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81.
82.
Enzymatic elimination of a class of substrates by the liver is analyzed in terms of a convective model of the microcirculation carrying the substrates. The elimination generates concentration gradients of the substrates which in turn affect the elimination rate through Michaelis-Menten saturation kinetics. The interplay of biochemical, anatomical and haemo-dynamic factors results in a variety of limiting regimes of elimination which are given a quantitative discussion and classification. The kinetic parameters of the enzymatic elimination reaction are expressed in terms of quantities observable on the intact liver. An overall elimination efficiency is defined by comparison with a homogenous process and evaluated for all elimination regimes, with clinical implications. Examples of two types of experiments supporting the validity of the model are presented. 相似文献
83.
Photosynthetic fructose-1,6-diphosphatase (FDPase) fractions I and II, earlier purified from spinach leaves, show a similar amino acid composition, with the exception of a higher glutamic acid content in the latter. In both fractions glutamic and aspartic acids are the main amino acids. pH activity profiles of fractions I and II are similar, with optima at 8·65–8·70, both showing a high specificity for fructose- 1,6-diphosphate. These two fractions are Mg2+-dependent for activity, with an Optimum Mg2+ concentration of 10 mM in standard conditions, which shifts to 5 mM when the MG2+/EDTA ratio is increased to 10; Mn2+ and Co2+ are slightly active. EDTA enhances FDPase activity slightly, with an optimum at 0·4–0·8 mM. Cysteine has no activating effect, and acts as an inhibitor above 10 mM. Both I and II have an optimum substrate concentration of 4 mM, and the substrate inhibits at concns above this value. Kinetic velocity curves are sigmoidal, with the concave zone located in the range of physiological substrate concns. (Hill coefficient 1·75 for both). This suggests a strong regulatory role of fructose-1,6-diphosphate. Km values are 1·4 × 10−3 M (fraction I) and 1·1 × 10−3 M (fraction II). The highest activity rate occurs at 60°, in accordance with the high thermostability of both fractions; the activation energies are 14·3 kcal/mol (fraction I) and 13·0 kcal/mol (fraction II). 相似文献
84.
Five spirostanol glycosides and two furostanol glycosides were isolated from Dioscorea floribunda. In addition to the IR spectra of the free glycosides and the MS of the peracetates and permethyl ethers, the most effective method for structural determination proved to be the NMR spectra of the free saponins in pyridine-d5. 相似文献
85.
Federico Riu Roberta Ibba Stefano Zoroddu Simona Sestito Michele Lai Sandra Piras Luca Sanna Valentina Bordoni Luigi Bagella Antonio Carta 《Journal of enzyme inhibition and medicinal chemistry》2022,37(1):2223
Introduction: Colchicine-binding site inhibitors are some of the most interesting ligands belonging to the wider family of microtubule-destabilising agents.Results: A novel series of 4′-fluoro-substituted ligands (5–13) was synthesised. The antiproliferative activity assays resulted in nM values for the new benzotriazole-acrylonitrile derivatives. Compound 5, the hit compound, showed an evident blockade of HeLa cell cycle in the G2-M phase, but also a pro-apoptotic potential, and an increase of early and late apoptotic cells in HeLa and MCF-7 cell cycle analysis. Confocal microscopy analysis showed a segmented shape and a collapse of the cytoskeleton, as well as a consistent cell shrinkage after administration of 5 at 100 nM. Derivative 5 was also proved to compete with colchicine at colchicine-binding site, lowering its activity against tubulin polymerisation. In addition, co-administration of 5 and doxorubicin in drug-resistant A375 melanoma cell line highlighted a synergic potential in terms of inhibition of cell viability.Discussion: The 4′-fluoro substitution of benzotriazole-acrylonitrile scaffold brought us a step forward in the optimisation process to obtain compound 5 as promising MDA antiproliferative agent at nanomolar concentration. 相似文献
86.
Steffen Winkler Katharina V. Meyer Christopher Heuer Carlotta Kortmann Michaela Dehne Janina Bahnemann 《Engineering in Life Science》2022,22(11):699
Additive manufacturing (3D printing) enables the fabrication of highly customized and complex devices and is therefore increasingly used in the field of life sciences and biotechnology. However, the application of 3D‐printed parts in these fields requires not only their biocompatibility but also their sterility. The most common method for sterilizing 3D‐printed parts is heat steam sterilization—but most commercially available 3D printing materials cannot withstand high temperatures. In this study, a novel heat‐resistant polyacrylate material for high‐resolution 3D Multijet printing was evaluated for the first time for its resistance to heat steam sterilization and in vitro biocompatibility with mouse fibroblasts (L929), human embryonic kidney cells (HEK 293E), and yeast (Saccharomyces cerevisiae (S. cerevisiae)). Analysis of the growth and viability of L929 cells and the growth of S. cerevisiae confirmed that the extraction media obtained from 3D‐printed parts had no negative effect on the aforementioned cell types, while, in contrast, viability and growth of HEK 293E cells were affected. No different effects of the material on the cells were found when comparing heat steam sterilization and disinfection with ethanol (70%, v/v). In principle, the investigated material shows great potential for high‐resolution 3D printing of novel cell culture systems that are highly complex in design, customized and easily sterilizable—however, the biocompatibility of the material for other cell types needs to be re‐evaluated. 相似文献
87.
Homeostasis of cell composition during prolonged darkness 总被引:1,自引:0,他引:1
The chemical composition of organisms in relation to their environmental resource availability is an area of intense research activity. We studied the changes in cell composition of the cyanobacterium Phormidium autumnale in response to prolonged darkness. Cells allocated their internal resources in a homeostatic manner, oxidizing all the three major cellular constituents in a proportional way. This resulted in constant C/N and carbohydrates, lipids and proteins ratios that remained unaltered throughout the whole incubation period. We propose the maintenance of balanced cell composition (homeostasis) as an evolutionary strategy related to environmental transitory changes. 相似文献
88.
Dietmar Moser Michael Kuttner Franz Essl Michael Leitner Manuela Winkler Siegrun Ertl Wolfgang Willner Ingrid Kleinbauer Norbert Sauberer Thomas Mang Niklaus E. Zimmermann Stefan Dullinger 《Global Change Biology》2016,22(7):2608-2619
Correlative species distribution models have long been the predominant approach to predict species’ range responses to climate change. Recently, the use of dynamic models is increasingly advocated for because these models better represent the main processes involved in range shifts and also simulate transient dynamics. A well‐known problem with the application of these models is the lack of data for estimating necessary parameters of demographic and dispersal processes. However, what has been hardly considered so far is the fact that simulating transient dynamics potentially implies additional uncertainty arising from our ignorance of short‐term climate variability in future climatic trends. Here, we use endemic mountain plants of Austria as a case study to assess how the integration of decadal variability in future climate affects outcomes of dynamic range models as compared to projected long‐term trends and uncertainty in demographic and dispersal parameters. We do so by contrasting simulations of a so‐called hybrid model run under fluctuating climatic conditions with those based on a linear interpolation of climatic conditions between current values and those predicted for the end of the 21st century. We find that accounting for short‐term climate variability modifies model results nearly as differences in projected long‐term trends and much more than uncertainty in demographic/dispersal parameters. In particular, range loss and extinction rates are much higher when simulations are run under fluctuating conditions. These results highlight the importance of considering the appropriate temporal resolution when parameterizing and applying range‐dynamic models, and hybrid models in particular. In case of our endemic mountain plants, we hypothesize that smoothed linear time series deliver more reliable results because these long‐lived species are primarily responsive to long‐term climate averages. 相似文献
89.
El-Kabbani O Darmanin C Schneider TR Hazemann I Ruiz F Oka M Joachimiak A Schulze-Briese C Tomizaki T Mitschler A Podjarny A 《Proteins》2004,55(4):805-813
The X-ray structures of human aldose reductase holoenzyme in complex with the inhibitors Fidarestat (SNK-860) and Minalrestat (WAY-509) were determined at atomic resolutions of 0.92 A and 1.1 A, respectively. The hydantoin and succinimide moieties of the inhibitors interacted with the conserved anion-binding site located between the nicotinamide ring of the coenzyme and active site residues Tyr48, His110, and Trp111. Minalrestat's hydrophobic isoquinoline ring was bound in an adjacent pocket lined by residues Trp20, Phe122, and Trp219, with the bromo-fluorobenzyl group inside the "specificity" pocket. The interactions between Minalrestat's bromo-fluorobenzyl group and the enzyme include the stacking against the side-chain of Trp111 as well as hydrogen bonding distances with residues Leu300 and Thr113. The carbamoyl group in Fidarestat formed a hydrogen bond with the main-chain nitrogen atom of Leu300. The atomic resolution refinement allowed the positioning of hydrogen atoms and accurate determination of bond lengths of the inhibitors, coenzyme NADP+ and active-site residue His110. The 1'-position nitrogen atom in the hydantoin and succinimide moieties of Fidarestat and Minalrestat, respectively, form a hydrogen bond with the Nepsilon2 atom of His 110. For Fidarestat, the electron density indicated two possible positions for the H-atom in this bond. Furthermore, both native and anomalous difference maps indicated the replacement of a water molecule linked to His110 by a Cl-ion. These observations suggest a mechanism in which Fidarestat is bound protonated and becomes negatively charged by donating the proton to His110, which may have important implications on drug design. 相似文献
90.
Mayor F Lucas E Jurado-Pueyo M Garcia-Guerra L Nieto-Vazquez I Vila-Bedmar R Fernández-Veledo S Murga C 《Archives of physiology and biochemistry》2011,117(3):125-130
G protein-coupled receptor kinase 2 (GRK2) is emerging as a key, integrative node in many signalling pathways. Besides its canonical role in the modulation of the signalling mediated by many G protein-coupled receptors (GPCR), this protein can display a very complex network of functional interactions with a variety of signal transduction partners, in a stimulus, cell type, or context-specific way. We review herein recent data showing that GRK2 can regulate insulin-triggered transduction cascades at different levels and that this protein plays a relevant role in insulin resistance and obesity in vivo, what uncovers GRK2 as a potential therapeutic target in the treatment of these disorders. 相似文献