Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.11.1.6 (catalase)
 55,569 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

TGF-beta1 and macrophages are important regulators of tissue fibrosis and remodeling. Here we show that TGF-beta1 induces the expression of macrophage-CSF (M-CSF) in vascular endothelial cells via a signaling pathway(s) involving hydrogen peroxide (H2O2). In a time-dependent manner, TGF-beta1 produced a 10- and a 6-fold increase in M-CSF mRNA and protein levels after 12 h, respectively. This increase in M-CSF expression was attenuated by a nitric oxide donor, S-nitrosoglutathione (GSNO), and by a nonspecific oxidase inhibitor, diphenylene iodonium. Furthermore, the TGF-beta1-induced M-CSF mRNA expression was inhibited by catalase, but not by superoxide dismutase, suggesting that H2O2 rather than superoxide anion (O2.-) is the primary mediator of the effects of TGF-beta1. Transient transfection studies using deletional M-CSF promoter constructs demonstrated that TGF-beta1 produced a 13-fold induction in M-CSF promoter activity that was repressed by >85% with GSNO and catalase, in part through inhibitory effects on kappaB cis-acting elements. Electrophoretic mobility shift assays revealed that the activation of nuclear factor-kappaB by TGF-beta1 was also inhibited by GSNO and catalase, but not by superoxide dismutase. In a concentration-dependent manner, treatment with exogenous H2O2 produced 14- and 4.6-fold increases in M-CSF promoter activity and mRNA expression, respectively. These results indicate that the generation of H2O2 and activation of NF-kappaB by TGF-beta1 are required for the induction of M-CSF gene transcription.
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PMID:Hydrogen peroxide-mediated transcriptional induction of macrophage colony-stimulating factor by TGF-beta1. 927 33

Human T-cell leukemia virus type-I (HTLV-I), the etiologic agent of adult T-cell leukemia (ATL) transforms human T cells both in vivo and in vitro. However, the long latency period between infection and development of ATL, as well as the small fraction of the infected population that actually develops this disease, suggest that factors in addition to the virus are involved in its pathogenesis. Mutation of tumor suppressor gene p53 has been found in both HTLV-I-transformed T-cell lines and ATL cases at relatively low frequency. However, increasing evidence supports p53 functional impairment in HTLV-I-transformed T cells. Tax, the major transactivator of HTLV-I, is critical for the initial events involved in transformation. We have considered the possibility that p53 may regulate transcription of viral and cellular genes important for viral replication and transformation. Inactivation of p53 function might then permit constitutive expression of these viral and cellular genes. We have investigated the effects of wild-type and mutant p53 on Tax-mediated activation of the HTLV-I long terminal repeat (LTR) and the promoters of several cellular genes including the interleukin (IL)-1alpha, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF ), and IL-2 receptor alpha chain gene. Jurkat, HuT78, and U937 cells were cotransfected with plasmids containing a chloramphenicol acetyltransferase (CAT ) reporter gene under viral or cellular promoter control and the Tax expression vector, in addition to vectors for a wild-type or mutant p53. Wild-type p53 is a potent repressor of viral and cellular activation by Tax. Mutations within p53 severely inhibit this downregulation. We also show that wild-type p53 suppresses transcription from the HTLV-I LTR in Jurkat-Tax, a T-cell line stably expressing Tax, and MT-2, a HTLV-I-transformed T-cell line. Wild-type, but not mutant, p53 interfered with the binding of TATA-binding protein (TBP) to the TATA motif of the HTLV-I LTR. These results suggest that p53 inactivation may lead to upregulation of viral and cellular genes and may also be important for establishment of productive viral infection and development of ATL.
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PMID:Repression of transcription from the human T-cell leukemia virus type I long terminal repeat and cellular gene promoters by wild-type p53. 938 10

We report a 50 years old woman admitted to the hospital due to progressive dysphagia and disarthria of there weeks duration. On admission a right hemiparesis was noted. CSF examination showed a protein of 9 mg/dl and no cells. A brain CAT scan showed rounded bilateral subcortical frontoparietal hypodense zones peripheral contrast material enhancement. Pseudobulbar palsies and hemiparesis worsened and the patient required nasoenteral feeding. She was discharged after four months, with severe disabilities, with the diagnosis of Balo concentric, a progressive demyelinating disease.
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PMID:[Balo concentric sclerosis. Report of one case]. 956 98

Neutrophils constitutively undergo apoptosis at both normal and inflamed sites: an important process that limits the toxic potential of the neutrophil. However, the signal pathway for neutrophil apoptosis is currently unknown. In this study, we evaluated the role of p38-mitogen-activated protein kinase (MAPK) in the spontaneous apoptosis of neutrophils in vitro. We found that p38-MAPK was constitutively tyrosine phosphorylated and activated during spontaneous apoptosis of neutrophils. Inhibition of p38-MAPK by SB203580 and an antisense oligonucleotide delayed apoptosis by approximately 24 h. The antioxidants catalase and N-acetylcysteine delayed neutrophil apoptosis, but failed to inhibit phosphorylation and activation of p38-MAPK. Granulocyte-macrophage CSF and anti-Fas Ab, which altered the rate of apoptosis, did not affect phosphorylation and activation of p38-MAPK. These results suggest that the constitutive phosphorylation and activation of p38-MAPK are involved in the program of spontaneous apoptosis in neutrophils.
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PMID:Role of p38-mitogen-activated protein kinase in spontaneous apoptosis of human neutrophils. 997 31

The present study is an analysis of 747 patients with hydrocephalus, treated and followed up in the Hydrocephalus Clinic run by the department of Paediatric Surgery at the All India Institute of Medical Sciences, New Delhi. The distribution of patients was: congenital-46%, post-meningomyelocoele excision-28%, post-meningitic-21% and others-5% (including post haemorrhagic and post encephalocoele excision hydrocephalus. The average age was 7 months in the shunted group and 10 months in the medical group with overall male to female ratio of 2.3:1. The data were analysed to study the effect of treatment on ventriculomegaly and mental development with special reference to the type of treatment (shunt versus medical) and age at starting treatment. The probability of shunt failure was also studied. A comparison of ventricular size in US/CAT scans between the time of starting treatment and last follow-up revealed improvement in ventriculomegaly in 60% of the shunted patients but only 30% of the medically treated patients. A significant difference was particularly noted in patients with severe hydrocephalus, 72% and 22%, respectively. Comparison of the mean Mental Performance Quotient (MPQ) scores in the shunted & medically treated patients also revealed significantly better MPQ scores in the shunted group (p = < 0.001). Probability of shunt survival, as depicted by the Kaplan-Meier survival curve, revealed that there is a high rate of shunt failure in the first 12 months, followed by a dramatic slowing down. Our observations support the contention that CSF shunt surgery offers better outcome than medical management even when ventriculomegaly is severe at the time of presentation.
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PMID:Management of hydrocephalus. 1112 81

We have found previously that astrocytes can provide cysteine to neurons. However, cysteine has been reported to be neurotoxic although it plays a pivotal role in regulating intracellular levels of glutathione, the major cellular antioxidant. Here, we show that cysteine toxicity is a result of hydroxyl radicals generated during cysteine autoxidation. Transition metal ions are candidates to catalyze this process. Copper substantially accelerates the autoxidation rate of cysteine even at submicromolar levels, whereas iron and other transition metal ions, including manganese, chromium, and zinc, are less efficient. The autoxidation rate of cysteine in rat CSF is equal to that observed in the presence of approximately 0.2 microm copper. In tissue culture tests, we found that cysteine toxicity depends highly on its autoxidation rate and on the total amount of cysteine being oxidized, suggesting that the toxicity can be attributed to the free radicals produced from cysteine autoxidation, but not to cysteine itself. We have also explored the in vivo mechanisms that protect against cysteine toxicity. Catalase and pyruvate were each found to inhibit the production of hydroxyl radicals generated by cysteine autoxidation. In tissue culture, they both protected primary neurons against cysteine toxicity catalyzed by copper. This protection is attributed to their ability to react with hydrogen peroxide, preventing the formation of hydroxyl radicals. Pyruvate, but not catalase or glutathione peroxidase, was detected in astrocyte-conditioned medium and CSF. Our data therefore suggest that astrocytes can prevent cysteine toxicity by releasing pyruvate.
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PMID:Pyruvate released by astrocytes protects neurons from copper-catalyzed cysteine neurotoxicity. 1133 61

Macrophages have various functions and play a critical role in host defense and the maintenance of homeostasis. However, macrophages are heterogeneous and exhibit a wide range of phenotypes with regard to their morphology, cell surface antigen expression, and function. When blood monocytes are cultured in medium alone in vitro, monocytes die, and colony-stimulating factors (CSFs) such as macrophage (M)-CSF or granulocyte-macrophage (GM)-CSF are necessary for their survival and differentiation into macrophages. However, M-CSF-induced monocyte-derived macrophages (M-Mphi) and GM-CSF-induced monocyte-derived macrophages (GM-Mphi) are distinct in their morphology, cell surface antigen expression, and functions, including Fcgamma receptor mediated-phagocytosis, H2O2 production, H2O2 sensitivity, catalase activity, susceptibility to human immunodeficiency virus type 1 and Mycobacterium tuberculosis, and suppressor activity. The characteristics of GM-Mphi resemble those of human alveolar macrophages.
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PMID:Functional heterogeneity of colony-stimulating factor-induced human monocyte-derived macrophages. 1213 92

Airway epithelial cells synthesize proinflammatory molecules such as IL-8, GM-CSF, RANTES, and ICAM-1, the expression of which is increased in the airways of patients with asthma. We investigated the regulation of these NF-kappa B-dependent genes by the novel protein kinase C (PKC) isoform PKC delta in 16HBE14o- human airway epithelial cells, focusing on IL-8 expression. Transient transfection with the constitutively active catalytic subunit of PKC delta (PKC delta-CAT), and treatment with bryostatin 1, an activator of PKC delta, each increased transcription from the IL-8 promoter, whereas overexpression of PKC epsilon had minor effects. Expression of a dominant negative PKC delta mutant (PKC delta-KR) or pretreatment of cells with rottlerin, a chemical PKC delta inhibitor, attenuated TNF-alpha- and phorbol ester-induced transcription from the IL-8 promoter. Bryostatin 1 treatment increased IL-8 protein abundance in primary airway epithelial cells. Selective activation of PKC delta by bryostatin also activated NF-kappa B, as evidenced by p65 RelA and p50 NF-kappa B1 binding to DNA, NF-kappa B trans-activation, and I kappa B degradation. The sufficiency of PKC delta to induce NF-kappa B nuclear translocation and binding to DNA was confirmed in a 16HBE14o- cell line inducibly expressing PKC delta-CAT under the tet-off system. Deletion of the NF-kappa B response element severely attenuated PKC delta-induced IL-8 promoter activity. Finally, PKC delta-CAT induced transcription from the GM-CSF, RANTES, and ICAM-1 promoters. Together these data suggest that PKC delta plays a key role in the regulation of airway epithelial cell NF-kappa B-dependent gene expression.
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PMID:Regulation of airway epithelial cell NF-kappa B-dependent gene expression by protein kinase C delta. 1275 50

SPAN-Xb is a novel cancer-testis antigen in multiple myeloma (MM). In this study, we determined the mechanisms regulating SPAN-Xb expression in MM. SPAN-Xb promoter sequence was first cloned into the CAT-reporter vector to determine the role of promoter methylation in the regulation of gene expression. Tumor cells were treated with 5-azacytidine and a panel of cytokines were used to determine their ability to induce SPAN-Xb expression. Bisulfite conversion with sequence analysis was applied to a panel of tumor cells and normal tissues to correlate the CpG dinucleotide hypomethylation and SPAN-Xb expression. We found that SPAN-Xb promoter function could be silenced by methylation. 5-Azacytidine induced promoter hypomethylation and resulted in SPAN-Xb expression, at both the transcript and protein levels. Hypomethylation of the CpG dinucleotides at positions -310, -307, -299 and -221 within the SPAN-Xb promoter strongly predict for SPAN-Xb expression. Both IL-7 and GM-CSF were also able to upregulate the expression of SPAN-Xb in myeloma cells, but only after the promoter sequence has been hypomethylated. Our results provide the first evidence showing the role of promoter methylation in the primary regulation of SPAN-Xb and the ability of IL-7 and GM-CSF to further enhance SPAN-Xb gene and protein expression in myeloma cells.
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PMID:SPAN-Xb expression in myeloma cells is dependent on promoter hypomethylation and can be upregulated pharmacologically. 1618 75

M-colony-stimulating factor (M-CSF)-induced monocyte-derived macrophages (M-Mphi) required continuous presence of M-CSF for their survival, and depletion of M-CSF from the culture induced apoptosis, whereas human alveolar macrophages (A-Mphi) and granulocyte-macrophage (GM)-CSF-induced monocyte-derived macrophages (GM-Mphi) survived even in the absence of CSF. The expression of BCL-2 was higher in M-Mphi, and M-CSF withdrawal down-regulated the expression. The expression of BCL-X(L) was higher in A-Mphi and GM-Mphi, and the expression was CSF-independent. The expression of MCL-1 and BAX were not different between M-Mphi and GM-Mphi and were CSF-independent. Down-regulation of the expression of BCL-2 and BCL-X(L) by RNA interference showed the important role of BCL-2 and BCL-X(L) in the survival of M-Mphi and GM-Mphi, respectively. Human erythrocyte catalase (HEC) and conditioned medium obtained from GM-Mphi or A-Mphi cultured in the absence of GM-CSF prevented the M-Mphi from apoptosis and restored the expression of BCL-2. The activity of the conditioned medium was abrogated by pretreatment with anti-HEC antibody. Anti-HEC antibody also induced the apoptosis of M-Mphi cultured in the presence of M-CSF and GM-Mphi and A-Mphi cultured in the presence or absence of GM-CSF and down-regulated the expression of BCL-2 and BCL-X(L) in these Mphis. GM-Mphi and A-Mphi, but not M-Mphi, can produce both extracellular catalase and cell-associated catalase in a CSF-independent manner. Intracellular glutathione levels were kept equivalent in these Mphis, both in the presence or absence of CSF. These results indicate a critical role of extracellular catalase in the survival of human macrophages via regulation of the expression of BCL-2 family genes.
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PMID:Catalase plays a critical role in the CSF-independent survival of human macrophages via regulation of the expression of BCL-2 family. 1620 28


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