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991.
Diesel B Kulhanek-Heinze S Höltje M Brandt B Höltje HD Vollmar AM Kiemer AK 《Biochemistry》2007,46(8):2146-2155
BACKGROUND AND AIM: Alpha-lipoic acid has cytoprotective potential which has previously been explained by its antioxidant properties. The aim of this study was to assess LA-induced-specific cytoprotective signalling pathways in hepatocytes. METHODS: Apoptosis of rat hepatocytes was induced by actinomycinD/TNF-alpha. Caspase-3-like activity was determined by a fluorometric; LDH by an enzymatic assay; and phosphorylation of the insulin receptor, Akt, and Bad by Western blot (after immunoprecipitation). Protein kinase and insulin receptor activities were measured by in vitro phosphorylation. Computer modeling studies were performed by using the program GRID. RESULTS: Alpha-lipoic acid decreased actinomycinD/TNF-alpha-induced apoptosis, as did the antioxidants Trolox and N-acetylcysteine. The activation of PI3-kinase/Akt involving phosphorlyation of Bad markedly contributed to the cytoprotective action of alpha-lipoic acid. Alpha-lipoic acid but not other antioxidants protected against actinomycinD/TNF-alpha-induced apoptosis via phosphorylation of the insulin receptor. Computer modeling studies revealed a direct binding site for alpha-lipoic acid at the tyrosine kinase domain of the insulin receptor, suggesting a stabilizing function in loop A that is involved in ATP binding. Treatment of immunoprecipitated insulin receptor with LA induced substrate phosphorylation. CONCLUSIONS: Alpha-lipoic acid mediates its antiapoptotic action via activation of the insulin receptor/PI3-kinase/Akt pathway. We show for the first time a direct binding site for alpha-lipoic acid at the insulin receptor tyrosine kinase domain, which might make alpha-lipoic acid a model substance for the development of insulin mimetics. 相似文献
992.
More histone structures 总被引:13,自引:0,他引:13
Claus Von Holt Walter N. Strickland Wolf F. Brandt Marie S. Strickland 《FEBS letters》1979,100(2):201-218
993.
994.
995.
Effect of freezing and thawing on the microcirculation and capillary endothelium of the hamster cheek pouch 总被引:1,自引:0,他引:1
Golden Syrian hamster cheek pouches were prepared in vivo for observation of microvasculature under the light microscope. On an apparatus designed especially for this purpose, pouches were cooled from plus 10 °C to minus 30 °C at 1 °C/min, held at minus 30 °C for 1 min and warmed at 1 °C/min to plus 10 °C whence spontaneous rewarming to ambient was permitted. Pouches were observed under the light microscope throughout freezing and for 1 hr after thaw. At 0, 1, 5, 15, 30, and 60 min after thaw pouch tissue was taken for electron microscopy. After thaw hemostasis evolved in a biphasic pattern. In the early phase in which the degree of stasis reached its peak at about 20 min after thaw, cessation of circulation was caused by obstructive embolic platelet aggregates and a second uncharacterized factor, possibly humoral in nature. After 30 min, blood flow spontaneously resumed in at least one portion of each pouch. In 6 specimens, by 45–50 min, blood flow had returned to normal in about 90% of the microvasculature. After 50 min hemostasis began again and by 60 min blood flow had ceased in virtually all areas of the pouch, this time in the absence of vascular obstruction by platelet aggregates. Ultrastructural damage to endothelial cells occurring immediately at thaw and progressing through 1 hr thereafter included the rupture of cell membranes, early thinning, and later condensation of ground substance, decrease in the number and concentration of pinocytotic vesicles, swelling of rough endoplasmic reticulum, and the swelling and loss of cristal structure of mitochondria. This endothelial destruction can account for the permanent hemostasis of frostbite. 相似文献
996.
Continuous assay for VanX, the D-alanyl-D-alanine dipeptidase required for high-level vancomycin resistance. 总被引:1,自引:0,他引:1
The reaction of L-alanine-p-nitroanilide with VanX was studied in an effort to develop a continuous assay for VanX activity for future kinetic and inhibition studies. VanX, containing Zn(II), Co(II), Fe(II), or Ni(II), catalyzes the hydrolysis of L-alanine-p-nitroanilide producing L-alanine and p-nitroaniline as products; the formation of the latter product (epsilon(404nm) = 10, 700 M(-1) cm(-1)) can be continuously monitored using UV-VIS spectrophotometry. Zn(II)-, Co(II)-, Fe(II)-, and Ni(II)-containing VanX exhibit saturation kinetics when L-alanine-p-nitroanilide is used as the substrate with K(m) and k(cat) values ranging from 300 to 700 microM and 0.028 to 0.080 s(-1), respectively. Inhibition studies using O-[(1S)-aminoethylhydroxyphosphinyl]-D-lactic acid as the inhibitor and L-alanine-p-nitroanilide as the substrate yielded a K(i) of 400 +/- 8 microM at pH 7.0. These studies reveal a continuous assay of VanX activity which could be used to further study the kinetic mechanism of VanX and to allow for the development of high-throughput screening for inhibitors of VanX. 相似文献
997.
E Sontag V Nunbhakdi-Craig G Lee R Brandt C Kamibayashi J Kuret C L White M C Mumby G S Bloom 《The Journal of biological chemistry》1999,274(36):25490-25498
Hyperphosphorylated forms of the neuronal microtubule (MT)-associated protein tau are major components of Alzheimer's disease paired helical filaments. Previously, we reported that ABalphaC, the dominant brain isoform of protein phosphatase 2A (PP2A), is localized on MTs, binds directly to tau, and is a major tau phosphatase in cells. We now describe direct interactions among tau, PP2A, and MTs at the submolecular level. Using tau deletion mutants, we found that ABalphaC binds a domain on tau that is indistinguishable from its MT-binding domain. ABalphaC binds directly to MTs through a site that encompasses its catalytic subunit and is distinct from its binding site for tau, and ABalphaC and tau bind to different domains on MTs. Specific PP2A isoforms bind to MTs with distinct affinities in vitro, and these interactions differentially inhibit the ability of PP2A to dephosphorylate various substrates, including tau and tubulin. Finally, tubulin assembly decreases PP2A activity in vitro, suggesting that PP2A activity can be modulated by MT dynamics in vivo. Taken together, these findings indicate how structural interactions among ABalphaC, tau, and MTs might control the phosphorylation state of tau. Disruption of these normal interactions could contribute significantly to development of tauopathies such as Alzheimer's disease. 相似文献
998.
Jörg Piontek Chi Chiung Chen Martina Kempf & Roland Brandt 《Journal of neurochemistry》1999,73(1):139-146
To determine the effect of neurotrophins on the survival and morphological differentiation of CNS neurons, we examined NT2-N cells, which provide a unique culture model for terminally differentiated and polar human neurons. Here we report the development of conditions for the long-term culture of NT2-N cells in low density and in chemically defined medium. We show that NT2-N cells express rRNAs for TrkA, TrkB, and TrkC tyrosine kinase receptors and the low-affinity nerve growth factor receptor (p75NTR). All members of the nerve growth factor-related family of neurotrophic factors promote neuronal survival in long-term cultures with approximately 1 ng/ml for half-maximal survival. At high concentrations (>20 ng/ml), the neurotrophins reversed the survival-promoting effect as judged by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] conversion. In contrast to the uniform effect of all neurotrophins on neuronal survival, brain-derived neurotrophic factor selectively induced an increased dendritic complexity. These results demonstrate that NT2-N cells provide a useful model to analyze the effect of neurotrophins on the survival and morphological differentiation of CNS neurons in vitro. In addition, the data indicate that neuronal survival and the development of morphological complexity are differentially regulated in a multireceptor context. 相似文献
999.
Identification of MINUS, a small polypeptide that functions as a microtubule nucleation suppressor.
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In eukaryotic cells, tubulin polymerization must be regulated precisely during cell division and differentiation. To identify new mechanisms involved in cellular microtubule formation, we isolated an activity that suppresses microtubule nucleation in vitro. The activity was due to a small acidic polypeptide of 4.7 kDa which we named MINUS (microtubule nucleation suppressor). MINUS inhibited tau- and taxol-mediated microtubule assembly in vitro and was inactivated by dephosphorylation. The protein was purified to homogeneity from cultured neural (PC12) cells and bovine brain. Microinjection of MINUS caused a transient loss of dynamic microtubules in Vero cells. The results suggest that MINUS acts with a novel mechanism on tubulin polymerization, thus regulating microtubule formation in living cells. 相似文献
1000.
Cathepsin H is involved in intracellular protein degradation and is implicated in a variety of physiological processes such as proenzyme activation, enzyme inactivation, hormone maturation, tissue remodeling, and bone matrix resorption. A model of the tertiary structure of the human lysosomal cysteine protease cathepsin H was constructed. The protein structure was built from its amino acid sequence and its homology to papain, actinidin, and cathepsin L for which crystallographic co-ordinates are available. The model was generated using the COMPOSER module of SYBYL.The position and interaction behavior of the so called mini-chain, the octapeptide EPQNCSAT, to the active-site cleft of cathepsin H could be determined by docking studies. Refinement was achieved through interactive visual and algorithmic analysis and minimization with the TRIPOS force field. The model was found to correlate with observed empirical data regarding ligand specificity. The model defines possible steric, hydrophobic, and electrostatic interactions. We anticipate that the model will serve as a tool to understand substrate specificity and may be used for the development of new specific ligands.Supplementary material to this paper is available in electronic form at http://dx.doi.org/10.1007/s008940050117 相似文献