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121.
122.
Zhang H Liu H Borok Z Davies KJ Ursini F Forman HJ 《Free radical biology & medicine》2012,52(8):1437-1442
Epithelial-mesenchymal transition (EMT) is implicated in the pathogenesis of lung fibrosis and cancer metastasis, two conditions associated with cigarette smoke (CS). CS has been reported to promote the EMT process. CS is the major cause of lung cancer and nearly half of lung cancer patients are active smokers. Nonetheless, the mechanism whereby CS induces EMT remains largely unknown. In this study we investigated the induction of EMT by CS and explored the underlying mechanisms in the human non-small-cell lung carcinoma (H358) cell line. We demonstrate that exposure to an extract of CS (CSE) decreases E-cadherin and increases N-cadherin and vimentin, markers of EMT, in H358 cells cultured in RPMI 1640 medium with 1% fetal bovine serum. Pretreatment with N-acetylcysteine (NAC), a potent antioxidant and precursor of glutathione, abrogated changes in these EMT markers. In addition, CSE activated Src kinase (shown as increased phosphorylation of Src at Tyr418), and the Src kinase inhibitor PP2 inhibited CS-stimulated EMT changes, suggesting that Src is critical in CSE-stimulated EMT induction. Furthermore, NAC treatment abrogated CSE-stimulated Src activation. However, co-incubation with catalase had no effect on CSE-mediated Src activation. Finally, acrolein, an unsaturated aldehyde present in CSE, caused Src activation. Taken together, these data suggest that CSE initiates EMT through Src, which is activated by CS through redox modification. 相似文献
123.
Structural and functional studies suggest a catalytic mechanism for the phosphotransacetylase from Methanosarcina thermophila
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Phosphotransacetylase (EC 2.3.1.8) catalyzes reversible transfer of the acetyl group from acetyl phosphate to coenzyme A (CoA), forming acetyl-CoA and inorganic phosphate. Two crystal structures of phosphotransacetylase from the methanogenic archaeon Methanosarcina thermophila in complex with the substrate CoA revealed one CoA (CoA1) bound in the proposed active site cleft and an additional CoA (CoA2) bound at the periphery of the cleft. The results of isothermal titration calorimetry experiments are described, and they support the hypothesis that there are distinct high-affinity (equilibrium dissociation constant [KD], 20 microM) and low-affinity (KD, 2 mM) CoA binding sites. The crystal structures indicated that binding of CoA1 is mediated by a series of hydrogen bonds and extensive van der Waals interactions with the enzyme and that there are fewer of these interactions between CoA2 and the enzyme. Different conformations of the protein observed in the crystal structures suggest that domain movements which alter the geometry of the active site cleft may contribute to catalysis. Kinetic and calorimetric analyses of site-specific replacement variants indicated that there are catalytic roles for Ser309 and Arg310, which are proximal to the reactive sulfhydryl of CoA1. The reaction is hypothesized to proceed through base-catalyzed abstraction of the thiol proton of CoA by the adjacent and invariant residue Asp316, followed by nucleophilic attack of the thiolate anion of CoA on the carbonyl carbon of acetyl phosphate. We propose that Arg310 binds acetyl phosphate and orients it for optimal nucleophilic attack. The hypothesized mechanism proceeds through a negatively charged transition state stabilized by hydrogen bond donation from Ser309. 相似文献
124.
Chambers RJ Abrams K Garceau NY Kamath AV Manley CM Lilley SC Otte DA Scott DO Sheils AL Tess DA Vellekoop AS Zhang Y Lam KT 《Bioorganic & medicinal chemistry letters》2006,16(2):307-310
Oxindole (2) is a potent and selective PDE2 inhibitor with a favorable ADME, physiochemical and pharmacokinetic profile to allow for use as a chemical tool in elucidating the physiological role of PDE2. 相似文献
125.
126.
Radak Z Atalay M Jakus J Boldogh I Davies K Goto S 《Free radical biology & medicine》2009,46(2):238-243
Exercise has been shown to modify the level/activity of the DNA damage repair enzyme 8-oxoguanine-DNA glycosylase (OGG1) in skeletal muscle. We have studied the impact of regular physical training (8 weeks of swimming) and detraining (8 weeks of rest after an 8-week training session) on the activity of OGG1 in the nucleus and mitochondria as well as its targeting to the mitochondrial matrix in skeletal muscle. Neither exercise training nor detraining altered the overall levels of reactive species; however, mitochondrial levels of carbonylated proteins were decreased in the trained group as assessed by electron spin resonance and biochemical approaches. Importantly, nuclear OGG1 activity was increased by daily exercise training, whereas detraining reversed the up-regulating effect of training. Interestingly, training decreased the outer-membrane-associated mitochondrial OGG1 levels, whereas detraining reversed this effect. These results suggest that exercise training improves OGG1 import into the mitochondrial matrix, thereby increasing OGG1-mediated repair of oxidized guanine bases. Taken together, our data suggest that physical inactivity could impair the mitochondrial targeting of OGG1; however, exercise training increases OGG1 levels/activity in the nucleus and specific activity of OGG1 in mitochondrial compartments, thereby augmenting the repair of oxidized nuclear and mitochondrial DNA bases. 相似文献
127.
128.
Kelvin Kian Loong Wong 《PloS one》2010,5(4)
A new treatment to determine the Pareto-optimal outcome for a non-zero-sum game is presented. An equilibrium point for any game is defined here as a set of strategy choices for the players, such that no change in the choice of any single player will increase the overall payoff of all the players. Determining equilibrium for multi-player games is a complex problem. An intuitive conceptual tool for reducing the complexity, via the idea of spatially representing strategy options in the bargaining problem is proposed. Based on this geometry, an equilibrium condition is established such that the product of their gains over what each receives is maximal. The geometrical analysis of a cooperative bargaining game provides an example for solving multi-player and non-zero-sum games efficiently. 相似文献
129.
Polysaccharides isolated from flaxseed meals using ethanol consisted of a soluble ( approximately 7.5% w/w) and an insoluble fraction (2% w/w). The soluble fraction was dialyzed in various salt concentrations and characterized using viscometry and light scattering techniques. Observations using a size-exclusion column coupled to a multiangle laser light scattering (SEC-MALLS) revealed three molecular weight fractions consisting of a small amount ( approximately 17%) of large molecular weight species (1.0 x 10(6)) and a large amount ( approximately 69%) of small molecular weight species (3.1 x 10(5) Da). Dynamic light scattering measurements indicated the presence of very small molecules (hydrodynamic radius approximately 10 nm) and a very large molecular species (hydrodynamic radius in excess of 100 nm); the latter were probably aggregates. The intrinsic viscosity, [eta], of the polysaccharide in Milli-Q water was 1030 +/- 20 mL/g. The viscosity was due largely to the large molecular weight species since viscosity is influenced by the hydrodynamic volume of molecules in solution. The Smidsrod parameter B obtained was approximately 0.018, indicating that the molecules adopted a semi-flexible conformation. This was also indicated by the slope ( approximately 0.56) from the plot of root-mean-square (RMS) radius versus molar mass (M(w)). 相似文献
130.
T cell apoptosis can be triggered by different mechanisms that lead to distinctive features such as cell shrinkage, membrane blebbing, phosphatidylserine externalization, and internucleosomal DNA fragmentation. Prevailing models for the induction of apoptosis place the cytoskeleton as a distal target of the death effector molecules ('executioners'). However, the cytoskeleton can also play a role in the induction of apoptosis as suggested by the finding that cytoskeletal disruption can induce apoptosis. The mechanism by which this occurs is unknown. Here, we report that T cell apoptosis by cytoskeletal disruption involves a protein synthesis-independent mechanism leading to up-regulation of caspase-3 protease activity and increased accessibility of active caspase-3 to its substrate. Thus, cytoskeleton integrity may regulate the subcellular compartmentalization of death effector molecules. 相似文献