Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.16.3.1 (ceruloplasmin)
5,074 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. In rats iron was absorbed after administration into the gut lumen as ferric iron bound to serum albumin, to nitrilotriacetic acid, and to 8-OH-quinoline sulfonic acid, or as isolated diferri-transferrin. 2. Iron absorption from 59Fe-labelled transferrin was inhibited by the addition of rat plasma. 3. The inhibitory component in the rat plasma turned out to be ceruloplasmin (ferrous iron oxidase, EC 1.16.2.1). 4. The absorption of iron from these ferric iron complexes was also inhibited by addition to the incubation medium of ferrozine, a strong anionic Fe(II)-ligand. 5. Uptake and absorptive utilization of transferrin-bound ferric iron was decreased after a prewash of the gut lumen and could be restored by the addition of ascorbate to the incubation medium. 6. The conclusion was drawn from these results that luminal reduction precedes ferric iron absorption and that this is a prerequisite for the uptake into the mucosa.
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PMID:Dependence of intestinal iron absorption on the valency state of iron. 312 86

An attempt has been made to assess the importance of systemic sites of interaction from the effect of dietary molybdenum (Mo) on the protection afforded by a single sc injection of copper (Cu) to 29 initially hypocupraemic 5-year-old ewes, maintained on a low Cu diet. They were fed a diet of 1 kg/day containing 1.3 mg of Cu/kg supplemented with sodium sulphate which provided 1.7 gm of sodium per kg. Group A was given no further supplement. Group B was given added Mo, 25 mg/kg. Group C was given added Cu, 10 mg/kg. After 7 months, several animals in each group were injected sc with a single dose of 46.5 mg of Cu in the form of copper calcium edetate (Coprin). Blood samples were taken at intervals from the injected ewes over a 250-day period. All ewes were mated after 12 months on the diet. Injected ewes were approaching the 4th month of gestation when the last blood sample was taken at 250 days. Total Cu in plasma was determined by atomic absorption spectometry. Direct reacting Cu in plasma, cerulosplasmin oxidase activity, and hemoglobin were also estimated. Plasma Cu concentrations had increased to normal levels in 14 days in Group A after the Cu injections. Group B animals showed a greater increase, mean values exceeding those of Groups A and C, between Days 28-129 (p less than .01). Plasma Cu levels declined in ewes not given supplementary Cu after the 177th day. The final values for Groups A and B were similar to those found before injection. The direct reacting Cu in each group was increased after 7 days (p less than .05). This effect was most marked in the Mo supplemented ewes (Group B). The effect of Mo persisted until the final bleeding. Direct reacting Cu was only a minor part of the early response in total plasma copper of Group B ewes. Dietary Mo did not inhibit the incorporation of injected Cu into ceruloplasmin. The Mo-supplemented ewes were in poorer condition than copper-supplemented ewes. All groups gained in weight after the injections. The sc injection of Cu at 5 months prior to mating imporved fertility in Groups A and B. There was no evidence that dietary Mo impa ired the metabolism of parenteral Cu. However, it is known to deplete r uminants of Cu when the diet provides the only source of Cu. It is ther efore thought that the site of the Cu with Mo interaction is in the gut. If infertility due to Cu deficiency is suspected in a flock, an injection of Cu immediately prior to mating may improve conception rate and provide sufficient Cu to reduce the incidence of swayback.
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PMID:The effect of dietary molybdenum on hypocupraemic ewes treated by subcutaneous copper. 444 11

We studied 2 of 4 affected boys with a new disease associated with abnormalities of copper metabolism. The four cases occurred in two generations of a family. This syndrome was similar to Menkes disease in some respects: X-linked recessive inheritance, marked psychomotor retardation with seizures, low serum copper and ceruloplasmin levels, and a block in gut copper absorption. There were also striking differences from Menkes disease. Patients had normal birthweight at term, no hypothermia, and survived beyond the usual Menkes age group with static neurologic disease including hypotonia and choreoathetosis. In addition, general examination of both children was unremarkable apart from undescended testes and growth retardation. The hair, facies, and skin were normal and there was no radiologic evidence of bony changes. Detailed studies of copper absorption were performed.
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PMID:An X-linked disease of the nervous system with disordered copper metabolism and features differing from Menkes disease. 719 7

Although interaction of vitamin C, copper and iron have been studied in several species, little is known about these interactions in species which require the vitamin in the diet. Young male Hartley guinea pigs were fed a basal diet, or a basal diet and supplemented daily with vitamin C, p.o. Pharmacologic doses (25 mg per 100 g BW per day) of vitamin C resulted in two-to-three-fold decreases in liver copper, when compared with those receiving normal (0.5 mg per 100 g BW per day) intakes. Under conditions of vitamin C deficiency, serum copper and ceruloplasmin were elevated along with liver copper. Serum and hepatic iron levels, hepatic microsomal cytochrome P-450 and cytochrome b5, and blood heme parameters all appeared to be directly related to vitamin C intake, i.e. the iron and heme parameters increased as the vitamin dose increased. These data are consistent with the hypothesis that interaction between vitamin C, copper and iron influence normal heme formation through the oxidation/reduction of iron and/or by regulating iron absorption and availability at the gut level.
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PMID:Effect of vitamin C on copper and iron metabolism in the guinea pig. 742 59

Manganese (Mn)-deficiency or Mn-excess can lead to adverse biological consequences. Central nervous system tissues, rich in dopaminergic neurons, are the targets whether the Mn gains entrance by inhalation, oral ingestion, or intravenous administration. Risk assessments with Mn need to ensure that brain concentrations in the globus pallidus and striatum stay within the range of normal. This paper first provides a critical review of the biological factors that determine the disposition of Mn in tissues within the body. Secondly, it outlines specific data needs for developing a physiologically based pharmacokinetic (PBPK) model for Mn to assist in conducting risk assessments for inhaled and ingested Mn. Uptake of dietary Mn appears to be controlled by several dose-dependent processes: biliary excretion, intestinal absorption, and intestinal elimination. Mn absorbed in the divalent form from the gut via the portal blood is complexed with plasma proteins that are efficiently removed by the liver. Absorption of Mn via inhalation, intratracheal instillation or intravenous infusions bypasses the control processes in the gastrointestinal tract. After absorption into the blood system by these alternate routes, Mn is apparently oxidized by ceruloplasmin and the trivalent Mn binds to the iron carrying protein, transferrin. Brain uptake of Mn occurs via transferrin receptors located in various brain regions. Transferrin-bound trivalent Mn is not as readily removed by the liver, as are protein complexes with divalent Mn. Thus, Mn delivered by these other dose routes would be available for uptake into tissues for a longer period of time than the orally administered Mn, leading to quantitative differences in tissue uptake for different dose routes. Several important data gaps impede organizing these various physiological factors into a multi-dose route PK model for Mn. They include knowledge of (1) oxidation rates of Mn in blood, (2) uptake rates of protein-bound forms of Mn by the liver, (3) neuronal transfer rates within the CNS, and (4) quantitative analyses of the control processes that regulate uptake of ingested Mn by the intestines and liver. These data gaps are the main obstacles to developing a risk assessment strategy for Mn that considers contributions of both inhalation and ingestion of this essential nutrient in determining brain Mn concentrations.
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PMID:Pharmacokinetic data needs to support risk assessments for inhaled and ingested manganese. 1038 80

Zinc administered on a long-term basis in excess to patients with Wilson a disease blocks in a significant way copper absorption from the gut, prevents its accumulation and toxic action in the organism. The authors investigated the effect of its long-term administration on the plasma concentration of copper, zinc, and selenium, on the superoxide dismutase activity in red blood cells and glutathione peroxidase activity in whole blood. In seven patients with Wilson a disease treated with zinc sulphate, 136 mg of elemental zinc for 1.5 years (18 months), the authors assessed the plasma concentration of zinc, copper, selenium and ceruloplasmin, the activity of superoxide dismutase in red blood cells, the activity of glutathione peroxidase in whole blood and the urinary excretion of zinc and copper in 24 hours. Envisaged findings with regard to the diagnosis of the investigated patients and their treatment: elevated plasma zinc concentration and increased urinary excretion, reduced copper and ceruloplasmin plasma concentration and increased urinary copper excretion. The authors recorded also a significantly elevated selenium plasma concentration and a significantly higher concentration of superoxide dismutase in red blood cells (p < 0.05). The increase of the glutathione peroxidase activity in whole blood in the investigated patients was not significant (p < 0.05). Changes in the values of the investigated parameters in patients with Wilson s disease treated on a long-term basis with zinc indicate the possible mutual interaction of zinc with other trace elements with an impact on the activity of the corresponding metalloenzymes, i.e. in the sphere in antioxidant systems.
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PMID:[Serum levels of zinc, copper and selenium in patients with Wilson's disease treated with zinc]. 1104 82

The liver lobule is formed by parenchymal cells, i.e., hepatocytes and nonparenchymal cells. In contrast to hepatocytes that occupy almost 80% of the total liver volume and perform the majority of numerous liver functions, nonparenchymal liver cells, which contribute only 6.5% to the liver volume, but 40% to the total number of liver cells, are localized in the sinusoidal compartment of the tissue. The walls of hepatic sinusoid are lined by three different cell types: sinusoidal endothelial cells (SEC), Kupffer cells (KC), and hepatic stellate cells (HSC, formerly known as fat-storing cells, Ito cells, lipocytes, perisinusoidal cells, or vitamin A-rich cells). Additionally, intrahepatic lymphocytes (IHL), including pit cells, i.e., liver-specific natural killer cells, are often present in the sinusoidal lumen. It has been increasingly recognized that both under normal and pathological conditions, many hepatocyte functions are regulated by substances released from neighboring nonparenchymal cells. Liver sinusoidal endothelial cells constitute the lining or wall of the hepatic sinusoid. They perform important filtration function due to the presence of small fenestrations that allow free diffusion of many substances, but not of particles of the size of chylomicrons, between the blood and the hepatocyte surface. SEC show huge endocytic capacity for many ligands including glycoproteins, components of the extracellular matrix (ECM; such as hyaluronate, collagen fragments, fibronectin, or chondroitin sulphate proteoglycan), immune complexes, transferrin and ceruloplasmin. SEC may function as antigen-presenting cells (APC) in the context of both MHC-I and MHC-II restriction with the resulting development of antigen-specific T-cell tolerance. They are also active in the secretion of cytokines, eicosanoids (i.e., prostanoids and leukotrienes), endothelin-1, nitric oxide, and some ECM components. Kupffer cells are intrasinusoidally located tissue macrophages with a pronounced endocytic and phagocytic capacity. They are in constant contact with gut-derived particulate materials and soluble bacterial products so that a subthreshold level of their activation in the normal liver may be anticipated. Hepatic macrophages secrete potent mediators of the inflammatory response (reactive oxygen species, eicosanoids, nitric oxide, carbon monoxide, TNF-alpha, and other cytokines), and thus control the early phase of liver inflammation, playing an important part in innate immune defense. High exposure of Kupffer cells to bacterial products, especially endotoxin (lipopolysaccharide, LPS), can lead to the intensive production of inflammatory mediators, and ultimately to liver injury. Besides typical macrophage activities, Kupffer cells play an important role in the clearance of senescent and damaged erythrocytes. Liver macrophages modulate immune responses via antigen presentation, suppression of T-cell activation by antigen-presenting sinusoidal endothelial cells via paracrine actions of IL-10, prostanoids, and TNF-alpha, and participation in the development of oral tolerance to bacterial superantigens. Moreover, during liver injury and inflammation, Kupffer cells secrete enzymes and cytokines that may damage hepatocytes, and are active in the remodeling of extracellular matrix. Hepatic stellate cells are present in the perisinusoidal space. They are characterized by abundance of intracytoplasmic fat droplets and the presence of well-branched cytoplasmic processes, which embrace endothelial cells and provide focally a double lining for sinusoid. In the normal liver HSC store vitamin A, control turnover of extracellular matrix, and regulate the contractility of sinusoids. Acute damage to hepatocytes activates transformation of quiescent stellate cells into myofibroblast-like cells that play a key role in the development of inflammatory fibrotic response. Pit cells represent a liver-associated population of large granular lymphocytes, i.e., natural killer (NK) cells. They spontaneously kill a variety of tumor cells in an MHC-unrestricted way, and this antitumor activity may be enhanced by the secretion of interferon-gamma. Besides pit cells, the adult liver contains other subpopulations of lymphocytes such as gamma delta T cells, and both "conventional" and "unconventional" alpha beta T cells, the latter containing liver-specific NK T cells. The development of methods for the isolation and culture of main liver cell types allowed to demonstrate that both nonparenchymal and parenchymal cells secrete tens of mediators that exert multiple paracrine and autocrine actions. Co-culture experiments and analyses of the effects of conditioned media on cultures of another liver cell type have enabled the identification of many substances released from non-parenchymal liver cells that evidently regulate some important functions of neighboring hepatocytes and non-hepatocytes. To the key mediators involved in the intercellular communication in the liver belong prostanoids, nitric oxide, endothelin-1, TNF-alpha, interleukins, and chemokines, many growth factors (TGF-beta, PDGF, IGF-I, HGF), and reactive oxygen species (ROS). Paradoxically, the cooperation of liver cells is better understood under some pathological conditions (i.e., in experimental models of liver injury) than in normal liver due to the possibility of comparing cellular phenotype under in vivo and in vitro conditions with the functions of the injured organ. The regulation of vitamin A metabolism provides an example of the physiological role for cellular cross-talk in the normal liver. The majority (up to 80%) of the total body vitamin A is stored in the liver as long-chain fatty acid esters of retinal, serving as the main source of retinoids that are utilized by all tissues throughout the body. Hepatocytes are directly involved in the uptake from blood of chylomicron remnants, and the synthesis of retinol-binding protein that transfers retinol to other tissues. However, more than 80% of the liver retinoids are stored in lipid droplets of hepatic stellate cells. HSC are capable of both uptake and release of retinol depending on the body's retinol status. The activity of some major enzymes of vitamin A metabolism have been found to be many times higher per protein basis in stellate cells than in hepatocytes. Despite progress in the understanding of the roles played by these two cell types in hepatic retinoid metabolism, the way in which retinoids move between the parenchymal cells, stellate cells, and blood plasma has not been fully elucidated. Sinusoidal blood flow is, to a great extent, regulated by hepatic stellate cells that can contract due to the presence of smooth muscle alpha-actin. The main vasoactive substances that affect constriction or relaxation of HSC derive both from distant sources and from neighboring hepatocytes (carbon monoxide, leukotrienes), endothelial cells (endothelin, nitric oxide, prostaglandins), Kupffer cells (prostaglandins, NO), and stellate cells themselves (endothelin, NO). The cellular cross-talk reflected by the fine-tuned modulation of sinusoidal contraction becomes disturbed under pathological conditions, such as endotoxemia or liver fibrosis, through the excess synthesis of vasoregulatory compounds and the involvement of additional mediators acting in a paracrine way. The liver is an important source of some growth factors and growth factor-binding proteins. Although hepatocytes synthesize the bulk of insulin-like growth factor I (IGF-I), also other types of nonparenchymal liver cells may produce this peptide. Cell-specific expression of distinct IGF-binding proteins observed in the rat and human liver provides the potential for specific regulation of hepatic IGF-I synthesis not only by growth hormone, insulin, and IGF-I, but also by cytokines released from activated Kupffer (IL-1, TNF-alpha, TGF-beta) or stellate cells (TGF-alpha, TGF-beta). Hepatic stellate cells may affect turnover of hepatocytes through the synthesis of potent positive as well as negative signals such as, respectively, hepatocyte-growth-factor or TGF-beta. Although hepatocytes seem not to produce TGF-beta, a pleiotropic cytokine synthesized and secreted in the latent form by Kupffer and stellate cells, they may contribute to its actions in the liver by the intracellular activation of latent TGF-beta, and secretion of the biologically active isoform. Many mediators that reach the liver during inflammatory processes, such as endotoxins, immune-complexes, anaphylatoxins, and PAF, increase glucose output in the perfused liver, but fail to do so in isolated hepatocytes, acting indirectly via prostaglandins released from Kupffer cells. In the liver, prostaglandins synthesized from arachidonic acid mainly in Kupffer cells in a response to various inflammatory stimuli, modulate hepatic glucose metabolism by increasing glycogenolysis in adjacent hepatocytes. The release of glucose from glycogen supports the increased demand for energetic fuel by the inflammatory cells such as leukocytes, and additionally enables enhanced glucose turnover in sinusoidal endothelial cells and Kupffer cells which is necessary for effective defense of these cells against invading microorganisms and oxidative stress in the liver. Leukotrienes, another oxidation product of arachidonic acid, have vasoconstrictive, cholestatic, and metabolic effects in the liver. A transcellular synthesis of cysteinyl leukotrienes (LTC4, LTD4, and LTE4) functions in the liver: LTA4, an important intermediate, is synthesized in Kupffer cells, taken up by hepatocytes, converted into the potent LTC4, and then released into extracellular space, acting in a paracrine way on Kupffer and sinusoidal endothelial cells. Thus, hepatocytes are target cells for the action of eicosanoids and the site of their transformation and degradation, but can not directly oxidate arachidonic acid to eicosanoids. (ABSTRACT TRUNCATED)
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PMID:Cooperation of liver cells in health and disease. 1172 49

Zinc therapy has replaced penicillamine as first-line therapy for Wilson's disease. New guidelines reflect the paradigm shift in treatment that has occurred in recent years. In the old paradigm, Wilson's disease was seen as genetic disorder associated with the accumulation of copper in the liver and in other organs once the liver had become overloaded with copper. When left untreated, the disease was regarded as uniformly fatal. The old treatment guidelines advised, 'decoppering' with penicillamine because this chelating agent was considered effective in restoring most patients to health. Before the start of treatment, patients were warned that their symptoms could worsen during the first weeks or months of therapy, so as to prevent them from abandoning penicillamine therapy in dismay. In the new paradigm, Wilson's disease is seen as a hereditary disorder associated with copper intoxication. The essence of symptomatic Wilson's disease is poisoning by free copper in the blood, that is, by copper that is not bound to ceruloplasmin. This form of copper is toxic, whereas accumulated copper and copper that is bound to ceruloplasmin or metallothionein is not. The treatment of symptomatic Wilson's disease is no longer aimed at 'decoppering', the removal of accumulated copper, but at the normalization of the free copper concentration in blood, to reverse the copper poisoning. This can be achieved safely and effectively with zinc therapy. Zinc induces metallothionein, a highly effective detoxification protein that binds copper. Oral zinc therapy leads to storage of metallothionein-bound copper in the mucosa of the gut and to the excretion of copper via the stools. New treatment guidelines advise against the use of chelating agents as initial treatment because they may aggravate copper intoxication and cause iatrogenic deterioration.
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PMID:Paradigm shift in treatment of Wilson's disease: zinc therapy now treatment of choice. 1690 56

Hephaestin (Hp) is a membrane protein with ferroxidase activity that converts Fe(II) to Fe(III) during the absorption of nutritional iron in the gut. Using anti-peptide antibodies to predicted immunogenic regions of rodent Hp, previous immunocytochemical studies in rat, mouse, and human gut tissues localized Hp to the basolateral membranes of the duodenal enterocytes where the Hp was predicted to aid in the transfer of Fe(III) to transferrin in the blood. We used a recombinant soluble form of human Hp to obtain a high-titer polyclonal antibody to Hp. This antibody was used to identify the intracellular location of Hp in human gut tissue. Our immunocytochemical studies confirmed the previous localization of Hp in human enterocytes. However, we also localized Hp to the entire length of the gastrointestinal tract, the antral portion of the stomach, and to the enteric nervous system (both the myenteric and submucous plexi). Hp was also localized to human pancreatic beta-cells. In addition to its expression in the same cells as Hp, ferroportin was also localized to the ductal cells of the exocrine pancreas. The localization of the ferroxidase Hp to the neuronal plexi and the pancreatic beta cells suggests a role for the enzymatic function of Hp in the protection of these specialized cell types from oxidative damage.
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PMID:Human hephaestin expression is not limited to enterocytes of the gastrointestinal tract but is also found in the antrum, the enteric nervous system, and pancreatic {beta}-cells. 2001 63

Seroma is a frequent complication of breast cancer surgery, the etiology of which remains indefinite. It represents a subcutaneous accumulation of fluid frequently reported after surgical procedures such as axillary lymph node dissection. Despite previous studies have associated seroma fluid to an inflammatory exudate, the surgical removal of draining lymph nodes may indicate that seroma might not represent a mere exudate but rather an accrual of lymph drained from tributary tissues. To verify this hypothesis, seromas were collected at different intervals of time in patients operated upon for axillary lymph node removal. Fluids were analyzed in details by flow cytometry and biochemical assays for their cellular content and for their molecular features and relevant cytokine content. Lymphocytes and other peculiar blood mononuclear cells were present, while erythrocytes, platelets and granulocytes were absent or extremely rare. The protein concentration resulted lower (median 64%) than in peripheral blood. However, specific proteins related to locoregional tissues resulted highly concentrated (e.g. up to 500% for ferritin and 300% for lactate deydrogenase and exclusive presence of interleukin-6) whereas all enzymes and proteins synthesized in the liver or other organs (e.g. alkaline phosphatase, ALT, gammaGT, prealbumin, transferrin, ceruloplasmin, C3 and C4, alpha2 macroglobulin from liver; apolipoproteins from liver and gut; amylase and lipase from pancreas) were represented in reduced concentrations, thus ruling out that seroma proteins derive directly from blood serum. As a whole, this comprehensive cytological and molecular analysis provided evidences that seroma is constituted by serum ultrafiltrated-derived extracellular fluid of regions located upstream of removed lymph nodes. This fluid is then enriched by proteins and cells collected in the drained regions. Remarkably, seroma fluids collected in the same patient at different time points (up to 50 days following surgery) displayed similar biochemical features, clearly indicating that fluid composition was not significantly affected by post-surgical locoregional flogosis. Finally, the period of seroma formation indicates that lymph accumulates in the axillary region during the interval of time needed for afferent lymphatic vessels to re-anastomose with the efferent ducts. Therefore, seroma fluid represents a font of biological material suitable for investigating the biology of breast cancer, healing tissues and lymph.
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PMID:Seroma fluid subsequent to axillary lymph node dissection for breast cancer derives from an accumulation of afferent lymph. 2029 20


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