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41.
K. Isensee M. Amon A. Galaparti X. Ligneau J.-C. Camelin M. Capet J.-C. Schwartz H. Stark 《Bioorganic & medicinal chemistry letters》2009,19(8):2172-2175
Fluorine substituents have become a widespread and important component in drug design and development. Here, the synthesis of fluorine containing compounds and some corresponding precursor molecules are presented for potential isotope labelling as well as their data obtained with in vitro and in vivo screenings. The compounds vary in the basic centres (piperidine or pyrrolidine) and are fluoro substituted in different positions of the basic alicyclic moiety. Pharmacological evaluation resulted in ligands with high affinities at hH3 receptor in the nanomolar and subnanomolar concentration range and some with high antagonist in vivo potencies. 相似文献
42.
43.
Sydney X. Lu Emma De Neef James D. Thomas Erich Sabio Benoit Rousseau Mathieu Gigoux David A. Knorr Benjamin Greenbaum Yuval Elhanati Simon J. Hogg Andrew Chow Arnab Ghosh Abigail Xie Dmitriy Zamarin Daniel Cui Caroline Erickson Michael Singer Hana Cho Robert K. Bradley 《Cell》2021,184(15):4032-4047.e31
44.
45.
R. Yang D. Yin D. Yang X. Liu Q. Zhou Y. Pan J. Li S. Li 《Letters in applied microbiology》2021,73(6):779-792
This study aims to explore the potential mechanisms of Xinnaokang in atherosclerosis treatment. Firstly, the active components of Xinnaokang were analysed by HPLC, which contains ginsenoside Rg1, puerarin, tanshinone, notoginsenoside R1, ammonium glycyrrhizate and glycyrrhizin. Network pharmacology analysis showed there were 145 common targets of Xinnaokang, including the chemical stress, lipid metabolite, lipopolysaccharide, molecules of bacterial origin, nuclear receptor and fluid shear stress pathways. Then, the animal experiment showed that Xinnaokang reduced the body weight and blood lipid levels of atherosclerotic mice. Vascular plaque formation was increased in atherosclerotic mice, which was markedly reversed by Xinnaokang. In addition, Xinnaokang reduced CAV-1 expression and increased ABCA1, SREBP-1 and LXR expressions in the vasculature. Xinnaokang promoted SREBP-2 and LDLR expressions in the liver but decreased IDOL and PCSK9 expressions, indicating that Xinnaokang regulated lipid transport-related protein expression. Cecal microbiota diversity was reduced in atherosclerotic mice but increased after Xinnaokang treatment. Xinnaokang treatment also improved gut microbiota communities by enriching Actinobacteria, Bifidobacteriales and Bifidobacteriaceae abundances. Metabolic profile showed that Xinnaokang significantly reduced homogentisate, phenylacetylglycine, alanine and methionine expressions in the liver of atherosclerotic mice. Xinnaokang effectively alleviated atherosclerosis, and this effect might be linked with the altered features of the liver metabolite profiles and cecal microbiota. 相似文献
46.
Endophilin is a key protein involved in clathrin-mediated endocytosis. Previous computational and experimental work suggested that the N-terminal helix is embedded into the membrane to induce curvature; however, the role of the SH3 domain remains controversial. To address this issue, we performed computer simulations of the endophilin dimer in solution to understand the interaction between the N-BAR and SH3 domains and its effect on biological function. We predict that the helix binds to the SH3 domain through hydrophobic and salt-bridge interactions. This protects the hydrophobic residues on both domains and keeps the SH3 domain near the end of the N-BAR domain, in agreement with previous experimental results. The complex has a binding strength similar to a few hydrogen bonds (13.0 ± 0.6 kcal/mol), and the SH3 domain stabilizes the structure of the N-terminal helix in solution. Electrostatic calculations show a large region of strongly positive electrostatic potential near the N-terminal that can orient the helix toward the membrane and likely embed the helix into the membrane surface. This predicted mechanism suggests that endophilin can select for both curvature and electrostatic potential when interacting with membranes, highlighting the importance of the SH3 domain in regulating the function of endophilin. 相似文献
47.
Afforestation of former croplands has been proposed as a promising way to mitigate rising atmospheric CO2 concentration in view of the commitment to the Kyoto Protocol. Central to this C sequestration is the dynamics of soil organic C (SOC) storage and stability with the development of afforested plantations. Our previous study showed that SOC storage was not changed after afforestation except for the 0–10 cm layer in a semi-arid region of Keerqin Sandy Lands, northeast China. In this study, soil organic C was further separated into light and heavy fractions using the density fractionation method, and their organic C concentration and 13C signature were analyzed to investigate the turnover of old vs. new SOC in the afforested soils. Surface layer (0–10 cm) soil samples were collected from 14 paired plots of poplar (Populus × xiaozhuanica W. Y. Hsu & Liang) plantations with different stand basal areas (the sum of the cross-sectional area of all live trees in a stand), ranging from 0.2 to 32.6 m2 ha−1, and reference maize (Zea mays L.) croplands at the same sites as our previous study. Soil ΔC stocks (ΔC refers to the difference in SOC content between a poplar plantation and the paired cropland) in bulk soil and light fraction were positively correlated with stand basal area (R
2 = 0.48, p<0.01 and R
2 = 0.40, p = 0.02, respectively), but not for the heavy fraction. SOCcrop (SOC derived from crops) contents in the light and heavy fractions in poplar plantations were significantly lower as compared with SOC contents in croplands, but tree-derived C in bulk soil, light and heavy fraction pools increased gradually with increasing stand basal area after afforestation. Our study indicated that cropland afforestation could sequester new C derived from trees into surface mineral soil, but did not enhance the stability of SOC due to a fast turnover of SOC in this semi-arid region. 相似文献
48.
Simon D X Chuong Robert T Mullen Douglas G Muench 《The Journal of biological chemistry》2002,277(4):2419-2429
The control of subcellular mRNA localization and translation is often mediated by protein factors that are directly or indirectly associated with the cytoskeleton. We report the identification and characterization of a rice seed protein that possesses both RNA and microtubule binding activities. In vitro UV cross-linking assays indicated that this protein binds to all mRNA sequences tested, although there was evidence for preferential binding to RNAs that contained A-C nucleotide sequence motifs. The protein was purified to homogeneity using a two-step procedure, and amino acid sequencing identified it as the multifunctional protein (MFP), a peroxisomal enzyme known to possess a number of activities involved in the beta-oxidation of fatty acids. The recombinant version of this rice MFP binds to RNA in UV cross-linking and gel mobility shift experiments, co-sediments specifically with microtubules, and possesses at least two enzymatic activities involved in peroxisomal fatty acid beta-oxidation. Taken together these data suggest that MFP has an important role in mRNA physiology in the cytoplasm, perhaps in regulating the localization or translation of mRNAs through an interaction with microtubules, in addition to its peroxisomal function. 相似文献
49.
G Y Song X G Zheng Y Kim Y J You D E Sok B Z Ahn 《Bioorganic & medicinal chemistry letters》1999,9(16):2407-2412
6-(1-Hydroxyalkyl)-5,8-dimethoxy-1,4-naphthoquinones, expressing a higher reactivity in conjugation with glutathione, showed a greater potency in the inhibition of DNA topoisomerase-I and the cytotoxicity against L1210 cells than 2-(1-hydroxyalkyl)-DMNQ derivatives, implying the participation of electrophilic arylation in the bioactivities. In further study 6-(1-Hydroxyalkyl)-5,8-dimethoxy-1,4-naphthoquinones with an alkyl group of shorter chain length (C2-C6) exerted a greater bioactivities than those with longer chain length(>C6). 相似文献
50.
E Estébanez-Perpi?á A Bayés J Vendrell M A Jongsma D P Bown J A Gatehouse R Huber W Bode F X Avilés D Reverter 《Journal of molecular biology》2001,313(3):629-638
The cotton bollworm Helicoverpa armigera (Hubner) (Lepidoptera: Noctuidae) is one of the most serious insect pests in Australia, India and China. The larva causes substantial economical losses to legume, fibre, cereal oilseed and vegetable crops. This pest has proven to be difficult to control by conventional means, mainly due to the development of pesticide resistance. We present here the 2.5 A crystal structure from the novel procarboxypeptidase (PCPAHa) found in the gut extracts from H. armigera larvae, the first one reported for an insect. This metalloprotease is synthesized as a zymogen of 46.6 kDa which, upon in vitro activation with Lys-C endoproteinase, yields a pro-segment of 91 residues and an active carboxypeptidase moiety of 318 residues. Both regions show a three-dimensional structure quite similar to the corresponding structures in mammalian digestive carboxypeptidases, the most relevant structural differences being located in the loops between conserved secondary structure elements, including the primary activation site. This activation site contains the motif (Ala)(5)Lys at the C terminus of the helix connecting the pro- and the carboxypeptidase domains. A remarkable feature of PCPAHa is the occurrence of the same (Ala)(6)Lys near the C terminus of the active enzyme. The presence of Ser255 in PCPAHa instead of Ile and Asp found in the pancreatic A and B forms, respectively, enlarges the S1' specificity pocket and influences the substrate preferences of the enzyme. The C-terminal tail of the leech carboxypeptidase inhibitor has been modelled into the PCPAHa active site to explore the substrate preferences and the enzymatic mechanism of this enzyme. 相似文献