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121.
Szabo M Agostino M Malone DT Yuriev E Capuano B 《Bioorganic & medicinal chemistry letters》2011,21(22):6782-6787
We have synthesised an extensive series of URB602 analogues as inhibitors of monoacylglycerol lipase (MAGL), which is the major enzyme responsible for metabolising the endocannabinoid 2-arachidonylglycerol. The recently identified crystal structure of MAGL was used in the design strategy and revealed three possible binding sites for URB602 and the proposed analogues. A test series of carbamate analogues were docked into the identified sites to predict the most favourable binding location. The synthesised analogues of URB602 explored the biological effects of isosteric replacement, ring size and substitution, para substitution of the biphenyl moiety and the incorporation of a bicyclic element. The compounds were tested for their ability to inhibit human MAGL. The carbamate analogue 16 displayed the most significant inhibitory activity, reducing MAGL activity to 26% of controls at 100 μM compared to 73% for the parent compound URB602. 相似文献
122.
Hênio Henrique Arag?o Rêgo Lidia A. Braunstein Gregorio D′Agostino H. Eugene Stanley Sasuke Miyazima 《PloS one》2014,9(10)
In linguistic studies, the academic level of the vocabulary in a text can be described in terms of statistical physics by using a “temperature” concept related to the text''s word-frequency distribution. We propose a “comparative thermo-linguistic” technique to analyze the vocabulary of a text to determine its academic level and its target readership in any given language. We apply this technique to a large number of books by several authors and examine how the vocabulary of a text changes when it is translated from one language to another. Unlike the uniform results produced using the Zipf law, using our “word energy” distribution technique we find variations in the power-law behavior. We also examine some common features that span across languages and identify some intriguing questions concerning how to determine when a text is suitable for its intended readership. 相似文献
123.
Lo Surdo P Bottomley MJ Calzetta A Settembre EC Cirillo A Pandit S Ni YG Hubbard B Sitlani A Carfí A 《EMBO reports》2011,12(12):1300-1305
The protein PCSK9 (proprotein convertase subtilisin/kexin type 9) is a key regulator of low-density lipoprotein receptor (LDLR) levels and cardiovascular health. We have determined the crystal structure of LDLR bound to PCSK9 at neutral pH. The structure shows LDLR in a new extended conformation. The PCSK9 C-terminal domain is solvent exposed, enabling cofactor binding, whereas the catalytic domain and prodomain interact with LDLR epidermal growth factor(A) and β-propeller domains, respectively. Thus, PCSK9 seems to hold LDLR in an extended conformation and to interfere with conformational rearrangements required for LDLR recycling. 相似文献
124.
125.
The emerging field of mass spectrometry-based chemical proteomics provides a powerful instrument in the target discovery of bioactive small-molecules, such as drugs or natural products. The identification of their macromolecular targets is required for a comprehensive understanding of their bio-pharmacological role and for unraveling their mechanism of action. We report the application of a chemical proteomics approach to the analysis of the cellular interactome of the marine metabolite bolinaquinone (BLQ). BLQ was linked to an opportune α,ω-diamino polyethylene glycol chain and then immobilized on a matrix support. The modified beads were then used as a bait for fishing the potential partners of BLQ in a THP-1 macrophage cell lysate. Surprisingly, we identified clathrin, a protein involved in the cell internalization of proteins, viruses and other biologically relevant macromolecules, as a specific and major BLQ partner. In addition, we verified the biochemical role of BLQ testing its ability to inhibit the clathrin-mediated endocytosis of albumin. This finding indicates BLQ as a new biotechnological tool for cell endocytosis studies and paves the way to further investigation on its potential role in modulating internalization process. 相似文献
126.
Santini V Girelli D Sanna A Martinelli N Duca L Campostrini N Cortelezzi A Corbella M Bosi A Reda G Olivieri O Cappellini MD 《PloS one》2011,6(8):e23109
Iron overload may represent an additional clinical problem in patients with Myelodysplastic Syndromes (MDS), with recent data suggesting prognostic implications. Beyond red blood cells transfusions, dysregulation of hepcidin, the key iron hormone, may play a role, but studies until now have been hampered by technical problems. Using a recently validated assay, we measured serum hepcidin in 113 patients with different MDS subtypes. Mean hepcidin levels were consistently heterogeneous across different MDS subtypes, with the lowest levels in refractory anemia with ringed sideroblasts (RARS, 1.43 nM) and the highest in refractory anemia with excess blasts (RAEB, 11.3 nM) or in chronic myelomonocytic leukemia (CMML, 10.04 nM) (P = 0.003 by ANOVA). MDS subtypes remained significant predictors of hepcidin in multivariate analyses adjusted for ferritin and transfusion history. Consistently with current knowledge on hepcidin action/regulation, RARS patients had the highest levels of toxic non-transferrin-bound-iron, while RAEB and CMML patients had substantial elevation of C-Reactive Protein as compared to other MDS subtypes, and showed lost of homeostatic regulation by iron. Growth differentiation factor 15 did not appear as a primary hepcidin regulator in this series. If confirmed, these results may help to calibrate future treatments with chelating agents and/or hepcidin modulators in MDS patients. 相似文献
127.
Gloria Formoso Merilda Taraborrelli Maria T. Guagnano Monica D’Adamo Natalia Di Pietro Armando Tartaro Agostino Consoli 《PloS one》2012,7(12)
Background
Obesity is characterized by a low grade chronic inflammation state. Indeed circulating pro-inflammatory cytokines, such as TNF-α and IL-6, are elevated in obese subjects, while anti-inflammatory cytokines, such as IL-10, appear to be reduced. Cytokines profile improves after weight loss, but how visceral or subcutaneous fat loss respectively affect pro- or anti-inflammatory cytokines plasma levels has not been precisely assessed. Therefore in the present study we correlated changes in circulating cytokine profile with quantitative changes in visceral and subcutaneous adipose tissue depots measured by an ad hoc Magnetic Resonance Imaging (MRI) protocol before and after weight loss.Materials and Methods
In 14 obese subjects, MRI determination of visceral and subcutaneous fat and plasma glucose, insulin, TNF-α IL-6, and IL-10 measurements were performed before and after a caloric restriction induced weight loss of at least 5% of the original body weight.Results
Weight loss improved insulin sensitivity (QUICKI Index: 0.35±0.03 vs 0.37±0.04; P<0.05), increased IL-10 (3.4±1.9 vs 4.6±1.0 pg/mL; P<0.03), and reduced TNF-α and IL-6 plasma levels (2.5±1.3 vs 1.6±1.5 pg/mL, P<0.0015, 2.3±0.4 vs 1.6±0.6 pg/mL, P<0.02 respectively). A significant correlation was observed between the amount of visceral fat loss and the percentage reduction in both TNF-α (r = 0.56, p<0.05) and IL-6 (r = 0.19 p<0.05) plasma levels. In a multiple regression analysis, the amount of visceral fat loss independently correlated with the increase in IL-10 plasma levels.Conclusion
The reduction in visceral adipose tissue is the main driver of the improved inflammatory profile induced by weight loss. 相似文献128.
129.
Abstract Fast-green absorption of cells localized in different regions of Allium cepa root cap.—The nuclear and cytoplasmic protein content of two cell population (C2 = columella cells; P2 = peripheral cells) has been determined by Barr and Stroud cytophotometer after Fast-green staining (after DNA extraction and without DNA extraction). The collected data seem indicate that: 1) histone content is higher in nuclei of C2 cells than in nuclei of P2 ones; 2) acid proteins content is higher in nuclei of P2 cells than in those of C2 ones; 3) the cytoplasmic proteins of the two cell populations are quite different in their Fast-green reactivity. 相似文献