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Query: UNIPROT:P06889 (Mol)
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Current evidence suggests that products of activated inflammatory cells cause or contribute to the acute lung injury of the adult respiratory distress syndrome (ARDS). To assess the possibility that these products may impair surfactant function during ARDS, we exposed surfactant in vitro to polymorphonuclear leukocytes (PMN) activated by phorbol myristate acetate and to the oxidant-producing pair ferric chloride/ascorbate (FeCl3/ASC). After incubation of surfactant with 8 to 32 x 10(6) activated PMN for 1 to 4 h or with FeCl3/ASC for 16 h, its isopycnic density (d), minimum surface tension (gamma min), time course of adsorption, compressibility (SC), and stability index (SI) were determined. We found progressive decreases of d, adsorption, and SI and progressive increases of gamma min and SC after exposure to activated PMN in increasing numbers or for longer time periods. Superoxide dismutase completely inhibited all of these effects except the decreased adsorption, which it did not significantly inhibit. Similar changes in all of these parameters occurred after exposure of surfactant to FeCl3/ASC. Polyacrylamide gel electrophoresis of surfactant after exposure to activated PMN showed a decrease of the major apoprotein that progressed with exposure time and was associated with the appearance of several bands with both lower and higher molecular weights than that of the apoprotein. The data show that activated PMN are capable of impairing surfactant function in vitro and of degrading the major apoprotein. They suggest that the effects upon d, gamma min, SC, and SI are mediated largely if not exclusively by oxidant radicals. While oxidants may contribute to delayed adsorption, proteolysis appears to play the principal role in this effect.
Am J Respir Cell Mol Biol 1991 Jan
PMID:Effects of activated polymorphonuclear leukocytes upon pulmonary surfactant in vitro. 198 76

Isolated and purified microsomal NADH-cytochrome b5 reductase (EC 1.6.2.2) was incubated with bleomycin (BLM) and FeCl3 in the presence of NADH. Only when purified cytochrome b5 was added could an increased NADH consumption be observed indicating redox cycling of the BLM-Fe(III) complex. In the presence of DNA, BLM-Fe(III)-related NADH consumption was accompanied by malondialdehyde (MDA) formation, further evidence for BLM activation yielding oxidative DNA cleavage. BLM, FeCl3, cytochrome b5 and NADH were absolutely necessary to provide these effects. Addition of DNA changed the initial velocity (V0) and the shape of the NADH consumption curves, both probably due to an interaction between DNA and BLM-Fe(III). Furthermore, DNA effectively protected BLM-Fe(III) from autoxidative degradation during redox cycling. BLM-Fe(III)-related, reductase-catalyzed NADH consumption and MDA formation were also dependent on oxygen, showing the involvement of oxygen in the reduction process and in the action of the drug-metal complex in attacking DNA. However, superoxide dismutase (EC 1.15.1.1) and catalase (EC 1.11.1.6) did not affect NADH consumption. Also, superoxide dismutase and catalase were almost without influence on MDA formation, suggesting that no free (or freely accessible) reactive oxygen species occurred during the redox cycle and DNA damage. The results reveal that the BLM-Fe(III) complex undergoes redox cycling by the microsomal NADH-dependent cytochrome b5 reductase-cytochrome b5 system. The significance of this effect for the action of BLM and the involvement of cytochrome b5 is discussed with regard to the presence of these enzymes in the cell nucleus.
Mol Pharmacol 1988 Oct
PMID:Redox cycling of bleomycin-Fe(III) and DNA degradation by isolated NADH-cytochrome b5 reductase: involvement of cytochrome b5. 245 94

To delineate the active free radical species mediating the toxic effects of autoxidizing dihydroxyfumarate (DHF), isolated rabbit right ventricular papillary muscles were exposed to 4.5 mM DHF in the presence of FeCl3, ADP and bovine albumin. In the absence of free radical scavengers a 47.3 +/- 11.5% (mean +/- standard deviation) depression in contractile force was noted over 60 minutes. Neither the combination of superoxide dismutase (SOD) 3,200 u/cc and catalase (CAT) 2,950 u/cc nor mannitol 0.1 M provided statistically significant protection. Deferoxamine mesylate (DFX) 10 mg/cc (15 mM) did provide significant protection of muscle function both in the presence and absence of SOD and CAT (p less than 0.01). The degree of protection conferred by DFX alone was statistically similar to that of DFX with SOD and CAT. This data suggests the involvement of an iron-oxygen complex not dependent on superoxide or hydrogen peroxide for its formation and not readily scavenged by mannitol. The perferryl ion may be representative of such a species. Alternatively, a reactive complex similar to the 'Crypto-OH' radical proposed by Youngman may be formed by the reaction of DHF with iron and oxygen.
Mol Cell Biochem 1987 Dec
PMID:The effects of dihydroxyfumarate on isolated rabbit papillary muscle function: evidence for an iron dependent non-hydroxyl radical mechanism. 344 Dec 52

The cathepsin D of Plasmodium lophurae was purified using a combination of CM-Sephadex, pepstatin-agarose and Sephadex G-100 chromatography. The plasmodial enzyme was distinct from that of the host red cell and bovine spleen in its low isoelectric point (pI 4.3). The cathepsin D of P. lophurae, as well as plasmodial extracts demonstrating such proteinase activity, were able to digest the membrane proteins of duckling and human red cells at pH 7.4; proteolysis was not inhibited in phosphate-buffered saline by 100 microM pepstatin. Membrane proteins most susceptible to proteolysis were those of the cytoskeleton, notably bands 1 and 2 (spectrin), bands 2.1-2.6 (spectrin-binding proteins) and band 3. Membrane protein degradation by crude plasmodial extracts was partially inhibited by a combination of 10 mM FeCl3, and 10 mM phenylmethylsulfonyl fluoride in phosphate-buffered saline. The changes induced in erythrocyte membrane proteins by exposure to plasmodial cathepsin D parallel the alterations observed in red cell membranes obtained from malaria infected cells. Since the action of the plasmodial protease was confined to the inner surface of the red cell membrane, it is possible that protease-induced modifications in the red cell cytoskeleton could lead to merozoite release.
Mol Biochem Parasitol 1983 Jul
PMID:Purification of Plasmodium lophurae cathepsin D and its effects on erythrocyte membrane proteins. 662 18

The free radical scavenging effect of "beta catechin", an antioxidant preparation containing green tea extract, ascorbic acid, sunflower seed extract, dunaliella carotene and natural vitamin E, was evaluated. Two techniques were used: electron spin resonance (ESR) spectrometry to measure radical-scavenging activity, and measurement of its effect on iron-induced lipid peroxidation in brain. A 0.05% solution of "beta catechin" completely scavenged 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals (6.1 x 10(15)spins/ml). A 10% solution of "beta catechin" completely scavenged superoxide (4.2 x 10(15) spins/ml) generated by the hypoxanthine-xanthine oxidase system. An undiluted solution of "beta catechin" scavenged about 90% of hydroxyl radicals (3.5 x 10(15) spins/ml) generated by the Fenton reaction. "beta catechin"s effect on the accumulation of thiobarbituric acid-reactive substances (TBARS) was evaluated from tissue obtained from the ipsilateral cortex of FeCl3-induced epileptic rats. Oral administration of "beta catechin" (1 or 2ml/kg body weight) both inhibited TBARS formation and increased the activity of superoxide dismutase (SOD) in the ipsilateral cortex 30 min after iron-salt injection into the left sensory motor cortex. These data suggest that "beta catechin" has an antioxidant effect and may have a prophylactic effect against aging and other neurological diseases related to free radical mechanisms.
Biochem Mol Biol Int 1995 Apr
PMID:Antioxidant effects of "beta catechin". 754 42

Iron ions play a central role in .OH radicals formation and induction of oxidative stress in living organisms. Iron-catalyzed .OH radical formation degrades deoxyribose to thiobarbituric acid reactive substances (TBA-RS). This paper analyzes kinetic properties of the Fe(III)-EDTA-catalyzed deoxyribose degradation in the presence of ascorbate. The yield of TBA-RS formation in the presence of EDTA was 4-fold higher than in its absence, contrasting with results reported elsewhere, Cu(II)-EDTA and Fe(III)-citrate were unable to catalyze deoxyribose degradation. The dependence on deoxyribose concentration was fitted to a Lineweaver Burk-like plot and it was calculated that approximately 4.5 mM deoxyribose scavenged half of the .OH radicals formed. The data for Fe(III)-EDTA concentration dependence could also be fitted to a rectangular hyperbolic function. This function was linear up to 1 microM added FeCl3 and this property could be utilized as an assay for the estimation of submicromolar iron concentrations. Submicromolar concentrations of iron could induce measurable yields of TBA-RS. Differences of as little as 0.1 microM Fe(III)-EDTA could be reproducibly detected under optimum experimental conditions, above a consistent background absorbance that was equivalent to 0.35 +/- 0.05 microM Fe(III)-EDTA and represented contaminating iron in the reactants that could not be removed with Chelex-100. The low method determination limit makes the deoxyribose degradation reaction potentially useful as a new, highly sensitive and cost effective assay for iron quantification.
Mol Cell Biochem 1994 Aug 17
PMID:Deoxyribose degradation catalyzed by Fe(III)-EDTA: kinetic aspects and potential usefulness for submicromolar iron measurements. 784 80

Hepatic microsomal NADPH cytochrome c reductase from nonhuman primate (Macaca mulatta) has been purified 76 fold by the combination of anion exchange, affinity and molecular sieve chromatographies. The purified preparation had approximate molecular wt of 63 kDa and carried out NADPH oxidation, cytochrome c reduction, 2,6-dichlorophenol indophenol (DCIP) reduction and production of superoxide anions (O2-.). The enhancement in NADPH cytochrome c reductase catalyzed NADPH oxidation by metal chelators viz. ethylenediaminetetra-acetic acid (EDTA)-FeCl3 and diethylenetriaminepenta-acetic acid (DTPA)-FeCl3 was dramatically higher than the enhancement in the reduction of cytochrome c and DCIP. DTPA-FeCl3 was found to be more potent stimulator of NADPH oxidation as compared to EDTA-FeCl3, but both had similar potency as for reduction of cytochrome c and DCIP were concerned. Superoxide dismutase (SOD) decreased EDTA-FeCl3 enhanced reduction of cytochrome c by 15%, but had no effect on the NADPH oxidation and DCIP reduction, whereas it significantly enhanced DTPA-FeCl3 stimulated NADPH oxidation, decreased cytochrome c reduction by 8% and did not affect DCIP reduction. In addition, SOD almost completely blocked the NADPH cytochrome c reductase catalyzed superoxide anion production. The results demonstrate that like rodents and lagomorphs, the hepatic microsomal NADPH cytochrome c reductase in nonhuman primate, Macaca mulatta can carry out single electron reduction of molecular oxygen.
Biochem Mol Biol Int 1994 Jan
PMID:Purification and characterization of hepatic microsomal NADPH cytochrome c reductase from rhesus monkey (Macaca mulatta). 801 90

The role of lipid peroxidation in menadione-mediated toxicity was studied in neonatal rat cardiomyocytes. Incubation of cardiomyocytes with menadione resulted in depleted cellular glutathione levels, increased intracellular Ca2+ and increased lipid peroxidation which all occurred prior to cell degeneration. Pre-treatment of cells with cysteine suppressed the menadione-induced cell degeneration and prevented changes in glutathione levels, intracellular Ca2+, and lipid peroxidation. Pre-treatment of cells with fura-2 acetoxymethyl ester, a Ca2+ chelator, reduced menadione-induced cell degeneration and lipid peroxidation but it did not block cellular glutathione depletion. Pre-treatment of cells with deferoxamine mesylate, an iron chelator, also reduced both menadione-induced cell degeneration and lipid peroxidation; however, it did not prevent the menadione-induced increase in intracellular Ca2+, nor the depletion of glutathione. Thus, the inhibition of menadione-induced lipid peroxidation by deferoxamine mesylate prevented cell degeneration even though intracellular Ca2+ remained elevated and glutathione remained depleted. The protective effects of deferoxamine mesylate and fura-2 AM on menadione's toxicity were inhibited by addition of FeCl3 to cells. Ferric ions did not inhibit the protective effect of cysteine. These data suggest that menadione-induced cardiomyocyte degeneration is directly linked to iron-dependent lipid peroxidation and less tightly coupled to elevation in intracellular Ca2+ or depletion of glutathione.
J Mol Cell Cardiol 1995 Sep
PMID:The role of lipid peroxidation in menadione-mediated toxicity in cardiomyocytes. 852 59

In planta expression of a high-affinity iron-uptake system involving the siderophore chrysobactin in Erwinia chrysanthemi 3937 contributes greatly to invasive growth of this pathogen on its natural host, African violets. A previous study reported that global regulation by iron in this strain was mediated at the transcriptional level via the cbr locus which, when inactivated by insertional mutation, prevents the chrysobactin system from being tightly repressed by FeCl3. Herein, we report the nucleotide sequence of this locus and the functional analysis of its encoded products. Sequence analysis of a 4.8 kb genomic segment of a plasmid encompassing the cbr locus and characterization of the cognate translated products made it possible to uncover a system exhibiting similarity with prokaryotic transporters implicated in the transport of iron complexes. Accordingly, the CbrA product was shown to be the periplasmic component of a permease complex also including two integral membrane proteins, CbrB and CbrC, and the ATP-binding unit CbrD. This system allowed internalization of Fe(III) when supplied to bacterial cells as 59FeCl3 or 59Fe dicitrate, via complexation to a second siderophore recently detected in strain 3937. Most notably, we demonstrate that this second siderophore-mediated iron-acquisition system is operational in bacterial cells grown in the presence of FeCl3. The regulatory effect of cbr was further assessed on a lacZ chrysobactin operon fusion indicating that the transcriptional control exerted by cbr on expression of the chrysobactin system is of homeostatic nature. in conclusion, E. chrysanthemi provides an interesting model in which iron acquisition involves an inductive process resulting in differential expression of two siderophore-mediated pathways in relation to external iron accessibility.
Mol Microbiol 1995 Oct
PMID:Differential expression of two siderophore-dependent iron-acquisition pathways in Erwinia chrysanthemi 3937: characterization of a novel ferrisiderophore permease of the ABC transporter family. 859 59

In the presence of Mg2+ ions, polynucleotide phosphorylase (PNPase, EC 2.7.7.8) is known to synthesize RNA-like polymers using ribonucleoside-5'-diphosphate (NDP) substrates but to be unable to utilize deoxyribonucleoside substrates. Our experiments show that when MgCl2 is replaced by FeCl3, PNPase becomes able to synthesize deoxyheteropolymers using deoxyribonucleoside-5'-diphosphates (dNDPs). The deoxyheteropolymer formed from the four dNDPs is degraded by pancreatic DNase, but not by RNase, and is readily used as a template by DNA-dependent DNA polymerase. Synthesis of this DNA-like polymer is accomplished de novo without the help of any primer or preexisting template. What is more, dA/dG and dC/dT ratios of polymers synthesized by different bacterial PNPases closely match ratios found in DNA of the bacterial species the enzyme came from.
J Mol Evol 1996 May
PMID:De Novo Synthesis of DNA-Like Molecules by Polynucleotide Phosphorylase In Vitro 866 1


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