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141.
The chirality of eschscholtzxanthin (all-trans (3S,3′S)-4′,5′-didehydro-4,5′-retro-β,βcarotene-3,3′-diol) at 3,3′ was assigned from the CD correlation of the natural material and the semi-synthetic carotenoid prepared by (NBS-dehydrogenation of natural zeaxanthin ((3R,3′R)-β,β-carotene-3,3′-diol). The δ6(6′)-trans configuration followed from 1H NMR evidence, including nuclear Overhauser experiments with rhodoxanthin, retrodehydro-carotene (4′,5′-didehydro-4,5′-retro-β,β-carotene) and smaller retro model compounds revealing a general preference for the δ6-trans configuration in retro compounds. Biosynthetic considerations are made. 相似文献
142.
Bourquin C Anz D Zwiorek K Lanz AL Fuchs S Weigel S Wurzenberger C von der Borch P Golic M Moder S Winter G Coester C Endres S 《Journal of immunology (Baltimore, Md. : 1950)》2008,181(5):2990-2998
Viral nucleic acids are recognized by specific pattern-recognition receptors of the Toll-like and RIG-I-like receptor families. Synthetic DNA and RNA oligonucleotides can activate the immune system through these receptors and potentiate Ab and CD8 cytotoxic responses to Ags. Systemic application of immunostimulatory oligonucleotides however also results in a generalized, non-Ag-specific stimulation of the immune system. In this study, we have dissociated the induction of an Ag-specific response from the systemic immune activation generally associated with immunostimulatory oligonucleotides. Delivery of CpG oligodeoxynucleotides that bind TLR9 by cationized gelatin-based nanoparticles potentiates the in vivo generation of an Ag-specific cytotoxic T cell and Ab response. Furthermore, immunization with CpG-loaded nanoparticles induces a protective antitumoral response in a murine model of melanoma. The systemic release of proinflammatory cytokines and widespread immunostimulation associated with free CpG is however completely abolished. In addition, we show that gelatin nanoparticle formulation prevents the destruction of lymphoid follicles mediated by CpG. Nanoparticle-delivered CpG, in contrast to free CpG, are selectively targeted to APCs in the lymph nodes where they mediate local immune stimulation. We describe a novel strategy to target immunostimulatory oligonucleotides to the initiation site of the immune response while at the same time protecting from an indiscriminate and generalized activation of the immune system. 相似文献
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144.
The electrochemical midpoint potentials (E(m)'s) of 13 cytochromes, in globin (c, c(2), c(551), c(553)), four-helix bundle (c', b(562)), alpha beta roll (b(5)), and beta sandwich (f) motifs, with E(m)'s spanning 450 mV were calculated with multiconformation continuum electrostatics (MCCE). MCCE calculates changes in oxidation free energy when a heme-axial ligand complex is moved from water into protein. Calculated and experimental E(m)'s are in good agreement for cytochromes with His-Met and bis-His ligated hemes, where microperoxidases provide reference E(m)'s. In all cytochromes, E(m)'s are raised by 130-260 mV relative to solvated hemes by the loss of reaction field (solvation) energy. However, there is no correlation between E(m) and heme surface exposure. Backbone amide dipoles in loops or helix termini near the axial ligands raise E(m)'s, but amides in helix bundles contribute little. Heme propionates lower E(m)'s. If the propionic acids are partially protonated in the reduced cytochrome, protons are released on heme oxidation, contributing to the pH dependence of the E(m). In all cytochromes studied except b(5)'s and low potential globins, buried side chains raise E(m)'s. MCCE samples ionizable group protonation states, heme redox states, and side chain rotamers simultaneously. Globins show the largest structural changes on heme oxidation and four-helix bundles the least. Given the calculated protein-induced E(m) shift and measured cytochrome E(m) the five-coordinate, His heme in c' is predicted to have a solution E(m) between that of isolated bis-His and His-Met hemes, while the reference E(m) for His-Ntr ligands in cytochrome f should be near that of His-Met hemes. 相似文献
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147.
Long-standing gastric mucosal barrier dysfunction in Helicobacter pylori-induced gastritis in mongolian gerbils 总被引:4,自引:0,他引:4
BACKGROUND AND AIMS: Helicobacter pylori infection causes chronic gastritis and leads to peptic ulcer and gastric adenocarcinoma. An impaired gastric mucosal barrier could be involved in these processes. Our aim was to investigate gastric barrier function in H. pylori-induced gastritis. METHODS: Stripped gastric mucosal tissues of H. pylori-infected Mongolian gerbils (4 weeks and 70 weeks after inoculation, respectively) and controls were mounted in Ussing chambers. (51)Cr-EDTA (paracellular probe) and horseradish peroxidase (HRP, protein antigen) were used to assess mucosal barrier function. The electrophysiological parameters of the mucosa (transepithelial potential, short circuit current, and transepithelial resistance) were monitored as measurements of barrier integrity and viability. Tissue histology was performed to assess inflammation. RESULTS: In the antrum, both short-term gastritis [4.68 (3.88-5.74) x 10(-6) vs. control 2.86 (2.34-3.77) x 10(-6) cm/s, p <.001] and gastritis of long-standing [5.72 (3.88-10.94) x 10(-6) cm/s, p <.001 vs. control] showed increased permeability to (51)Cr-EDTA. In long-standing antral gastritis there was also an increased HRP flux [9.01 (2.98-45.02) vs. control 0.52 (0.06-1.20) pmol/h/cm(2), p <.001]. In the corpus, permeability to (51)Cr-EDTA was increased only in long-standing gastritis [4.63 (3.64-7.45) x 10(-6) vs. control 2.86 (2.12-3.98) x 10(-6) cm/s, p <.01]. Gastric mucosal permeability to (51)Cr-EDTA was correlated to histological inflammation and inflammatory activity. The levels of serum anti-H. pylori immunoglobulin G were positively correlated to HRP flux and (51)Cr-EDTA permeation. CONCLUSIONS: Helicobacter pylori-induced gastritis in Mongolian gerbils was associated with a long-standing gastric mucosal barrier dysfunction. The barrier defect extended from the antrum into the corpus over time. This impaired barrier function may contribute to perpetuation of chronic inflammation and may be involved in H. pylori-associated carcinogenesis. 相似文献
148.
The specific binding to bovine serum albumin (BSA) of anionic and non-ionic surfactants with C12 acyl chains has been studied by high sensitivity isothermal titration calorimetry. This method proved particularly effective in resolving the binding of anionic surfactants into separate classes of sites with different affinity. For sodium dodecylsulfate (SDS) the measured binding curves could be rationalized as association to two classes (high affinity/low affinity) of sites comprising, respectively, three and six similar (i.e. thermodynamically equivalent), independent sites. Changes in the thermodynamic functions enthalpy, standard free energy, standard entropy and heat capacity could be discerned for each class of binding site, as well as for micelle formation. These data suggest that binding to low affinity sites (in analogy with micelle formation) exhibits energetic parameters; in particular, a large negative change in heat capacity, which is characteristic of hydrophobic interactions. The thermodynamics of high affinity binding, on the other hand, is indicative of other dominant forces; most likely electrostatic interactions. Other anionic ligands investigated (laurate and dodecyl benzylsulfonate) showed a behavior similar to SDS, the most significant difference being the high affinity binding of the alkylbenzyl sulfonate. For this ligand, the thermodynamic data is indicative of a more loosely associated complex than for SDS and laurate. BSA was found to bind one or two of the non-ionic surfactants (NIS) hepta- or penta(ethylene glycol) monododecyl ether (C12EO7 and C12EO5) with binding constants about three orders of magnitude lower than for SDS. Hence, the free energy of the surfactant in the weakly bound BSA-NIS complex is only slightly favored over the micellar state. The binding process is characterized by very large exothermic enthalpy changes (larger than for the charged surfactants) and a large, positive increment in heat capacity. These observations cannot be reconciled with a molecular picture based on simple hydrophobic condensation onto non-polar patches on the protein surface. 相似文献
149.
Nanna Røjel Jeppe Kari Trine H. Sørensen Kim Borch Peter Westh 《Biotechnology and bioengineering》2020,117(2):382-391
Understanding the pH effect of cellulolytic enzymes is of great technological importance. In this study, we have examined the influence of pH on activity and stability for central cellulases (Cel7A, Cel7B, Cel6A from Trichoderma reesei, and Cel7A from Rasamsonia emersonii). We systematically changed pH from 2 to 7, temperature from 20°C to 70°C, and used both soluble (4-nitrophenyl β- d -lactopyranoside [pNPL]) and insoluble (Avicel) substrates at different concentrations. Collective interpretation of these data provided new insights. An unusual tolerance to acidic conditions was observed for both investigated Cel7As, but only on real insoluble cellulose. In contrast, pH profiles on pNPL were bell-shaped with a strong loss of activity both above and below the optimal pH for all four enzymes. On a practical level, these observations call for the caution of the common practice of using soluble substrates for the general characterization of pH effects on cellulase activity. Kinetic modeling of the experimental data suggested that the nucleophile of Cel7A experiences a strong downward shift in pKa upon complexation with an insoluble substrate. This shift was less pronounced for Cel7B, Cel6A, and for Cel7A acting on the soluble substrate, and we hypothesize that these differences are related to the accessibility of water to the binding region of the Michaelis complex. 相似文献
150.
Pre-steady-state kinetics for hydrolysis of insoluble cellulose by cellobiohydrolase Cel7A 总被引:1,自引:0,他引:1
Cruys-Bagger N Elmerdahl J Praestgaard E Tatsumi H Spodsberg N Borch K Westh P 《The Journal of biological chemistry》2012,287(22):18451-18458
The transient kinetic behavior of enzyme reactions prior to the establishment of steady state is a major source of mechanistic information, yet this approach has not been utilized for cellulases acting on their natural substrate, insoluble cellulose. Here, we elucidate the pre-steady-state regime for the exo-acting cellulase Cel7A using amperometric biosensors and an explicit model for processive hydrolysis of cellulose. This analysis allows the identification of a pseudo-steady-state period and quantification of a processivity number as well as rate constants for the formation of a threaded enzyme complex, processive hydrolysis, and dissociation, respectively. These kinetic parameters elucidate limiting factors in the cellulolytic process. We concluded, for example, that Cel7A cleaves about four glycosidic bonds/s during processive hydrolysis. However, the results suggest that stalling the processive movement and low off-rates result in a specific activity at pseudo-steady state that is 10-25-fold lower. It follows that the dissociation of the enzyme-substrate complex (half-time of ~30 s) is rate-limiting for the investigated system. We suggest that this approach can be useful in attempts to unveil fundamental reasons for the distinctive variability in hydrolytic activity found in different cellulase-substrate systems. 相似文献