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)

The anemia of chronic inflammatory and malignant diseases is partly due to impaired synthesis of the hormone erythropoietin (Epo). The proinflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor a (TNF-alpha) suppress in vitro Epo gene expression and Epo protein secretion. However, the molecular mechanisms of this inhibition are poorly understood. The human Epo promoter and the 5' flanking region contain several recognition sequences for transcription factors acting either positively or negatively. Herein, we investigated the roles of the transcription factors GATA-2 and NF-kappaB in the modulation of Epo gene expression by IL-1beta and TNF-alpha in the human hepatoma cell line HepG2. Electrophoretic mobility shift assays revealed increased GATA-2 and NF-kappaB DNA binding in cells treated with IL-1beta or TNF-alpha. Reporter gene assays with a sequence from the Epo promoter in front of the firefly luciferase gene showed that the cytokines reduced Epo reporter gene activity. Functional inactivation of GATA-2 and NF-kappaB by oligo-decoy techniques prevented the inhibition of Epo production by IL-1beta and TNF-alpha. In HepG2 cells stably transfected with a dominant-negative form of IkappaBalpha, the activation of NF-kappaB was inhibited, while Epo mRNA levels and Epo secretion increased. Thus, both GATA-2 and NF-kappaB seem to be involved in the suppression of Epo gene expression by IL-1beta and TNF-alpha in vitro and may be responsible for impaired Epo synthesis in inflammatory diseases in vivo.
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PMID:Inhibition of erythropoietin gene expression signaling involves the transcription factors GATA-2 and NF-kappaB. 1222 49

The intensity of malaria transmission is related to the pattern of malarial disease observed in different regions, but populations may also differ in their underlying predispositions to severe malarial anemia or cerebral malaria. In western Kenya, where severe malarial anemia is much more common than cerebral malaria, the distributions of tumor necrosis factor (TNF)-alpha, interleukin (IL)-10, transforming growth factor (TGF)-beta, IL-6, and interferon (IFN)-gamma alleles were examined in a cohort of young men. The cohort displayed a marked bias toward genotypes associated with low expression of IFN-gamma and IL-6, cytokines that, at high levels, have been implicated in malarial anemia and poor malaria outcomes. By contrast, the frequency of the TNF-alpha -238A allele, which has been associated with severe malarial anemia, was found to be similar to the frequency previously reported in comparison populations in Africa and elsewhere. IFN-gamma and IL-6 genotypes may play roles in the development of severe malaria and could contribute to the relative frequency of severe malarial anemia or cerebral malaria in exposed populations.
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PMID:Profound bias in interferon-gamma and interleukin-6 allele frequencies in western Kenya, where severe malarial anemia is common in children. 1223 42

Fanconi anemia (FA) is a chromosomal instability disorder characterized by a progressive bone marrow (BM) failure and an increased incidence of myeloid leukemias. Children with FA are currently being enrolled in clinical trials to evaluate the safety of retroviral-mediated gene transfer. Previously, we used Fancc(-/-) mice to show that Fancc(-/-) hematopoietic stem cells (HSCs) have a profound defect in repopulating ability. Here, we examined whether retroviral-mediated gene transfer of recombinant Fancc (rFancc) would restore the repopulating ability of Fancc(-/-) HSC to wild-type levels. Fancc(-/-) HSCs transduced with a retrovirus encoding rFancc exhibited a repopulating ability that approached wild-type levels. Interestingly, approximately 30% of primary recipients (7 of 22) transplanted with uncorrected Fancc(-/-) cells developed a range of hematopoietic abnormalities including pancytopenia and BM hypoplasia similar to individuals with FA. Hematopoietic abnormalities were detected in only 1 of 22 mice transplanted with Fancc(-/-) cells transduced with a retrovirus encoding rFancc. Moreover, several mice with hematopoietic defects had progenitors that displayed a marked resistance to IFN-gamma, TNF-alpha, and MIP-1alpha compared to both Fancc(-/-) progenitors, which are uniquely hypersensitive to these cytokines, and wild-type progenitors. These data are analogous to studies using progenitors from patients with myelodysplasia and provide functional support for clonal evolution in these mice. Collectively, these data show that gene transfer can enhance HSC repopulating ability and suppresses the tendency for clonal evolution. These studies also reveal potential detrimental effects of ex vivo manipulation for untransduced Fancc(-/-) HSCs.
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PMID:Retroviral-mediated expression of recombinant Fancc enhances the repopulating ability of Fancc-/- hematopoietic stem cells and decreases the risk of clonal evolution. 1239 4

Atherosclerosis is a multifaceted process which may be initiated by various insults to vascular endothelium. Independently of the nature of the offending factor, the endothelial dysfunction that results from the initial insult is characterized by increased adhesiveness of the endothelium to leukocytes and platelets and by the synthesis of vasoactive molecules, cytokines and procoagulant factors. This defensive response is characterized by classical inflammatory changes and may lead to plaque formation, luminal obstruction and plaque rupture. Factors involved in arterial damage in end-stage renal disease (ESRD) span from classical risk factors to disease-peculiar factors (anemia, secondary hyperparathyroidism and exposure to bioincompatible dialysis membranes and/or contaminated dialysis fluid) and to emerging and novel risk factors such as hyperhomocysteinemia, infections and accumulation of the endogenous inhibitor of NO synthase, asymmetric dimethylarginine (ADMA). There is strong and consistent evidence that acute phase reactants like C-reactive protein and cytokines like IL-beta, TNF-alpha and IL-6 are independently associated with death and atherosclerosis in ESRD patients. The experimental and epidemiological data collected thus far coherently show that endothelial dysfunction resulting from inflammation may promote abnormal vascular behavior and thrombosis in ESRD. There are several possible therapeutic approaches for reducing the risk excess associated with inflammation in ESRD. These possibilities range from drugs interfering with the angiotensin system or with adrenergic activity to anti-inflammatory and antilipid agents to vitamins, antioxidants, to the amino acid precursor of nitric oxide, L-arginine, and perhaps to antibiotics. The intellectual framework is well delineated but very few controlled trials have been performed or are underway in patients with ESRD.
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PMID:Inflammation and atherosclerosis in end-stage renal disease. 1256 58

Here we describe a lethal mouse model infected with dengue virus type 2 with several similarities to human DEN-2 infection. Clinically animals demonstrated anemia, thrombocytopenia, pre-terminal paralysis and shock. The most impressive changes were seen with tumor necrosis factor (TNF)-alpha, which abruptly and steeply increased 24 h before the exitus (mean at day 6). Serum levels of IL-1beta, IL-6, IL-10, IL-1 receptor antagonist and soluble TNF receptor I continuously increased during the time of infection. A 100% mortality rate was noted in that group of animals. Treating animals with anti-TNF-alpha serum reduced mortality rate down to 40% (P<0.05). Our model supports the view that activation of innate immune response is at least partially responsible for mortality in DEN-2 infection, and in line with this concept, anti-TNF treatment significantly reduces mortality rates.
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PMID:Anti-TNF antibody treatment reduces mortality in experimental dengue virus infection. 1258 55

Leukopenia and anaemia are observed in about a fifth of all patients with systemic lupus erythematosus (SLE) and may be due either to the destruction of blood cells or their decreased production. The former may be humoral or cell-mediated or result from apoptosis of peripheral blood cells. Several observations suggest the occurrence of the latter reduced in vitro proliferation of pluripotent bone marrow progenitors from the bone marrow aspirates of SLE patients,reduced counts of CD34+ cells in bone marrow aspirates in SLE patients, apoptosis of lymphopoietic progenitors and apoptosis of bone marrow cells. The aim of our study was to investigate whether humoral factors may induce suppression of haematopoiesis by increased apoptosis of CD34+ cells. For this purpose, we incubated allogeneic CD34+-enriched cells with sera of 18 leukopenic SLE patients. Apoptosis was induced by four of 18 sera. This effect was independent of complement-inhibition and FAS-blockade. Although reduced proliferation of autologous pluripotent bone marrow progenitors has been attributed to an IgG serum inhibitor, removal of IgG from these four proapoptotic sera had no effect on apoptosis of allogeneic CD34+ cells. The proapoptotic effect was associated with high titres of anti-dsDNA antibodies and low haemoglobin concentrations, but not with high titres of antinuclear antibodies, TNF-alpha and IFN-alpha of the sera tested.
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PMID:Apoptosis of CD34+ cells after incubation with sera of leukopenic patients with systemic lupus erythematosus. 1287 50

To investigate if severe malarial anemia is associated with specific cytokine overproduction, we evaluated serum levels of soluble Fas ligand (sFasL), tumor necrosis factor (TNF-alpha) and interleukin-10 (IL-10) from three groups of young children with Plasmodium falciparum infection (asymptomatic cases, uncomplicated malaria cases and severe malarial anemia cases), in a hyperendemic area of Gabon. In uncomplicated cases, only TNF levels were significantly (p < 0.001) increased in comparison to asymptomatic cases with P. falciparum infection. High levels of sFasL, TNF-alpha and IL-10 were associated with low hemoglobin concentrations, sFasL levels were significantly higher in children with severe malarial anemia (p < 0.001) as compared to both other groups. The parasite density was positively correlated with IL-10, TNF-alpha and sFasL levels. TNF-alpha and sFasL, but not IL-10 or parasitemia, were independent predictors of hemoglobin concentrations. These results suggest that, in malaria, a specific dysregulation of the cytokine balance may lead to complications such as severe anemia.
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PMID:Severe malarial anemia associated with increased soluble Fas ligand (sFasL) concentrations in Gabonese children. 1471 16

Cancer-related fatigue (CRF) is a prevalent and distressing symptom experienced by patients during cancer therapy. One proposed mechanism for the development of fatigue is the increased secretion of proinflammatory cytokines and/or the development of anemia. The major purpose of this pilot study was to investigate the levels of fatigue and cytokines during radiation therapy and determine whether there was a correlation between the two. A secondary purpose was to explore the relationships among hemoglobin values, cytokines, and fatigue. Participants included 15 women diagnosed with uterine cancer, who received curative external radiation therapy. Fatigue was assessed by a self-report instrument (Multidimensional Fatigue Inventory [MFI-20]) and hemoglobin and cytokines (Il-1, Il-6, and TNF-alpha) were measured before, during, and after radiotherapy. The degree of fatigue increased during radiotherapy without a significant change in IL-1, IL-6, or TNF-alpha levels. There was no significant correlation between changes in general fatigue and the changes in IL-1 and TNF-alpha. There was a significant negative correlation between the change in IL-6 and general fatigue. The hemoglobin levels did decrease significantly during radiotherapy, but there was no significant correlation between general fatigue and hemoglobin after 3 weeks of therapy or after the completion of therapy. In conclusion, pelvic radiotherapy in women with uterine cancer is associated with increased fatigue. There were no significant relationships between anemia or cytokine levels and fatigue. The pathogenesis of fatigue during radiation therapy remains to be elucidated.
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PMID:Levels of fatigue compared to levels of cytokines and hemoglobin during pelvic radiotherapy: a pilot study. 1473 21

Trypanosoma cruzi infection in mice is associated with severe hematological changes, including anemia, which may contribute to mortality. TNF-alpha and nitric oxide (NO) play a critical role in establishing host resistance to this pathogen. We hypothesized that phagocyte-derived NO damages erythrocytes and contributes to the anemia observed during T. cruzi infection. To test this hypothesis, two strains of mice that differed in susceptibility and NO response to T. cruzi infection were used in these studies. We also blocked endogenous NO production by aminoguanidine (AG) treatment or blocked TNF-alpha with a neutralizing antibody and used mice that cannot produce phagocyte-derived NO (C57BL/6 iNOS(-/-)). Following infection with T. cruzi, resistant (C57BL/6) and susceptible (Swiss) mice displayed a parasitemia that peaked at the same time (i.e., day 9), yet parasitemia was 3-fold higher in Swiss mice (P < 0.05). All Swiss mice were dead by day 23 post-infection, while no C57BL/6 mice died during the study. At 14 days post-infection anemia in C57BL/6 mice was more severe than in Swiss mice. Treatment of both strains with the NO inhibitor, AG (50 mg/kg), and the use of iNOS(-/-) mice, revealed that the anemia in T. cruzi-infected mice is not caused by NO. However, the reticulocytosis that occurs during infection was significantly reduced after treatment with AG in both Swiss and C57BL/6 mice (P < 0.05). In addition, we showed that neutralization of TNF-alpha in vivo induced a significant increase in circulating reticulocytes in T. cruzi-infected C57BL/6 mice (P < 0.05), but did not modify other hematologic parameters in these mice. The evaluation of the oxidative stress after induction by t-butyl hydroperoxide (t-BHT) revealed that the treatment with AG completely protected against NO-mediated haemoglobin oxidation. Further, treatment with AG, but not with anti-TNF-alpha, protected against the infection-induced reduction of antioxidant capacity of erythrocytes as assessed by oxygen uptake and induction time. In summary, this is the first report showing the participation of NO and TNF-alpha in the oxidative stress to erythrocytes in acute T. cruzi infection. Further, our data suggest that NO does not play a direct role in development of the anemia. However, NO may contribute to other hematological changes noted during T. cruzi infection, such as the elevation of circulating reticulocytes and the reduction in circulating leukocytes and neutrophils.
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PMID:Involvement of nitric oxide (NO) and TNF-alpha in the oxidative stress associated with anemia in experimental Trypanosoma cruzi infection. 1509 69

To address the role of cellular immunity during ehrlichia infection, we have used a newly described model of monocytic ehrlichiosis that results from infection of mice by an ehrlichia that was isolated from an Ixodes ovatus tick (Ixodes ovatus ehrlichia, IOE). Immunocompetent C57BL/6 and BALB/c mice exhibited a dose-dependent susceptibility to IOE infection. Mice infected with a high dose inoculum ( approximately 1000 organisms) exhibited pronounced thrombocytopenia, lymphopenia, anemia, and morbidity within 12 days postinfection. Infection was associated with bacterial colonization of a number of tissues. In contrast, mice infected with a low dose inoculum ( approximately 100 organisms) exhibited only transient disease and were able to resolve the infection. SCID mice were highly susceptible to low-dose infection, indicating that adaptive immunity was required. Resistance to sublethal challenge in both C57BL/6 and BALB/c mice was CD4-, but not CD8-, dependent and required IL-12p40-dependent cytokines, IFN-gamma, and TNF-alpha, but not IL-4. CD4 T cells purified from infected mice proliferated in vitro in response to IOE Ags. T cell proliferation was associated with production of IFN-gamma, and the production of this cytokine by CD4 T cells rescued IFN-gamma-deficient mice from fatal infection. Exogenous IFN-gamma was capable of inducing microbiocidal activity in infected macrophages. The data suggest that classical immune mechanisms involving CD4 cells and type 1 cytokines are responsible for macrophage activation and for elimination of this intracellular bacterial pathogen.
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PMID:Production of IFN-gamma by CD4 T cells is essential for resolving ehrlichia infection. 1515 8


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