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101.
Tumor necrosis factor and reactive oxygen species cooperative cytotoxicity is mediated via inhibition of NF-kappaB 总被引:3,自引:0,他引:3
Ginis I Hallenbeck JM Liu J Spatz M Jaiswal R Shohami E 《Molecular medicine (Cambridge, Mass.)》2000,6(12):1028-1041
BACKGROUND: Tumor necrosis factor alpha (TNFalpha) plays a key role in pathogenesis of brain injury. However, TNFalpha exhibits no cytotoxicity in primary cultures of brain cells. This discrepancy suggests that other pathogenic stimuli that exist in the setting of brain injury precipitate TNFalpha cytotoxicity. The hypothesis was tested that reactive oxygen species (ROS), that are released early after brain injury, act synergistically with TNFalpha in causing cell death. MATERIALS AND METHODS: Cultured human and rat brain capillary endothelial cells (RBEC), and cortical astrocytes were treated with TNFalpha alone or together with different doses of H2O2, and apoptotic cell death and DNA fragmentation were measured by means of 3'-OH-terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and Hoechst fluorescence assay, respectively. The effect of H2O2 on TNFalpha-induced activation of nuclear factor kappa B (NF-kappaB) was measured by Western blots of cytoplasmic and nuclear extracts of RBEC using anti-inhibitor of NF-kappaB (IkappaB) and anti-p65 subunit of NF-kappaB antibodies. Nuclear translocation of NF-kappaB was investigated by immunofluorescent staining of RBEC with anti-p65 antibodies. RESULTS: TNFalpha alone had no cytotoxic effect in brain endothelial cells and astrocytes at concentrations up to 100 ng/ml. Co-treatment with 5-10 microM of H2O2 caused a two-fold increase in the number of apoptotic cells 24 hr later. Similar doses (1-3 microM) of H2O2 initiated early DNA fragmentation. H2O2 inhibited TNFalpha-induced accumulation of p65 in the nucleus, although it had no effect on degradation of the IkappaB in cytoplasm. Immunostaining confirmed that H2O2 inhibited p65 transport to the nucleus. CONCLUSIONS: Reactive oxygen species could act synergistically with TNFalpha in causing cytotoxicity via inhibition of a cytoprotective branch of TNFalpha signaling pathways, which starts with NF-kappaB activation. 相似文献
102.
Syndecan-4-dependent Rac1 regulation determines directional migration in response to the extracellular matrix 总被引:1,自引:0,他引:1
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Bass MD Roach KA Morgan MR Mostafavi-Pour Z Schoen T Muramatsu T Mayer U Ballestrem C Spatz JP Humphries MJ 《The Journal of cell biology》2007,177(3):527-538
Cell migration in wound healing and disease is critically dependent on integration with the extracellular matrix, but the receptors that couple matrix topography to migratory behavior remain obscure. Using nano-engineered fibronectin surfaces and cell-derived matrices, we identify syndecan-4 as a key signaling receptor determining directional migration. In wild-type fibroblasts, syndecan-4 mediates the matrix-induced protein kinase Calpha (PKCalpha)-dependent activation of Rac1 and localizes Rac1 activity and membrane protrusion to the leading edge of the cell, resulting in persistent migration. In contrast, syndecan-4-null fibroblasts migrate randomly as a result of high delocalized Rac1 activity, whereas cells expressing a syndecan-4 cytodomain mutant deficient in PKCalpha regulation fail to localize active Rac1 to points of matrix engagement and consequently fail to recognize and respond to topographical changes in the matrix. 相似文献
103.
Jordan M. Spatz Marc N. Wein Jonathan H. Gooi Yili Qu Jenna L. Garr Shawn Liu Kevin J. Barry Yuhei Uda Forest Lai Christopher Dedic Mercedes Balcells-Camps Henry M. Kronenberg Philip Babij Paola Divieti Pajevic 《The Journal of biological chemistry》2015,290(27):16744-16758
Although bone responds to its mechanical environment, the cellular and molecular mechanisms underlying the response of the skeleton to mechanical unloading are not completely understood. Osteocytes are the most abundant but least understood cells in bones and are thought to be responsible for sensing stresses and strains in bone. Sclerostin, a product of the SOST gene, is produced postnatally primarily by osteocytes and is a negative regulator of bone formation. Recent studies show that SOST is mechanically regulated at both the mRNA and protein levels. During prolonged bed rest and immobilization, circulating sclerostin increases both in humans and in animal models, and its increase is associated with a decrease in parathyroid hormone. To investigate whether SOST/sclerostin up-regulation in mechanical unloading is a cell-autonomous response or a hormonal response to decreased parathyroid hormone levels, we subjected osteocytes to an in vitro unloading environment achieved by the NASA rotating wall vessel system. To perform these studies, we generated a novel osteocytic cell line (Ocy454) that produces high levels of SOST/sclerostin at early time points and in the absence of differentiation factors. Importantly, these osteocytes recapitulated the in vivo response to mechanical unloading with increased expression of SOST (3.4 ± 1.9-fold, p < 0.001), sclerostin (4.7 ± 0.1-fold, p < 0.001), and the receptor activator of nuclear factor κΒ ligand (RANKL)/osteoprotegerin (OPG) (2.5 ± 0.7-fold, p < 0.001) ratio. These data demonstrate for the first time a cell-autonomous increase in SOST/sclerostin and RANKL/OPG ratio in the setting of unloading. Thus, targeted osteocyte therapies could hold promise as novel osteoporosis and disuse-induced bone loss treatments by directly modulating the mechanosensing cells in bone. 相似文献
104.
Permeability of brain cells to radiolabeled glucose analogues with sucrose or inulin or L-glucose was studied in the living, intact state of the organotypic cerebellar cultures. In vitro uptake of 3H 3-O-methyl D-glucose and 3H 2-deoxy-D-glucose exhibited saturation kinetics with increasing substrate concentrations. Each of the labeled sugars uptake could be self-inhibited in the presence of unlabeled (cold) substrate and cross-inhibited with cold glucose or xylose or phlorizin present in the incubating medium. The uptake was Na-independent and stereo-specific for D-form. 相似文献
105.
Dimitris Missirlis Tams Haraszti Lara Heckmann Joachim P. Spatz 《Biophysical journal》2020,119(12):2558
The mechanics of fibronectin-rich extracellular matrix regulate cell physiology in a number of diseases, prompting efforts to elucidate cell mechanosensing mechanisms at the molecular and cellular scale. Here, the use of fibronectin-functionalized silicone elastomers that exhibit considerable frequency dependence in viscoelastic properties unveiled the presence of two cellular processes that respond discreetly to substrate mechanical properties. Weakly cross-linked elastomers supported efficient focal adhesion maturation and fibroblast spreading because of an apparent stiff surface layer. However, they did not enable cytoskeletal and fibroblast polarization; elastomers with high cross-linking and low deformability were required for polarization. Our results suggest as an underlying reason for this behavior the inability of soft elastomer substrates to resist traction forces rather than a lack of sufficient traction force generation. Accordingly, mild inhibition of actomyosin contractility rescued fibroblast polarization even on the softer elastomers. Our findings demonstrate differential dependence of substrate physical properties on distinct mechanosensitive processes and provide a premise to reconcile previously proposed local and global models of cell mechanosensing. 相似文献
106.
A minimal model of cellular mechanosensing system that consists of a single stress fiber adhering on a substrate via two focal adhesions made of catch bonds is adopted to investigate the phenomena of cell reorientation on substrates induced by an applied uniaxial cyclic stretch. The model indicates that the catch bonds in the focal adhesions experience a periodically oscillating internal force with amplitude and frequency controlled by two intrinsic clocks of the stress fiber, one associated with localized activation and the other with homogeneous activation of sarcomere units along the stress fiber. It is shown that this oscillating force due to cyclic stretch tends to destabilize focal adhesions by reducing the lifetime of catch bonds. The resulting slide or relocation of focal adhesions then causes the associated stress fiber to shorten and rotate to configurations nearly perpendicular to the stretching direction. These predicted behaviors from our model are consistent with a wide range of experimental observations. 相似文献
107.
D. Menne H. -C. Spatz 《Journal of comparative physiology. A, Neuroethology, sensory, neural, and behavioral physiology》1977,114(3):301-312
Summary Using a fully automatized procedure and a training scheme symmetrical with respect to the visual stimuli as well as to the aversive stimulus,Drosophila could be conditioned to blue and yellow lights. With constant test conditions and variation of the light intensities during the training procedure, it could be shown that the flies respond primarily to the colour of the light.We are grateful to Dr. W. Edrich and K.-F. Fischbach for exchange of ideas. Dr. J. Bammert gave advice for the statistical treatment. 相似文献
108.
109.
G. Spatz 《Plant Ecology》1980,43(1-2):39-41
Summary Some successional patterns on mountain pastures in the Hohe Tauern mountains, Austria, are described. A close relation with former pasture management is shown. Very clear gradients in the nutritional status of the soil exist from stables towards more remote areas where no nutrients are added. Dwarf shrub or Alnus viridis woodland vegetation will develop after abandoning pastures, depending on elevation and nutrient status. Above the tree line culturally influenced pastures will rapidly develop to natural grasslands.Nomenclature follows: F. Ehrendorfer. 1973. Liste der Gefaszpflanzen Mitteleuropas. 2. erw. Aufl. 相似文献
110.
Yadav P Tran H Ebegbe R Gottlieb P Wei H Lewis RH Mumbey-Wafula A Kaplan A Kholdarova E Spatz L 《PloS one》2011,6(1):e14488