Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Groups of 20 male and 20 female rats were given five different oral doses of a mixture of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 1, 2,3,7,8-pentaCDD, (PCDD) 1,2,3,4,7,8-hexaCDD (HxCDD), and 1,2,3,4,6, 7,8-heptaCDD (HpCDD) divided into four daily loading doses and six biweekly maintenance doses. PCDD and HxCDD were used as positive controls. The dosing period was 13 weeks, after which half of the rats were necropsied and the rest provided with an off-dose period of another 13 weeks. Liver ethoxyresorufin O-deethylase (EROD) activity was dose-dependently increased in rats dosed with the mixture starting at the lowest dose (13- to 16-fold increase), with the effect reaching maximum at the middle dosage (74- to 112-fold increase), as well as in the positive control groups. There was some indication of reversibility at the lower doses and in positive controls during the off-dose period. The activity of phosphoenolpyruvate carboxykinase (PEPCK) in liver was dose-dependently decreased (maximally by 51%). This effect was more distinct in males than in females. Liver tryptophan 2,3-dioxygenase (TdO) activity decreased maximally by 53% at the two highest doses. This effect was more distinct in females than in males. Serum tryptophan concentrations were increased in rats moribund due to wasting. Some reversibility was apparent by the end of the off-dose period regarding all three biochemical markers of CDD toxicity. Serum glucose concentrations were decreased at the three highest doses of the mixture and in positive controls, maximally by 30%, with some reversibility during the off-dose period. There was a dose-dependent decrease of serum thyroxine (T4) concentrations in rats given the mixture and in the PCDD and HxCDD dosage groups (maximally by 69%), with some reversibility in males during the off-dose period. Serum triiodothyronine (T3) levels were not much affected, except that they tended to be decreased in rats moribund with hemorrhage or anemia. The results demonstrate that comparable biochemical changes occur after multiple as after single dosing with CDDs and that TEFs derived from acute studies can be used to predict the toxicity of mixtures of CDDs regardless whether they are administered as single compounds or as a mixture. This study supports the validity of the toxic equivalency factor (TEF) method and the notion of additive toxicity for CDDs as currently used in the risk assessment of these compounds.
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PMID:Subchronic/chronic toxicity of a mixture of four chlorinated dibenzo-p-dioxins in rats. II. Biochemical effects. 970 88

In vitro and in vivo, tryptophan degradation was found to be associated with T cell functional loss and tolerance induction. In systemic lupus erythematosus (SLE) besides the Th2-type cytokine interleukin-10, Th1-type cytokines including interferon-gamma (IFN-gamma) are expressed especially during exacerbation of the disease. IFN-gamma stimulates the enzyme indoleamine (2,3)-dioxygenase (IDO) converting tryptophan to the metabolite kynurenine which in macrophages is subsequently degraded to other, partly neurotoxic compounds like quinolinic acid, and finally to nicrotinamides. We measured kynurenine and tryptophan concentrations in the sera of 55 SLE patients. In these patients, the concentrations of tryptophan (median, interquartile range: 53.9, 45.7-64.1 microM) were lower (p < 0.0001), and the kynurenine concentrations (2.45, 1.75-3.40 microM) were increased (p < 0.0005) compared to healthy blood donors (70.0, 63.8-80.6; 1.80, 1.45-2.27 microM, respectively). Also the kynurenine per tryptophan quotients (K/T), which allow to estimate IDO activity, were significantly higher in patients than in normals (0.043, 0.033-0.062 vs. 0.027, 0.021-0.030; p < 0.0001), indicating enhanced IDO-induced tryptophan degradation in SLE. There was no significant relationship between tryptophan, kynurenine and the SLEDAI, and also the correlation of K/T with SLEDAI was rather weak (rs = 0.243, p < 0.05). Higher K/T was found in patients presenting with serositis (p = 0.01), decrease of complement (c3, c4; p < 0.01) and blood count change (anemia, leucopenia, lymphopenia; p = 0.032) than in patients without such disease manifestations. The significant correlation found between K/T and neopterin (rs = 0.808, p < 0.001), a marker of immune activation, points to a role of immune activation to be responsible for tryptophan degradation in SLE patients.
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PMID:Enhanced tryptophan degradation in systemic lupus erythematosus. 1083 18

Clostridia are normally found in the healthy colon, where their numbers are kept in check by other bacteria. However, when they establish themselves in the ileum they become formidable foes. They produce medium-length fatty acids that increase water absorption, causing hypertension and drying up the feces, causing constipation.Furthermore, they can deconjugate bile (impaired fat absorption), metabolyze tryptophan (the most scarce of the essential amino acids), digest fiber (so that the more fiber the patient takes, the more the constipation is exacerbated), digest lecithin, produce carcinogenic metabolites and copious amounts of extremely foul smelling gas, etc. They can also prevent vitamin B12 absorption in the ileum, causing anemia. The synthetic sugar lactulose, which can only be digested by lactobacilli, can help displace the clostridia and resolve the constipation by causing the lactobacilli to produce short fatty acids that have the opposite effect to that of the medium fatty acids produced by clostridia and their accomplices: they cause water retention in the intestines.
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PMID:Clostridial constipation's broad pathology. 1133 61

We report a Turkish family with parental consanguinity and at risk for sialidosis type II, an inherited autosomal recessive disorder caused by lysosomal alpha-N-acetyl-neuraminidase (sialidase, NEU1) deficiency. The proband was a premature male infant that presented with hydrops, hepatomegaly, respiratory distress syndrome, and anemia and that died of respiratory insufficiency 2 months after birth despite intensive care. An abnormally increased [14C]methylamine incorporation and an isolated deficiency of lysosomal alpha-N-acetyl-neuraminidase were found in cultured skin fibroblasts. A previous pregnancy of the mother terminated in a spontaneous abortion in the 13th week of gestation. A successive pregnancy showed hydrops fetalis, and an enzymatic assay of cultured amniotic fluid cells indicated a deficiency of alpha-N-acetyl-neuraminidase. Following pregnancy termination at 20 weeks gestation, light microscopy of fetal tissues revealed classic vacuolation not only in liver, bone marrow, brain, and kidney, but also in endocrine organs such as the thyroid gland, adrenal gland, hypophysis, and testes, and in the thymus. DNA analysis of the family showed that both the proband and the third sibling had a novel homozygous nonsense point mutation at nucleotide 87 in exon 1 of the alpha-N-acetyl-neuraminidase (neu1) gene causing a substitution of tryptophan at codon 29 by a termination codon (W29X). DNA sequencing of polymerase chain reaction products identified the parents as heterozygous carriers. To detect neu1 mRNA expression, a real-time reverse transcription/polymerase chain reaction was performed, and similar rates of neu1 mRNA expression were found in the fibroblasts of the fetus, the 2nd sibling, and in controls. The very early termination codon with complete loss of neuraminidase activity is probably the molecular basis of the unusually severe vacuolation pattern in this form of congenital sialidosis.
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PMID:Prenatal diagnosis and fetal pathology in a Turkish family harboring a novel nonsense mutation in the lysosomal alpha-N-acetyl-neuraminidase (sialidase) gene. 1170 24

Pathogenicity was reportedly restored to an avirulent molecular clone of equine infectious anemia virus (EIAV) by substitution of 3' sequences from the pathogenic variant strain (EIAV(PV)). However, the incidence of disease in horses/ponies was found to be significantly lower (P = 0.016) with the chimeric clone (EIAV(UK)) than with EIAV(PV). This was attributable to 3' rather than 5' regions of the proviral genome, where EIAV(UK) differs from the consensus EIAV(PV) sequence by having a 68-bp duplication in the 3' LTR and arginine (R(103)) rather than tryptophan (W(103)) at position 103 in the second exon of rev. In EIAV(UK) recipients the duplication was rapidly eliminated and R(103) replaced by W(103) in the viral population. Furthermore, removal of the 3' variant sequences from EIAV(UK) (EIAV(UK3)) resulted in an equivalent (P = 0.013) disease potential in Equus caballus to EIAV(PV). The 68-bp duplication and/or R(103) may limit peak viral RNA accumulation during acute infection.
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PMID:Enhancement of equine infectious anemia virus virulence by identification and removal of suboptimal nucleotides. 1295 24

Anaemia of inflammation (AI) is a frequent complication in patients suffering from chronic inflammatory disorders including infections, autoimmune and malignant disease. Cytokine imbalance with a shift towards T-helper (Th)1-type immune response seems to be important in the pathogenesis of this type of anaemia. Interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha may affect the growth and differentiation of erythroid progenitor cells. In macrophages, IFN-gamma strongly induces indoleamine (2,3)-dioxygenase, an enzyme which degrades tryptophan (trp) to kynurenine (kyn). Trp availability is rate limiting for protein biosynthesis and thus cell growth, including erythropoiesis. In this study, trp and kyn concentrations and their relationship to haemoglobin concentrations and to immune activation was examined in 22 patients with AI. Patients with AI presented with lower trp concentrations than healthy controls of similar age, and a significantly higher kyn to trp ratio, suggesting enhanced trp degradation and, because of a positive correlation with neopterin, immune activation. The kyn to trp ratio was inversely correlated to haemoglobin levels. Thus, the limitation of trp availability to erythroid progenitors may be a key mechanism in cytokine-mediated inhibition of erythropoiesis, and the therapeutic modulation of indoleamine (2,3)-dioxygenase and trp levels may be promising targets for AI therapy.
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PMID:Possible role of cytokine-induced tryptophan degradation in anaemia of inflammation. 1496 50

The essential amino acid tryptophan is a constituent of proteins and is also a substrate for two important biosynthetic pathways: the generation of neurotransmitter 5-hydroxytryptamine (serotonin) by tryptophan 5-hydroxylase, and the formation of kynurenine derivatives and nicotinamide adenine dinucleotides. The latter pathway is initiated by the enzymes tryptophan pyrrolase (tryptophan 2,3-dioxygenase, TDO) and indoleamine 2,3-dioxygenase (IDO). TDO is located in liver cells, whereas IDO is expressed in a variety of cells including monocyte-derived macrophages and dendritic cells and is preferentially induced by Th1-type cytokine interferon-gamma. Tryptophan depletion via IDO is part of the cytostatic and antiproliferative activity mediated by interferon-gamma in cells. In vivo tryptophan concentration can be measured by HPLC by monitoring its natural fluorescence (285 nm excitation and 365 nm emission wavelength). IDO activity is characterized best by the kynurenine to tryptophan ratio which correlates with concentrations of immune activation markers such as neopterin. Low serum/plasma tryptophan concentration is observed in infectious, autoimmune, and malignant diseases and disorders that involve cellular (Th1-type) immune activation as well as during pregnancy due to accelerated tryptophan conversion. Thus, in states of persistent immune activation, low tryptophan concentration may contribute to immunodeficiency. Decreased serum tryptophan can also effect serotonin biosynthesis and thus contribute to impaired quality of life and depressive mood. As such, monitoring tryptophan metabolism in chronic immunopathology provides a better understanding of the association between immune activation and IDO and its role in the development of immunodeficiency, anemia and mood disorders.
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PMID:Monitoring tryptophan metabolism in chronic immune activation. 1613 56

Normocytic normochromic anaemia is a common syndrome present in patients with chronic renal insufficiency (CRI). Simultaneously in these patients the increase in L-tryptophan (TRP) degradation via kynurenine pathway is observed. On the basis of these observations we tried to examine whether one of the TRP metabolites, anthranilic acid (AA), shows interaction with membranes of erythrocytes and because of that it may contribute to anaemia development. In patients with CRI we have observed changes characteristic for normocytic normochromic anaemia, such as the decrease in erythrocyte count, haemoglobin concentration, haematocrit and the decrease in erythrocyte osmotic resistance as well as the increase in AA concentration in plasma in comparison to healthy subjects. We have also noticed the existence of a positive correlation between anthranilic acid concentration and creatinine and urea concentrations and also negative relationships between anthranilic acid concentration and haematological parameters. Moreover, incubation of healthy erythrocytes with 10 and 100 microM AA caused haemolysis curve movement to the right, which shows decrease in osmotic resistance. In conclusion, the increase in plasma AA concentration might be one of many factors, which damage erythrocyte membrane, and thereby contributes to anaemia development in patients with CRI.
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PMID:Anthranilic acid-uraemic toxin damaged red cell's membrane. 1630 52

Fanconi anemia (FA) is an autosomal recessive disorder characterized by aplastic anemia, cancer susceptibility, and cellular sensitivity to mitomycin C. Eight of the 11 cloned Fanconi anemia gene products (FANCA, -B, -C, -E, -F, -G, -L, and -M) form a multisubunit nuclear complex (FA core complex) required for monoubiquitination of a downstream FA protein, FANCD2. FANCL, which possesses three WD40 repeats and a plant homeodomain (PHD), is the putative E3 ubiquitin ligase subunit of the FA complex. Here, we demonstrate that the WD40 repeats of FANCL are required for interaction with other subunits of the FA complex. The PHD is dispensable for this interaction, although it is required for FANCD2 mono-ubiquitination. The PHD of FANCL also shares sequence similarity to the canonical RING finger of c-CBL, including a conserved tryptophan required for E2 binding by c-CBL. Mutation of this tryptophan in the FANCL PHD significantly impairs in vivo mono-ubiquitination of FANCD2 and in vitro auto-ubiquitination activity, and partially impairs restoration of mitomycin C resistance. We propose a model in which FANCL, via its WD40 region, binds the FA complex and, via its PHD, recruits an as-yet-unidentified E2 for mono-ubiquitination of FANCD2.
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PMID:The WD40 repeats of FANCL are required for Fanconi anemia core complex assembly. 1647 67

This study focuses on the development and application of biophysical methodology to characterize conformations of Epogen and Eprex, the injectable formulations of recombinant human Epoetin alfa produced by different manufacturers and commonly used for the treatment of renal anemia. In these studies Eprex, from prefilled syringes, and Epogen bulk product formulated in a buffer similar to the Eprex formulation, were purified by anion-exchange chromatography. Analytical ultracentrifugation studies of the purified main peak from each sample demonstrated that Epogen contains a single component with an s value of 2.51 while Eprex contains a single component with the same molecular weight but with an s value of 2.44 suggesting a slight difference in hydrodynamic structure. The degree of alpha-helicity was compared by far-UV circular dichroism and shown to contain slight differences. Intrinsic tryptophan fluorescence and near-UV circular dichroism were assessed and demonstrated additional differences between the proteins. Finally, the global stability of the proteins was monitored using thermal unfolding monitored by far-UV circular dichroism. The Epoetin alfa of Epogen demonstrated complete reversibility while the Epoetin alfa purified from Eprex demonstrated only 80%-85% thermal reversibility when heated to 100 degrees C. Together the data indicate that the proteins are not structurally identical.
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PMID:Biophysical comparability of the same protein from different manufacturers: a case study using Epoetin alfa from Epogen and Eprex. 1772 76


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