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:3.2.1.23 (beta-galactosidase)
14,648 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To optimize polynucleotide vaccinations for protective antitumor immunity we used a self-replicating RNA vaccine in which Semliki Forest virus replicase drives RNA expression of the lacZ gene coding for beta-galactosidase as model tumor-associated antigen (TAA). This was compared with replicase-deficient control RNA and with lacZ DNA plasmids with respect to gene expression in vitro and in vivo and for vaccination using the mouse ear pinna as an optimal immunization site. In vitro, the highest expression was observed with self-replicating RNA. Gene expression following pinna inoculation of either non-replicating DNA plasmids or self-replicating RNA was similar, lasting for 2-3 weeks. Higher antibody responses were obtained with RNA than with DNA. beta-Gal peptide specific CTL memory responses to lacZ DNA or RNA lasted for more than 6 weeks while respective responses induced by lacZ-transfected tumor cells lasted for only 2 weeks. To achieve a protective response against lacZ tumor cells with self-replicating RNA about a 100-fold lower dose of polynucleotide was sufficient in comparison to DNA. The extent of protective antitumor immunity not only depended on the gene dose used for vaccination, but also on the aggressiveness of the lacZ-transfected tumor line used for challenge. In comparison to lacZ-transfected tumor cells as vaccines, polynucleotide vaccination also demonstrated superiority with regard to cross-protection. Protective antitumor immunity could be strongly increased upon co-inoculation of lacZ DNA with IL-2 DNA or IL-12 RNA. IL-2 DNA, but not IL-12 RNA, also augmented the CTL response while IL-12 RNA, but not IL-2 DNA, reduced the antibody response. These results demonstrate efficient protective antitumor immunity after intra-pinna lacZ TAA polynucleotide vaccination and show additional immunomodulatory effects by co-administration of cytokine polynucleotides.
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PMID:Intra-pinna anti-tumor vaccination with self-replicating infectious RNA or with DNA encoding a model tumor antigen and a cytokine. 1091 81

The rheumatoid arthritis (RA) joint is characterized by an inflammatory synovial pannus which mediates tissue destruction. IL-13 is a cytokine that inhibits activated monocytes/macrophages from secreting a variety of proinflammatory molecules. The aim of this study was to examine whether gene therapy-delivered IL-13 could reduce the production of key proinflammatory mediators in RA synovial tissue (ST) explants. Adenoviral vectors encoding the genes for human IL-13 (AxCAIL-13) and bacterial beta-galactosidase were generated and examined for protein production. Vectors were used to infect RA ST explants and RA synovial fibroblasts, and conditioned medium (CM) was collected at various times for analysis by ELISA and competitive immunoassay. AxCAIL-13 decreased the production of RA ST explant proinflammatory IL-1beta by 85% after 24 h. Likewise, TNF-alpha levels were decreased by 82 and 75% whereas IL-8 levels were reduced 54 and 82% after 24 and 48 h, respectively, in RA ST explant CM. Monocyte chemotactic protein-1 concentrations were decreased by 88% after 72 h in RA ST explant CM. RA ST explant epithelial neutrophil-activating peptide-78 concentrations were decreased 85 and 94% whereas growth-related gene product-alpha levels were decreased by 77 and 85% at 24 and 48 h, respectively, by AxCAIL-13. Further, IL-13 significantly decreased PGE2 and macrophage inflammatory protein-1alpha production. These results demonstrate that increased expression of IL-13 via gene therapy may decrease RA-associated inflammation by reducing secretion of proinflammatory cytokines and PGE2.
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PMID:Reduction of inflammatory cytokines and prostaglandin E2 by IL-13 gene therapy in rheumatoid arthritis synovium. 1094 7

Treatment of hepatitis B virus carriers with the nucleoside analog lamivudine suppresses virus replication. However, rather than completely eliminating the virus, long-term treatment often ends in the outgrowth of drug-resistant variants. Using woodchucks chronically infected with woodchuck hepatitis virus (WHV), we investigated the consequences of combining lamivudine treatment with immunotherapy mediated by an adenovirus superinfection. Eight infected woodchucks were treated with lamivudine and four were infected with approximately 10(13) particles of an adenovirus type 5 vector expressing beta-galactosidase. Serum samples and liver biopsies collected following the combination therapy revealed a 10- to 20-fold reduction in DNA replication intermediates in three of four woodchucks at 2 weeks after adenovirus infection. At the same time, covalently closed circular DNA (cccDNA) and viral mRNA levels both declined about two- to threefold in those woodchucks, while mRNA levels for gamma interferon and tumor necrosis factor alpha as well as for the T-cell markers CD4 and CD8 were elevated about twofold. Recovery from adenovirus infection was marked by elevation of sorbitol dehydrogenase, a marker for hepatocyte necrosis, as well as an 8- to 10-fold increase in expression of proliferating cell nuclear antigen, a marker for DNA synthesis, indicating significant hepatocyte turnover. The fact that replicative DNA levels declined more than cccDNA and mRNA levels following adenovirus infection suggests that the former decline either was cytokine induced or reflects instability of replicative DNA in regenerating hepatocytes. Virus titers in all four woodchucks were only transiently suppressed, suggesting that the effect of combination therapy is transient and, at least under the conditions used, does not cure chronic WHV infections.
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PMID:Combination therapy with lamivudine and adenovirus causes transient suppression of chronic woodchuck hepatitis virus infections. 1109 Jan 75

Xenotransplantation of hepatocytes appears to be a novel promising therapy for some forms of liver disease, and may well overcome the problem of donor shortage. We have previously reported that hepatocytes with a spheroidal shape (spheroids) are ideal for cell transplantation. The application of gene transfer techniques to this hepatocyte transplantation could possibly regulate the xenogeneic rejection reaction and, therefore, result in prolongation of the survival of the transplanted hepatocytes. In this study, we chose the adenovirus as a vector and an immunosuppressive cytokine named viral IL-10 (vIL-10) for transfection. A series of experiments was performed to elucidate the efficacy of transfection to the spheroids with adenovirus vectors and the effect of transfected vIL-10 on the survival of xenogeneic hepatocytes. We examined the cell survival quantitatively by evaluating beta-galactosidase (beta-gal) activity, which was transfected into the hepatocytes in the xenogeneic spleen, and semiquantitatively by the histological findings. The results of in-vitro studies identified an efficient expression of the beta-gal gene within the spheroids infected with Ad-CMVLacZ (LacZ-encoding adenovirus vector with CMV promotor) and the presence of BCRF1 mRNA within the spheroids transfected with AdCMVvIL-10 (vIL-10-expressing adenovirus vector with CMV promotor) under the condition of 1 MOI, for 1 h. Xenogeneic hepatocytes with a spheroidal shape showed comparable survival to syngeneic hepatocytes for up to 4 days after transplantation with co-transplantation of the vIL-10-transfected hepatocytes. From this study, we concluded that adenovirus-mediated vIL-10 gene transfer prolongs the survival of xenogeneic hepatocyte spheroids. Furthermore, spheroids possess ideal properties for gene transfection, as well as cell transplantation.
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PMID:Adenovirus-mediated viral IL-10 gene transfer prolongs survival of xenogeneic spheroidal aggregate-cultured hepatocytes. 1111 60

In this study, we have evaluated the role of cytokine-induced neutrophil chemoattractant (CINC), in the upregulation of neutrophil Ca(2+) signaling in neutrophils from thermally injured rats treated with anti-CINC antibody. Additionally, we have determined the effect of the treatment with CINC antibody on the accumulation of activated neutrophils in the intestinal wall, and the effect of such accumulation on gut bacterial translocation. Measurements of myeloperoxidase (MPO) activity and immunohistochemical localization of neutrophils determined neutrophil sequestration in the rat intestine. Agar culture analyses and a specific Escherichia coli beta-galactosidase gene polymerase chain reaction was carried out to detect gut indigenous bacterial invasion into intestinal wall and extraintestinal mesenteric lymph nodes (MLN). The results showed that pretreatment of rats with anti-CINC antibody attenuated the thermal injury-induced enhancement in [Ca(2+)](i) responses in neutrophils both in the basal and Formyl-Met-Leu-Phe stimulated conditions. Moreover, treatment with the CINC antibody decreased neutrophil infiltration into the gut and attenuated thermal injury-caused translocation of bacteria into the MLN.
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PMID:CINC blockade prevents neutrophil Ca(2+) signaling upregulation and gut bacterial translocation in thermal injury. 1111 31

Previous work has implicated the cytokine leukemia inhibitory factor (LIF) in cutaneous inflammation, although results have differed as to whether LIF is pro- or anti-inflammatory in this setting. We examined edema, inflammatory cell infiltration, and cytokine responses following CFA injection in the adult mouse footpad. Inflammatory cell infiltration and edema are significantly enhanced when CFA is injected in LIF knockout mice as compared with injection of wild-type littermates. Moreover, local injection of an adenoviral vector encoding LIF suppresses both measures of inflammation. In contrast, injection of an adenoviral vector encoding beta-galactosidase has no discernable effect on inflammation. In addition, comparison of the CFA responses in LIF knockout vs wild-type skin reveals that LIF is an important regulator of IL-1beta, IL-6, IL-7, IL-2Ralpha, and IFN-gamma in cutaneous inflammation. These and our previous data indicate that both endogenous and exogenous LIF are anti-inflammatory in the CFA model and that LIF is a key regulator of the cytokine cascade. The results also indicate that adenoviral gene delivery can be an effective therapeutic approach in this paradigm.
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PMID:Studies using leukemia inhibitory factor (LIF) knockout mice and a LIF adenoviral vector demonstrate a key anti-inflammatory role for this cytokine in cutaneous inflammation. 1116 Feb 55

Interleukin-1beta is a potent pro-inflammatory cytokine that has been shown to inhibit islet beta cell function as well as to activate Fas-mediated apoptosis in a nitric oxide-dependent manner. Furthermore, this cytokine is effective in recruiting lymphocytes that mediate beta cell destruction in IDDM onset. The insulin-like growth factor I (IGF-I) has been shown to block IL-1beta actions in vitro. We hypothesized that gene transfer of the insulin-like growth factor I to intact human islets could prevent IL-1beta-induced beta cell dysfunction and sensitization to Fas-triggered apoptosis activation. Intact human islets were infected with adenoviral vectors encoding IGF-I as well as beta-galactosidase and enhanced green fluorescent protein as controls. Adenoviral gene transfer of human IGF-I prevented IL-1beta-mediated nitric oxide production from human islets in vitro as well as the suppression of beta cell function as determined by glucose-stimulated insulin production. Moreover, IGF-I gene transfer prevented IL-1beta-induced, Fas-mediated apoptosis. These results suggest that locally produced IGF-I from cultured islets may be beneficial in maintaining beta cell function and promoting islet survival before and following islet transplantation as a potential therapy for type I diabetes.
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PMID:Prevention of beta cell dysfunction and apoptosis activation in human islets by adenoviral gene transfer of the insulin-like growth factor I. 1117 13

Adenovirus-mediated gene delivery of anticytokines is a powerful tool for modulating the cytokine environment under conditions of respiratory disease. In order to determine the feasibility of cytokine modulation in the context of respiratory disease in swine, nonreplicating E1- and E3-deficient adenovirus constructs expressing a model protein, beta-galactosidase, and an anticytokine, the IL-1 receptor antagonist (IL-1Ra), were evaluated for in vitro expression in porcine PK15 cells, and in vivo following endotracheal instillation into the lungs. beta-Galactosidase and IL-1Ra were readily expressed in vitro in swine cells. Endotracheal administration of lacZ-containing adenovirus demonstrated that endothelial and epithelial cells in the alveolar spaces and bronchi of the middle and lower lobes were the principal sites of infection and expression, whereas beta-galactosidase staining was not observed in the upper lobe. Endotracheal administration of IL-1Ra recombinant adenovirus resulted in sustained expression of IL-1Ra into the alveolar spaces, where it was recovered in a concentration of 660 pg/ml in 500 ml of lavage fluid, equivalent to 330 ng IL-1Ra, in the lungs 7 days after treatment. Moreover, in vivo instillation of nonreplicating adenovirus did not induce an inflammatory response in the 1-week time frame of the study period. Lung weight as a percent of body weight, serum zinc, serum amyloid A, leukocyte differentials, neutrophil activity, and TNF levels all were the same between untreated pigs and pigs treated with either recombinant adenovirus. The results indicate that the delivery of IL-1Ra to swine lungs via nonreplicating, recombinant adenovirus may be an effective method for in vivo modulation of IL-1 activity and investigation of cytokine involvement in respiratory disease pathogenesis.
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PMID:Adenovirus-mediated expression of interleukin-1 receptor antagonist in swine cells in vitro and in vivo. 1118 49

Vasoactive intestinal peptide (VIP) is a 28-amino acid peptide that has several functions, including the regulation of water and electrolyte secretion, hormone and cytokine release, bronchodilitation, and neurogenesis. VIP effects are mediated by specific G-protein coupled receptors. Three distinct receptor subtypes, with differing affinity for VIP, have been cloned and characterized as receptors 1 and 2 (VPAC1 and VPAC2) and pituitary adenylate cyclase activating polypeptide receptor (PAC1). Our laboratory has demonstrated that upregulation of VPAC1 in SK-N-SH neuroblastoma cells results in marked shift in cell type to the glial lineage with a corresponding loss of neuronal lineage and suppression of xenograft tumor growth. To understand the molecular mechanisms responsible for regulation of the VPAC1 gene in neuronal lineage, we have cloned and sequenced 2.6-kb of the 5'-flanking sequences of the human VPAC1 gene. Sequence analysis demonstrated that the human VPAC1 promoter sequence contains putative binding sites for several known transcription factors, including Sp1, NFkB, and cETS-1. To study the temporal and spatial expression pattern of human VPAC1 promoter sequences, we have generated transgenic mice expressing the bacterial beta-galactosidase gene under the control of the 2.6-kb 5'-flanking and promoter sequence of the human VPAC1 gene. Transgene expression was detected in brain, spinal cord, and lung in 14-day-old animals. Taken together, these results demonstrate that VPAC1 may play an important role in the nervous system, and suggest a role for VIP in neuronal differentiation.
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PMID:Regulation of vasoactive intestinal peptide receptor expression in developing nervous systems. 1119 20

The objective of this study was to determine whether transfection of human islets with an adenovirus construct encoding an inhibitor of tumor necrosis factor (TNFi) was effective at limiting damage to beta cells induced by human peripheral blood leukocytes (huPBL). Human islets transfected with TNFi or control islets were transplanted under the kidney capsule of NOD-scid mice. After a 15-day engraftment period, half of the mice received injections of activated huPBL and half received buffer injections. Islet graft function was assessed by two different methods, both of which use a species-specific radioimmunoassay to determine human insulin. In some mice, insulin production following intraperitoneal glucose injection was determined in serum. In other mice, total graft insulin content was determined by acid ethanol extraction. Histochemical stains were performed on some kidneys at the termination of the experiment to evaluate graft presence, transgene expression, and huPBL infiltration. In huPBL injected mice, graft performance was maintained in mice whose grafts were transfected with TNFi but declined substantially in control groups with sham transfected or beta-galactosidase transfected islet grafts. Similar results were obtained using either glucose-stimulated insulin release or graft insulin content as a measure of graft survival. There was no significant difference in graft function between control groups receiving buffer injections, regardless of whether the islets had been transfected. Human leukocytes were found in all huPBL groups regardless of islet transfection status. We conclude that transfection of human islets with an adenovirus encoding TNFi protects beta cells from destruction induced by human leukocytes. The local production of TNFi does not prevent graft infiltration by leukocytes, only the destruction of grafts by the infiltrating leukocytes. These results raise the possibility that local expression of an inhibitor of the proinflammatory cytokine TNF-alpha may also prevent graft failure in clinical islet transplantation.
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PMID:Human pancreatic islets transfected to produce an inhibitor of TNF are protected against destruction by human leukocytes. 1120 71


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