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Biomedical subjects

J R Prohaska

Publications and source records attributed to J R Prohaska.

At least 55 records · Page 3Linked to original sources
PubMed1985

Serum cholesterol levels are not elevated in young copper-deficient rats, mice or brindled mice.

Experiments were conducted with suckling male C57BL mice and Sprague-Dawley rats to investigate the relationship between copper deficiency and elevated serum cholesterol. Brindled mice, which have a genetic defect that affects copper distribution, were compared to their normal brothers. Dietary copper deficiency was produced in dams heterozygous for the brindled gene, in normal mouse dams and in rat dams. The subsequent male offspring were compared to those from copper-supplemented dams. Copper deficiency, as assessed by liver copper levels or ceruloplasmin activity, was demonstrated in 12-d-old rats, brindled mice, and in genotypically normal mice from dams fed the copper-deficient diet. However, serum cholesterol levels were not elevated in these "copper-deficient" rats or mice. In one experiment serum cholesterol levels of brindled mice were significantly lower than that of their littermate controls. An additional study was done with older mice. Their dams were fed a low copper diet from parturition throughout lactation, and the pups were fed the same copper-deficient diet for 4 wk after weaning. The 7-wk-old male copper-deficient mice had liver copper levels below 1 microgram/g, but no elevation in serum cholesterol was observed. The failure to demonstrate a rise in serum cholesterol in these perinatal models may be due in part to less severe hepatic copper deficiency because of neonatal copper reserves in liver.

Animals↗
PubMed1985

Adenine nucleotide and lactate levels in organs from copper-deficient mice and brindled mice.

Experiments were conducted with 12-d-old suckling male mice to investigate energy metabolism during copper deficiency. Brindled mice, which have a genetic defect that affects copper distribution, were compared to their normal brothers and to nonbrindled mice that were copper deficient (-Cu) because their dams were consuming a diet low in copper since impregnation and to a fourth group of control suckling mice (+Cu) from copper-supplemented dams. A second study was done with older mice. Dietary copper deficiency was initiated at birth through dams and continued for 7 wk. Organs were fast-frozen in liquid nitrogen and then analyzed for adenine nucleotides by high performance liquid chromatography and for lactate spectrophotometrically. Levels of ATP, ADP and AMP were equivalent for liver, brain, heart and kidney from the young mice regardless of their copper status. Nucleotide levels were low in spleens from brindled mice. Lactate concentrations were elevated in brains from both -Cu and brindled mice but not in other organs. Older -Cu mice, in comparison, did have lower ATP levels and "energy charge" in heart but not liver compared to +Cu mice. Lactate levels were not higher despite a much lower cytochrome c oxidase activity. Thus, organs from copper-deficient mice with major reductions in cytochrome c oxidase activity do not necessarily have altered steady-state levels of adenine nucleotides. The reduction in cytochrome c oxidase activity in copper deficiency may play a minor role in the expression of pathophysiology.

Adenine Nucleotides↗
PubMed1985

Alterations in lymphocyte subpopulations in copper-deficient mice.

Analyses of cell surface determinants of splenocytes from copper-deficient C58 mice indicate alterations in lymphocyte subpopulation characteristics. Both the absolute number and the relative percentage of surface immunoglobulin-bearing (B) cells from copper-deficient mice were significantly greater than those from copper-supplemented controls. The relative percentage of Thy 1.2-positive (T) cells was decreased, and the decrease was most prominent within the Lyt 1-positive (helper) T-cell subset. The functional responsiveness of both B cells and T cells was decreased in copper deficiency.

Animals↗
PubMed1984

Cardiac norepinephrine and intrinsic properties of isolated hypertrophied hearts from DOCA hypertensive rats.

Alterations in cardiac norepinephrine (NE) levels often accompany cardiac hypertrophy. The present study addresses the question of whether such differences in endogenous NE might be responsible for hypertrophy-dependent differences in acutely measured mechanical and metabolic properties of isolated rat heart preparations. Hypertrophied hearts (H) of deoxycorticosterone acetate-hypertensive rats and normal hearts (N) of sham-treated rats were perfused in Langendorff fashion with atrial tissue removed. Assessment of ventricular NE after 3 to 5 min indicated that the concentration was lower in H than N but total content of the left ventricle was not significantly different. Assessment of ventricular NE after three hours suggested that some washout or depletion of NE occurred in H but not N. Mechanical and metabolic characteristics of the isovolumic preparation were determined. When compared to N, H had greater spontaneous ventricular beating rates and, when paced with field stimuli, higher systolic pressures, longer relaxation times and mechanical refractory periods, and greater oxygen consumption. When the latter was normalized for ventricular mass and systolic pressure, H utilized less oxygen/g/100 mmHg pressure than N. Elimination of the acute effects of endogenous NE by either blockade (propranolol) or depletion (reserpine) eliminated the difference in ventricular automaticity between H and N, but did not influence the other differences (or similarities) between H and N. We conclude that aside from changes in ventricular automaticity, hypertrophy-dependent alterations in cardiac mechanical and metabolic properties are not likely to be a result of differing acute influences of endogenous norepinephrine.

Animals↗
PubMed1984

Repletion of copper-deficient mice and brindled mice with copper or iron.

Studies were conducted in suckling mice to investigate copper-dependent anemia. Brindled (Mobr/y) mice, which have a genetic defect that affects copper metabolism, were compared to their normal brothers (Mo+/y) as well as to anemic suckling mice that were copper-deficient (-Cu) because their dams were consuming a diet low in copper and to a fourth group of control suckling mice (+Cu) from copper-supplemented dams. Mice were given a subcutaneous injection of NaCl, FeCl2 or CuCl2 providing 50 micrograms of Na, Fe or Cu, respectively, when 7 days old and were killed 5 days later. Injection of FeCl2 into -Cu mice elevated liver iron 2.7-fold and raised hemoglobin levels to those observed in the +Cu and Mo+/y mice. Ceruloplasmin activity remained low at 5% of control levels. Injection of CuCl2 into -Cu mice resulted in significant increases in body and brain weight, elevations in serum copper and ceruloplasmin activities and hemoglobin levels. Liver copper rose and iron fell, both to levels observed in +Cu and Mo+/y mice. Brain copper and norepinephrine concentrations rose to control levels. Injection of CuCl2 into Mobr/y mice, although resulting in darker pigmentation and normal serum copper and ceruloplasmin levels, failed to stimulate growth or change brain weight. Furthermore, liver and brain copper levels did not rise to normal levels despite significant improvements. Similarly, brain norepinephrine levels rose, but were still below normal. Brindled mice do not respond to copper therapy to the same degree as do -Cu mice. Iron therapy was successful in reversing the anemia of -Cu mice but was without effect on growth or brain development.

Animals↗
PubMed1983

Changes in tissue growth, concentrations of copper, iron, cytochrome oxidase and superoxide dismutase subsequent to dietary or genetic copper deficiency in mice.

Experiments were conducted in suckling mice to investigate copper-dependent anemia. Brindled (Mobr/y) mice, which are not anemic, were compared to their normal brothers (Mo+/y) as well as to anemic suckling mice that were copper-deficient (-Cu) because their dams were consuming a diet low in copper and a fourth group of suckling mice that served as dietary controls (+Cu). Compared to +Cu and Mo+/y mice, -Cu mice were smaller and exhibited cardiac hypertrophy and significant atrophy of lymphoid tissues (spleen and thymus), Mobr/y mice were also small and demonstrated modest atrophy of both liver and spleen. Cu levels were decreased in all -Cu mouse tissues studied, whereas Fe levels tended to be unaltered. Mobr/y mice also exhibited lower tissue Cu levels in soft tissues, except for kidney and small intestine; however, Cu levels in Mobr/y mice were greater than in -Cu mice. Functional copper deficiency was demonstrated in -Cu tissues by decreases in cytochrome c oxidase (CO) and cuprozinc-superoxide dismutase (SOD). The magnitude of the change was tissue specific. Mobr/y tissues, which were low in Cu, also exhibited decreased SOD and CO activity. However, the drop in Mobr/y tissue was less than in -Cu tissue. This was most pronounced in bone marrow, where both CO and SOD were four times higher in Mobr/y than in -Cu mice. Both Mobr/y and -Cu mice had low serum ceruloplasmin activities. The presence of anemia in -Cu mice and the absence of anemia in Mobr/y mice may result from a more severe copper-deficient state in erythropoietic tissues in -Cu mice rather than from differences in ceruloplasmin activity.

Animals↗
PubMed1983

Decreased brain ascorbate levels in copper-deficient mice and in brindled mice.

Mutant brindled mice, which exhibit signs of copper deficiency, were compared to their normal brothers as well as to age-matched suckling mice that were copper-deficient (-Cu) because their dams were consuming a copper-deficient diet, and a fourth group of copper-supplemented (+Cu) suckling mice, which served as dietary controls. Copper deficiency, genetic and dietary, resulted in mice with smaller brains (87 and 75%) and lower levels of the serum cuproprotein ceruloplasmin (10 and 6.1%) when compared to their respective controls. Brain ascorbic acid concentrations were determined in these mice by high performance liquid chromatography with electrochemical detection, and levels in brindled mice and -Cu mice were significantly lower (81 and 80%) than those measured in their respective controls. Injection of cupric chloride into -Cu pups raised brain ascorbate to levels found in +Cu mice and returned catecholamine levels to normal by raising norepinephrine from a major deficit (91%) and decreasing dopamine from an excess (22%). In another study, dietary copper deficiency was produced beginning at birth and continued for 7 weeks. These older -Cu mice had minor reductions in brain ascorbate (10%) and more severe reductions in norepinephrine levels (43%). Older +Cu mice had lower ascorbate and higher norepinephrine levels compared to suckling control mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Chronic dietary copper deficiency alters biochemical and morphological properties of mouse lymphoid tissues.

Chronic copper deficiency in mice impairs both humoral and cell-mediated immunity, but the mechanisms are unknown. Copper deficiency was produced in C58 mice by feeding dams a diet low in copper throughout lactation and weaning the pups to this diet. Control mice were from dams fed the same diet but with copper supplementation the drinking water. Six-week-old mice were sampled for biochemical and morphological studies. Compared to copper-supplemented mice, copper-deficient animals were smaller, anemic and exhibited hypoceruloplasminemia. The copper-deficient mice have small thymus glands, enlarged spleens, and livers equivalent in size to copper-supplemented mice. Thymic atrophy is not caused by elevated serum corticosterone. Liver, spleen, and thymus tissues from copper-deficient mice exhibit low cytochrome oxidase (56, 38, and 45%, respectively) and superoxide dismutase activities (61, 60, and 43%, respectively) compared to tissues from copper-supplemented mice, indicating a functional copper deficiency. Electron micrographs taken of thymus and spleen from copper-deficient mice demonstrate altered morphology characterized by abnormal mitochondria and misshapen nuclei. Chronic copper deficiency alters the size, biochemistry and morphology of primary (thymus) and secondary (spleen) lymphoid tissue.

Animals↗
PubMed1982

Mechanical properties of the copper-deficient rat heart.

Copper deficiency is known to induce cardiac hypertrophy, cardiac morphologic lesions and altered electrocardiograms. These findings suggest that copper deficiency may also influence the mechanical properties of the myocardium. In the present study, weanling albino rats were fed a copper-deficient (-Cu) diet and compared to rats fed the same diet but with copper supplementation in the drinking water (+Cu). Rats were studied during a 1-week period following 4.5-5.5 weeks of treatment. When compared to +Cu rats, the -Cu rats exhibited characteristic signs of copper deficiency, such as reduced body weight, hypoceruloplasminemia, depressed hematocrit, low copper and elevated iron concentration in the liver. The -Cu rats also exhibited cardiac hypertrophy and both a dilution and depletion of left ventricular norepinephrine. Hearts were perfused and paced at both 27 degrees and 37 degrees. When compared to hearts from +Cu rats, the -Cu hearts: 1) had lower spontaneous heart rates, 2) had decreased coronary resistance, 3) gained significant weight during perfusion, 4) consumed more oxygen per unit pressure developed, and 5) developed less systolic pressure with a reduced rate of pressure development. However, the time to peak pressure development, one-halt relaxation time, and refractory period were not affected. The altered characteristics of the copper-deficient myocardium may be due to changes in the elastic properties of the muscle, aberrant energy metabolism or norepinephrine depletion.

Animals↗
PubMed1982

Effect of dietary or genetic copper deficiency on brain catecholamines, trace metals and enzymes in mice and rats.

Previous studies by others indicated that alterations in brain catecholamines were different for perinatal copper deficiency produced by diet in rats and that resulting from a genetic mutation of the X-chromosome, Menkes' syndrome in humans and brindled mice. Thus, copper deficiency was studied in a model in which dietary and genetic deficiency (brindled mice) were compared in two strains of the same species. C57BL and C3H/HeJ mice. Dietary copper deficiency was also produced in rats for comparison. In brain, both dietary and genetic copper deficiency resulted in impaired growth, low brain copper levels, greatly decreased norepinephrine concentrations but normal dopamine levels. The activity of brain cytochrome oxidase was greatly depressed following both dietary and genetic copper deficiency, suggesting a functional deficit of copper. However, the activity of another cuproenzyme, dopamine-beta-hydroxylase, was significantly elevated in deficient animals. The elevation was observed when either copper or N-ethylmaleimide was added to inactivate an endogenous inhibitor. The cause of low brain norepinephrine remains unknown; however, depressed brain norepinephrine may be partly responsible for functional changes in the deficient animals, such as hypomyelination, since the activity of the myelin protein, 2',3'-cyclic nucleotide 3'-phosphodiesterase, was lower in the most deficient animals.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1982

Immunization against transplantable leukemia impaired in copper-deficient mice.

Inbred C58 mice, kept on a copper-deficient (-Cu) diet from birth, were tested for their ability to be immunized to, and subsequently challenged with, line Ib syngeneic transplantable malignant lymphocytes (Ib cells). -Cu mice had significantly lowered hematocrits and serum ceruloplasmin (EC 1.16.3.1) values in contrast to those of the copper-supplemented (+Cu) controls. All male +Cu mice (17/17) survived the immunization regimen (consisting of approximately 10(3) viable and 10(7) inactivated Ib cells) and the challenge dose (10(6) viable Ib cells). Male -Cu mice had a survival rate of only 15% (4/27) after the immunization process and an overall survival rate of 11% (3/27). Female +Cu mice had survival rates of 86% (19/22) after immunization and of 74% (14/19) after the challenge dose, compared to 54% (15/28) and 47% (7/15) survival rates, respectively, for the female -Cu mice. Overall, the +Cu mice had a 79% (31/39) survival of both immunization and challenge compared to an 18% (10/55) survival for the -Cu mice. These results indicate that the initiation and maintenance of cell-mediated immunity to leukemia cells are severely impaired in -Cu animals.

Animals↗
PubMed1981

Copper deficiency suppresses the immune response of mice.

Mice fed a purified diet low in copper display anemia, hypoceruloplasminemia, depressed concentrations of liver copper, and elevated concentrations of liver iron. An impaired humoral-mediated immune response (decreased numbers of antibody-producing cells) is observed in mice with severe as well as marginal copper deficiency. The magnitude of this impairment is highly correlated with the degree of functional copper deficiency (hypoceruloplasminemia).

Animals↗
PubMed1980

Oxidized forms of ovine erythrocyte glutathione peroxidase. Cyanide inhibition of a 4-glutathione:4-selenoenzyme.

[75Se]Glutathione peroxidase (glutathione:hydrogen-peroxide oxidoreductase, EC 1.11.1.9) containing 4 mol selenium per mol was isolated in 33% yield using 10% ethanol to stabilize the purified enzyme. When reduced with GSH and rapidly separated from GSH by gel filtration chromatography, GSH peroxidase was eluted in a labile oxidized (iodoacetate-insensitive) form which was stable at 4 degrees C but unstable at 25 degrees C (form A). When GSH-reduced enzyme was allowed to oxidize in the course of dialysis a more stable oxidized form was obtained (form C) which was rapidly inactivated by cyanide. Using [35S]GSH, form C was shown to contain tightly bound glutathione in approx. equimolar ratio with selenium. The cyanide sensitivity of GSH peroxidase is therefore correlated with the presence of a glutathione moiety in the enzyme. The isolation of GSH peroxidase containing bound glutathione suggests that intermediates containing glutathione bound to selenium may be formed during the catalytic cycle.

Animals↗
PubMed1980

The glutathione peroxidase activity of glutathione S-transferases.

Glutatione transferases (RX:glutathione R-transferases, EC 2.5.1.18) B and AA were purified from rat liver to investigate the mechanism for their apparent GSH peroxidase activity (GSSG formation). Both transferases catalyze an overall reaction in which loss of cumene hydroperoxide is accompanied by a stoichiometric increase in GSSG. Inclusion of cysteamine, a thiol, results in a reduction of GSSG formation but has no effect on hydroperoxide loss. Cysteamine does not inhibit the transferase-catalyzed conjugation of GSH and 1-chloro-2,4-dinitrobenzene. Peroxidase reactions carried out in the presence of cyanide, another nucleophile, also result in a reduction of GSSG formation without altering the rate of cumene hydroperoxide loss; cyanide does not inhibit transferase activity with 1-chloro-2,4-dinitrobenzene. Both cysteamine and cyanide are capable of blocking GSSG formation in the non-enzymic oxidation of GSH by hydrogen peroxide without blocking H2O2 loss. These results are consistent with a mechanism for GSH transferases in which nucleophilic attack by GS- on hydroperoxide results in a reactive intermediate, presumably the sulfenic acid of glutathione, GSOH. GSH + ROOH in equilibrium GSHO + ROH (1) This sulfenic acid then reacts non-enzymically with GSH to produce GSSG. GSOH + GSH in equilibrium GSSG + H2O (2) The summing of Reactions 1 and 2 explains the observed stoichiometry. Cysteamine and cyanide can compete with GSH for the sulfenic acid in Reaction 2, thus reducing GSSG formation. Thios.

Animals↗