drug crystals were selectively micronized and the resultant miniaturized Phe particles were adhered/fixed on the surface of un-milled CS particles. The mechanical characteristics detected by the indentation test assumed that the brittle Phe crystals sandwiched between elastic CS particles would be successfully crushed down by high shearing stress in the processor. The newly-established dispersion-sedimentation test indicated that the fine Phe particles were immediately detached from the composite particles in aqueous phase, constructing the suspension. The dissolution behavior from the processed particles was found to be improved and strongly dependent on the size and amount of detached Phe particles. Such milling and ordered-mixturization have been also successfully done by using recrystallized larger Phe particles than 100μm. These results would propose the contamination-free dry milling technique without using hard milling balls or beads. The mechanism of the current milling and ordered-mixing phenomena is also provided in this report.
    背景与目标: : 通过使用机械粉末处理器开发了新颖的干磨技术,以改善水溶性差的药物的溶解性能。发现通过与玉米淀粉 (CS) 的细颗粒共加工,药物晶体被很好地粉碎。形态观察和粒度评估表明,加工后的产品形成了具有有序混合结构的复合颗粒,具有具有CS核心和苯妥英 (Phe) 涂层的双层颗粒,作为模型药物。该结果表明,药物晶体被选择性微粉化,并且所得的微型Phe颗粒粘附/固定在未研磨的CS颗粒的表面上。通过压痕测试检测到的机械特性假设夹在弹性CS颗粒之间的脆性Phe晶体将被处理器中的高剪切应力成功压碎。新建立的分散沉降测试表明,细小的Phe颗粒立即从水相中的复合颗粒中分离出来,形成了悬浮液。发现处理后的颗粒的溶解行为得到改善,并且在很大程度上取决于分离的Phe颗粒的大小和数量。通过使用重结晶的大于100微米的较大Phe颗粒也成功地完成了这种研磨和有序混合。这些结果将提出无污染的干磨技术,而无需使用硬磨球或珠。本报告还提供了当前铣削和有序混合现象的机理。
  • 【日本一家儿科三级保健医院住院患者直肠携带产超广谱 β-内酰胺酶肠杆菌的比例。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Minami K,Shoji Y,Kasai M,Ogiso Y,Nakamura T,Kawakami Y,Saito Y,Kuzumoto K,Kubota N,Yumoto K,Ishii K
    BACKGROUND & AIMS: :Extended-spectrum β-lactamase (ESBL)-producing-Enterobacteriaceae strains were detected in 12% (6 out of 50) of fecal samples collected from the inpatients of a Japanese pediatric hospital. All the ESBLs belonged to the CTX-M-1 group. The proportion of carriage of ESBL producers was higher among patients who had received antibiotics within the past 3 months and among those who had cardiologic diseases.
    背景与目标: : 在从日本一家儿科医院的住院患者收集的粪便样本中,检测到产生超广谱 β-内酰胺酶 (ESBL) 的肠杆菌科菌株的12% 个 (50个中的6个)。所有的ESBLs都属于CTX-M-1集团。在过去3个月内接受过抗生素治疗的患者和心脏病患者中,ESBL生产者的携带比例较高。

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