Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.2.1.23 (beta-galactosidase)
 14,648 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rats received bilateral lesions of the nucleus basalis magnocellularis by infusion of biotenic acid. Two weeks after the lesion, a suspension of genetically modified primary rat fibroblasts was grafted dorsal to the nucleus basalis magnocellularis (2 x 10(5) cells per side). The fibroblasts were either infected with the gene for human beta-nerve growth factor or Escherichia coli beta-galactosidase. The nerve growth factor-producing fibroblasts released 67 ng nerve growth factor/10(5) cells per day in vitro. Two weeks after implantation of the fibroblasts, spatial learning was tested in the Morris water-maze. Nerve growth factor-producing fibroblasts, but not beta-galactosidase-producing fibroblasts ameliorated the deficit in acquisition of the water-maze task. In addition, spatial acuity was improved to near-normal levels by the nerve growth factor-producing grafts. Choline acetyltransferase activity in cortical areas and hippocampus was not affected by the nerve growth factor-producing grafts. Both grafted groups showed a similar reduction in the level of dopamine, but not homovanillic acid or 3-methoxytyramine, in the frontal cortex. Levels of norepinephrine, epinephrine and serotonin and their metabolites in the neocortex and hippocampus were not affected by the lesion or the grafts. Nerve growth factor-producing grafts increased the size of remaining nerve growth factor-receptor (p75) immunoreactive neurons in the nucleus basalis magnocellularis by 25%. Nucleus basalis magnocellularis lesions reduced the integrated optic density of choline acetyltransferase-positive fiber staining in the ventral neocortex by 46%, but nerve growth factor-producing grafts restored this area to 86% of control. These data suggest that nerve growth factor-producing grafts can cause a marked behavioral improvement, probably through the partial restoration of the lesioned projection from nucleus basalis magnocellularis to neocortex.
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PMID:Grafting of nerve growth factor-producing fibroblasts reduces behavioral deficits in rats with lesions of the nucleus basalis magnocellularis. 807 85

The functional role of human tumor necrosis factor receptor (TNFR) p75 was studied by the use of TNFR p75-specific agonistic antibodies. Human SW480T adenocarcinoma cells, stably transfected with a reporter construct containing beta-galactosidase under the control of human cytomegalovirus immediate early enhancer, were stimulated with anti-TNFR p75 polyclonal antiserum or monoclonal antibodies followed by measurement of beta-galactosidase activity and analysis by electrophoretic mobility shift assays. It was found that cross-linking of TNFR p75 led to strong induction of the human cytomegalovirus enhancer as well as activation of nuclear factor-kappa B (NF-kappa B). Stimulation of TNFR p75 also mediated activation of NF-kappa B in human KYM-1 rhabdomyosarcoma cells but not in other cell types such as U937 and HL-60 monocytic cells or in Eahy 926 endothelial cells. NF-kappa B activation induced by TNFR p75 was delayed approximately 15 min compared with NF-kappa B activation induced by TNFR p55, indicating that the two TNFRs activate NF-kappa B through different signaling pathways. The data presented in this study identify intracellular responses mediated by TNFR p75 which have not been reported previously and suggest that TNFR p75-induced activation of NF-kappa B is strictly cell type-specific.
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PMID:Tumor necrosis factor receptor p75 mediates cell-specific activation of nuclear factor kappa B and induction of human cytomegalovirus enhancer. 812 5

We have been developing both local and systemic gene therapy approaches to treat inflammatory and autoimmune diseases. To determine if systemic, constitutive expression of biologically active anti-inflammatory agents is therapeutic and/or has associated toxicity, mouse hematopoietic stem cells were infected with retroviral vectors carrying the genes for human IL-1 receptor antagonist (IL-1Ra), human soluble TNF receptor p75 (sTNFR), or the beta-galactosidase (lacZ) gene, and transplanted into lethally irradiated recipients. The serum levels of human IL-1Ra and human sTNFR in the long-term reconstituted mice, 2-7 months after transplantation, were 596 and 158 ng/ml respectively. The long-term expression of human IL-1Ra had minimal effects on the PBMC profile whereas human sTNFR expression increased the percentage of B220 and Mac.1 stained cells and decreased slightly the specific T cell subsets. The ability of these proteins to protect the transplanted mice from endotoxin treatment was determined by measuring serum interleukin-6 (IL-6) and interleukin-10 (IL-10) responses after LPS injection at 1.5, 3, 4.5 and 24 h after treatment. The IL-1Ra group showed diminished IL-10 levels and less mortality after injection of LPS. These results demonstrate that constitutive, systemic expression of IL-1Ra and sTNFR is able to confer partial protective effects following treatment with endotoxin. These results further demonstrate that gene transfer methods which result in systemic, long-term expression of immunodulatory proteins could be applied to the treatment of inflammatory diseases.
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PMID:Constitutive systemic expression of IL-1Ra or soluble TNF receptor by genetically modified hematopoietic cells suppresses LPS induction of IL-6 and IL-10. 913 39

Recombinant adenovirus-mediated gene therapy has demonstrated great promise for the delivery of genes to the pulmonary epithelium. However, dose-dependent inflammation and local immune responses abbreviate transgene expression. The purpose of these studies was to determine the role of TNF-alpha and individual TNF receptor signaling to adenovirus clearance and immune responses, and whether coexpression of human IL-10 could reduce inflammation and extend the duration of transgene expression in the lung. beta-Galactosidase expression in mice receiving intratracheal instillation of Adv/beta-gal (adenovirus construct expressing beta-galactosidase) was transient (less than 14 days), but a significant early increase of beta-galactosidase expression was seen in mice lacking either or both TNF-alpha receptors. Absence of TNF-alpha or the p55 receptor significantly attenuated the Ab response to both adenovirus and beta-galactosidase. Human IL-10 expression in the lung suppressed local TNF-alpha production following AdV/hIL-10 (adenovirus construct expressing human IL-10) delivery, but did not lead to increased or prolonged transgene expression when coexpressed with beta-galactosidase. Expression of human IL-10 following AdV/hIL-10 instillation extended at least 14 days, was nonimmunogenic, and suppressed the development of neutralizing Abs against adenoviral proteins as well as against human IL-10. We conclude that TNF-alpha signaling through both the p55 and p75 receptor plays important roles in the clearance of adenoviral vectors and the magnitude of the humoral immune response. Additionally, although coexpression of human IL-10 with beta-galactosidase had only modest effects on transgene expression, we demonstrate that AdV/hIL-10 is well tolerated, has extended expression compared with beta-galactosidase, and is nonimmunogenic in the lung.
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PMID:TNF-alpha receptor signaling and IL-10 gene therapy regulate the innate and humoral immune responses to recombinant adenovirus in the lung. 1060 41

In mice that express lacZ under the control of a human dopamine beta-hydroxylase gene promoter (DbetaH-nlacZ mice), the nuclei of enteric neurons express the transgene, as shown by the presence of beta-galactosidase (beta-gal) staining (Mercer et al. [1991] Neuron 7:703-716). The transgene is also expressed by neural crest-derived cells in the developing gut before their differentiation into neurons or glial cells (Kapur et al. [1992] Development 116:167-175). However, the cell types expressing the DbetaH-nlacZ transgene within the developing and adult gut have not been fully characterized. Whole-mount preparations of embryonic and adult gut were processed for histochemistry or immunohistochemistry to reveal beta-gal plus markers of undifferentiated neural crest cells (in embryos) or enteric neurons (in adults). In embryonic mice, over 90% of undifferentiated neural crest-derived cells (identified using antibodies to p75) were beta-gal(+). Importantly, crest-derived cells at the migratory wavefront were all beta-gal(+). In adult mice, only a subpopulation of enteric neurons was beta-gal(+), while glial cells showed no beta-gal staining. Considerable variation was observed between the small intestine and colon in the proportion of myenteric neurons that showed beta-gal staining. We examined whether known classes of enteric neurons varied in their expression of DbetaH-nlacZ. In the myenteric plexus of the jejunum and colon, large calretinin(+) neurons did not express lacZ, suggesting that the incomplete penetrance of the DbetaH-nlacZ transgene observed in adult mice is not random. We conclude that the DbetaH-nlacZ transgene provides a reliable marker for examining the colonization of the developing gut by neural crest cells. However, in adult mice, there is variation between mice, between gut regions, and between different classes of enteric neurons in the expression of the transgene.
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PMID:Characterization of lacZ-expressing cells in the gut of embryonic and adult DbetaH-nlacZ mice. 1289 13

Human lens epithelium-derived growth factor (LEDGF)/p75 protein forms a specific nuclear complex with human immunodeficiency virus type 1 (HIV-1) integrase and is essential for nuclear localization and chromosomal association of the viral protein. We now studied nuclear import of LEDGF/p75 in live and semipermeabilized cells. We show that nuclear import of LEDGF/p75 is GTP-, Ran-, importin-alpha/beta-, and energy-dependent and that the protein competes with the canonical SV40 large T antigen nuclear localization signal (NLS) for nuclear import receptors. We identified the NLS of LEDGF/p75 through deletion analysis and site-directed mutagenesis. The LEDGF/p75 NLS, 148GRKRKAEKQ156, belongs to the canonical SV40-like family. Fusion of this short peptide to the amino terminus of Escherichia coli beta-galactosidase rendered the fusion protein nuclear, confirming that the LEDGF/p75 NLS is transferable. Moreover, a single amino acid change in the NLS was sufficient to exclude the mutant LEDGF/p75 protein from the nucleus and abolish nuclear import of HIV-1 integrase.
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PMID:Identification and characterization of a functional nuclear localization signal in the HIV-1 integrase interactor LEDGF/p75. 1516 64