Cardiac glycosides regulate endothelial tissue factor expression in culture.
(49/181)
BACKGROUND: Tissue factor (TF) plays an important role in acute coronary syndromes and stent thrombosis. This study investigates whether Na(+)/K(+)-ATPase regulates TF expression in human endothelial cells. METHODS AND RESULTS: Ouabain inhibited tumor necrosis factor (TNF)-alpha-induced endothelial TF protein expression; maximal inhibition occurred at 10(-5) mol/L, reached more than 70%, and was observed throughout the 5 hours stimulation period. The decrease in protein expression was paralleled by a reduced TF surface activity. Similarly, lowering of extracellular potassium concentration inhibited TNF-alpha-induced TF protein expression. In contrast, ouabain did not affect TNF-alpha-induced expression of full-length TF mRNA for up to 5 hours of stimulation; instead, expression of alternatively-spliced TF mRNA was upregulated after 3 and 5 hours of stimulation. Ouabain did not affect TNF-alpha-induced activation of the MAP kinases p38, extracellular signal-regulated kinase (ERK), and c-Jun terminal NH(2) kinase; activation of Akt and p70S6 kinase remained unaltered as well. Similar to the MAP kinases, ouabain did not affect TNF-alpha-induced degradation of IkappaB-alpha. Ouabain had no effect on TF protein degradation. CONCLUSIONS: Na(+)/K(+)-ATPase is required for protein translation of endothelial TF in culture. This observation provides novel insights into posttranscriptional regulation of TF expression. (+info)
The sodium pump alpha1 subunit as a potential target to combat apoptosis-resistant glioblastomas.
(50/181)
PURPOSE: To review the involvement of the ion transporter Na+/K+-ATPase (NaK) in the migration and proliferation of glioma cells. Preliminary studies indicate that NaK alpha1 subunits seem to be upregulated in a proportion of glioblastomas but not in normal brain tissues. DESIGN: The present review focuses on (1) the natural resistance of migrating malignant glioma cells to apoptosis, (2) autophagic cell death as an alternative to combat malignant gliomas, (3) the fact that reducing the levels of malignant glioma cell motility can restore proapoptotic drug sensitivity,and (4) on the observation that inhibiting the NaK activity reduces both glioma cell proliferation and migration. RESULTS: The natural ligands of the NaK are the cardiotonic steroids. A hemisynthetic derivative of 2"-oxovoruscharin (UNBS1450), a novel cardenolide, displays unique structural features, making its binding affinity to NaK alpha subunits (including alpha1) 10 to 100 times higher than that of other cardenolides. UNBS1450 markedly decreases intracellular ATP concentration in glioma cells, disorganizes the actin cytoskeleton, and leads to autophagic cell death in NaK alpha1 over-expressing glioma cells. CONCLUSIONS: Glioblastoma patients who do not respond to chemotherapy and whose tumors over-express NaK alpha1 subunits could benefit from a treatment using ligands with marked binding affinity for the NaK alpha1 subunit. (+info)
Cardiac glycosides isolated from the Indian-snuff, Maquira sclerophylla Ducke.
(51/181)
The hydroalcoholic extract of the powdered bark of the Indian-snuff Maquira sclerophylla Duck was purified by column chromatography in silica-gel and the major cardenolide isolated from preparative TLC was identified by 1H-NMR, 12C-NMR and IR analyses. The spectra showed that the active substance has strophanthidin as the aglycone. (+info)
Effects of cardiotonic steroids on dermal collagen synthesis and wound healing.
(52/181)
The bufodienolides are natriuretic steroids, which also have the capacity to cause vasoconstriction, and are cardiac inotropes. Their mechanism of action appears to be related to their ability to inhibit Na+/K+ ATPase. The actions of one of these compounds, marinobufagenin (MBG), have been investigated in a rat model of preeclampsia, an example of volume expansion-mediated hypertension. The urinary excretion of MGB is increased in this model. Furthermore, this increment in its excretion occurs prior to the development of hypertension and proteinuria. The animals also demonstrate intrauterine growth restriction. Studies of the effect of MBG on cytotrophoblast cells reveal that MGB inhibits the migration, proliferation and invasion of these cells. We propose that MGB is an important etiologic factor in at least some forms of preeclampsia and that the level of its excretion in the urine may prove to be of diagnostic value. (+info)
High-throughput screening identifies cardiac glycosides as potent inhibitors of human tissue kallikrein expression: implications for cancer therapies.
(55/181)