losartan-potassium and fluorexon

Hypoxia-inducible factor (HIF) prolyl 4-hydroxylases are a family of iron- and 2-oxoglutarate-dependent dioxygenases that negatively regulate the stability of several proteins that have established roles in adaptation to hypoxic or oxidative stress. These proteins include the transcriptional activators HIF-1alpha and HIF-2alpha. The ability of the inhibitors of HIF prolyl 4-hydroxylases to stabilize proteins involved in adaptation in neurons and to prevent neuronal injury remains unclear. We reported that structurally diverse low molecular weight or peptide inhibitors of the HIF prolyl 4-hydroxylases stabilize HIF-1alpha and up-regulate HIF-dependent target genes (e.g. enolase, p21(waf1/cip1), vascular endothelial growth factor, or erythropoietin) in embryonic cortical neurons in vitro or in adult rat brains in vivo. We also showed that structurally diverse HIF prolyl 4-hydroxylase inhibitors prevent oxidative death in vitro and ischemic injury in vivo. Taken together these findings identified low molecular weight and peptide HIF prolyl 4-hydroxylase inhibitors as novel neurological therapeutics for stroke as well as other diseases associated with oxidative stress.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Brain; Central Nervous System; Cerebral Cortex; Cyclin-Dependent Kinase Inhibitor p21; Erythropoietin; Fluoresceins; Hypoxia-Inducible Factor 1, alpha Subunit; Iron; Luciferases; Male; Mass Spectrometry; Microscopy, Fluorescence; Models, Molecular; Molecular Weight; Neurons; Oxidative Stress; Peptides; Phosphopyruvate Hydratase; Procollagen-Proline Dioxygenase; Protein Binding; Rats; Rats, Sprague-Dawley; Up-Regulation; Vascular Endothelial Growth Factor A; Zinc

Intravenous iron (iv.Fe) is used to optimize response to recombinant human erythropoietin (r-HuEPO) in ESRD, but no consensus exists with respect to the best regimen to avoid transferrin "oversaturation," oxidative stress, and the occurrence of non-transferrin-bound iron (NTBI). Iv.Fe was stopped for 1 wk in 35 hemodialysis (HD) patients who were routinely receiving iv.Fe and r-HuEPO. The iv.Fe group received 100 mg of ferric saccharate (Venofer) at the end of the first HD session, whereas the time-control group was treated under the same conditions but received no iv.Fe. Serum samples were taken before the first HD session, immediately and 60 min after iv.Fe administration, and before the next HD session. Sera were analyzed for NTBI and peroxides; transferrin saturation was analyzed by urea-PAGE and Western blot. In an in vitro model system with HepG2 cells, the effects of ESRD serum on the labile iron pool (LIP) were assayed using the fluorescence calcein assay. NTBI significantly increased after iv.Fe-administration and returned to baseline values before the next HD-session. There was a shift from apo- to monoferric transferrin, but no "oversaturation" of transferrin after iv.Fe-treatment. Peroxides increased in both groups after HD. Hemodialysis decreased bioavailable iron for the LIP in HepG2-cells, whereas serum of iv.Fe-treated HD patients highly increased the LIP in these cells. A total of 100 mg of iv.Fe led to NTBI generation but not to an oversaturation of transferrin. Peroxide concentrations significantly increased during HD but were not correlated to iv.Fe administration and seemed to result from other sources of oxidative stress related to HD. NTBI can enter liver cells and increase the potentially harmful LIP.

Topics: Blotting, Western; Cell Line; Citric Acid; Electrophoresis, Polyacrylamide Gel; Erythropoietin; Ferric Compounds; Ferric Oxide, Saccharated; Fluoresceins; Glucaric Acid; Humans; Iron; Oxidative Stress; Peroxides; Quaternary Ammonium Compounds; Renal Dialysis; Time Factors; Transferrin; Urea