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)

We collected diesel exhaust particles (DEPs) emitted from three diesel-engine vehicles--a car, a bus, and a truck--in daily use, and prepared DEP extracts (DEPEs), designated as EC, EB, or ET, respectively. The androgenic and antiandrogenic effects of the DEPE samples were examined by a luciferase reporter assay in human prostate carcinoma PC3/AR cells transiently transfected with a prostate specific antigen gene promoter-driven luciferase expression vector pGLPSA5.8. PC3/AR is a subline of human prostate carcinoma PC3 transformed to stably express wild-type human androgen receptor (AR). While DEPE samples did not exhibit any androgenic effect, they exerted antiandrogenic effect, inhibiting dihydrotestosterone (10 pM) -induced luciferase activity by 24 to 52% at an extract concentration of 10 microg/ml. The antiandrogenic effect was greater in the following order: ET > EB > EC. Co-treatment of PC3/AR cells with SKF-525A, a nonselective inhibitor of cytochrome P450 (CYP) enzymes, enhanced the antiandrogenic effect, indicating that the antiandrogenic effect is caused by intact species of DEPE constituents. The antiandrogenic effect of DEPE samples was reversed by alpha-naphthoflavone, an aryl hydrocarbon receptor (AhR) antagonist. The antiandrogenic activity of a DEPE sample correlated with its AhR agonist activity assayed in PC3/AR cells transiently transfected with CYP1A1 gene promoter-driven luciferase expression vector pLUC1A1. Equimolar mixtures of ten polycyclic aromatic hydrocarbons (PAHs) having four or more rings, structures found in the DEPEs, showed significant antiandrogenic effects and AhR agonist activity at concentrations equivalent to those found in DEPE samples. Further, DEPE samples elicited only antiandrogenic effects in recombinant yeast cells, which express beta-galactosidase in response to androgen. A competitive AR binding assay showed that AR-binding constituents exist in DEPE samples, indicating that greater part of AR-binding constituents in DEPEs are AR antagonists. All these findings show that DEPE samples exhibit significant antiandrogenic effect in cell-based transcription assay and that this effect is due in part to the constituents with AhR agonist activity including PAHs and to the constituents with AR antagonist activity.
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PMID:Antiandrogenic activities of diesel exhaust particle extracts in PC3/AR human prostate carcinoma cells. 1297 May 80

Our previous report of predominant activation of nuclear transcription factor NF-kappaB in the bladder urothelium of interstitial cystitis (IC) patients suggests a potential role for this nuclear factor in the pathogenesis of the disease. Although NF-kappaB has been implicated in the pathogenesis of several inflammatory diseases, the downstream mechanism(s) by which it can mediate its effects are still fragmentary. In this study, we examined the role of this nuclear factor on the induction of proinflammatory cytokine gene expression in human bladder carcinoma T24 cells and further examined their corresponding protein levels in the urine of IC patients. T24 cells transduced with a dominant-negative super-repressor IkappaB mutant (pAxCAmIkappaB-M) or wild-type adenoviral vectors in the presence or absence of rhTNF-alpha. Transduction efficiency and ability of pAxCAmIkappaB-M to inhibit NF-kappaB activation were monitored by in situ reporter beta-galactosidase and gel mobility shift assays, respectively. Expression profile analysis of proinflammatory cytokines was measured in cells and urine of IC patients using RT-PCR and ELISA, respectively. The activation of NF-kappaB by rhTNF-alpha was associated with 27, eight, ten and sevenfold increases in the TNF-alpha, IL-1beta, IL-6 and IL-8 transcripts, respectively. In contrast, abrogation of the TNF-alpha-induced cytokine gene expression by an adenovirus super-repressor IkappaB mutant vector demonstrate that these effects were NF-kappaB-dependent. Interestingly, the NF-kappaB-induced expression of these transcripts correlates with increased protein levels of NF-kappaB-regulated proinflammatory factors in the urine of IC patients in comparison to controls. That these factors are capable of activating NF-kappaB in urothelial cells suggests a pivotal role for this nuclear transcription factor in the pathophysiology of the disease, possibly by inducing aberrant immune and inflammatory responses within the bladder of IC patients.
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PMID:NF-kappaB-dependent gene expression of proinflammatory cytokines in T24 cells: possible role in interstitial cystitis. 1457 33

p16 is an important regulator of the cell cycle at the G(1) phase. Frequent aberration of p16 in nasopharyngeal carcinoma (NPC) suggests a role for this tumor suppressor gene in disease development. p16 gene transfer has been demonstrated to be effective in various human cancer models, including breast, lung, and prostate, causing cell cycle arrest, apoptosis, and tumor growth delay. We investigated the potential of adenoviral-mediated p16 therapy, in combination with ionizing radiation (RT), in two distinct NPC models. Two deltaE1 adenoviral vectors were employed: one carrying the human p16 gene (adv.p16), and the other a beta-galactosidase reporter gene (adv.beta-gal), both driven by the cytomegalovirus (CMV) promoter. Two NPC cell lines with differential endogenous p16 expression, CNE-1 (low) and CNE-2Z (high), were evaluated for protein expression, cytotoxicity, cell cycle analysis, apoptosis, and senescence. The CNE-1 cells were exquisitely sensitive to adv.p16, with 0.1% survival level after gene therapy [25 plaque-forming unit (pfu)/cell], which further decreased to 0.01% with the addition of RT (2 Gy). This reduction in survival was effected through necrosis, G1 arrest, and senescence. In contrast, CNE-2Z cells were resistant to adv.p16 gene transfer, with 75% surviving at an equivalent viral dose. This differential sensitivity was recapitulated in vivo in that adv.p16-treated CNE-1 cells formed no tumors in severe-combined-immunodeficiency (SCID) mice, followed for over 100 days. In contrast, tumor formation was detected 40 days after implantation of adv.p16-treated CNE-2Z cells. In conclusion, adv.p16 gene transfer appears to be highly effective against NPC that lack functional p16, which is the situation in the majority of NPC patients.
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PMID:p16 gene therapy: a potentially efficacious modality for nasopharyngeal carcinoma. 1457 61

Intratumoral injection is a routine method for local viral gene delivery that may improve interstitial transport of viral vectors in tumor tissues and reduce systemic toxicity. However, the concentration of transgene products in normal organs, such as in the liver, may still exceed normal tissue tolerance if the products are highly toxic. The elevated concentration in normal tissues is likely to be caused by the dissemination of viral vectors from the tumor. Therefore, we investigated transgene expression in the liver, the serum, and a mouse mammary carcinoma (4T1) in mice after intratumoral injection of adenoviral vectors for mouse interleukin-12, luciferase, enhanced green fluorescence protein, or beta-galactosidase. We also performed numerical simulations of virus transport in tumors after intratumoral injection, based on the Krogh cylinder model. Our experimental data and numerical simulations demonstrated that virus dissemination was significant in mice and it occurred mainly during the intratumoral injection. To reduce virus dissemination, we mixed these vectors with a viscous alginate solution and injected the mixture into the tumors. Our data showed that the alginate solution could significantly reduce virus dissemination while having minimal effects on transgene expression in tumors and on interleukin-12-induced tumor growth delay. These data suggest that virus dissemination is a potential problem in local viral gene therapy of cancer and that the dissemination could be significantly reduced by the alginate solution without compromising the efficacy of gene therapy.
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PMID:Systemic dissemination of viral vectors during intratumoral injection. 1461 97

Since transcriptional activation of genes downregulating cell proliferation mediates the tumor suppressor activity of p53, induction of p53 targets was assumed to adequately reflect the state of p53-dependent pathways. To estimate the p53 activity in cultured cells, self-inactivating retrovirus constructs pSIP-ConA-GFP and pSIP-ConA-LacZ were obtained to express the GFP or beta-galactosidase reporter gene under the control of a promoter containing p53-responsive elements. The advantages of these constructs were efficient delivery, comparable expression in different cells of a culture, and, consequently, the possibility of quantitating the p53 activity induced by various agents. With pSIP-ConA-LacZ, p53 activation in response to 12 chemotherapeutic agents was analyzed in human carcinoma cell line HCT116 and its derivatives HCT116/mdm2 and HCT116ARF, which expressed genes affecting the p53 activity. The analysis was also carried out with human cell lines HEF, WI-38, U2OS, and HT1080 originating from connective tissue. The construct proved suitable for detecting fine differences in p53 activation induced by various stress factors. The constructs were proposed for generating reporter cell lines from various cultures in order to identify the genetic or chemical factors that modulate the p53 activity and may be employed in new antitumor drugs.
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PMID:[Construction of a reporter system for fine quantitative assessment of activity of p53 protein in cultured cells]. 1471 96

The relatively low efficiency of target cell transduction and variations in the stability of transgene expression by retroviral vectors based on the Moloney murine leukemia virus (MoMLV) are major impediments to the use of such vectors in cancer gene therapy approaches. The present study was designed to investigate the stability and efficiency of transgene expression in human lung and breast cancer cell lines transduced with vectors based on human immunodeficiency virus type 1 (HIV-1) in vitro and in vivo in nude mouse models of metastasis. H460 lung carcinoma cells and MDA-MB-231 breast carcinoma cells were transduced with lentiviral vectors encoding enhanced green fluorescent protein (EGFP) and beta-galactosidase (beta-Gal), respectively. Transduced H460 cells were administered to nude mice by either intravenous or subcutaneous injection and MDA-MB-231 cells were implanted orthotopically into the mammary fat pad of such mice to induce primary tumor and metastatic lung tumor formation. High-level EGFP expression was maintained in transduced H460 cells in metastatic lung nodules for up to 6 weeks and transgene expression in vitro persisted for at least 23 days after retrieval of EGFP-positive H460 cells from the lungs of tumor-bearing mice and subsequent cultivation in vitro. Likewise, beta-Gal expression levels in metastatic MDA-MB-231 cells in lungs remained high for up to 11 weeks. Southern blot analyses carried out with DNA from lung nodules showed that proviral DNAs in H460 cells were maintained stably over many cell generations and during subsequent reimplantation in vivo. However, molecular analyses revealed variations in transgene copy numbers and expression levels among individual lung clones. These results demonstrate the usefulness of HIV-1-based lentiviral vectors for sustained and stable transgene expression in human lung and breast cancer cell lines in vitro and in vivo.
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PMID:Stable transgene expression in tumors and metastases after transduction with lentiviral vectors based on human immunodeficiency virus type 1. 1514 75

Expression of galectin-3, a member of the beta-galactosidase binding lectin family, is reported to correlate with cell adhesion. The present immunohistochemical study was performed to clarify the impact of galectin-3 expression on patients with esophageal squamous cell carcinoma. Galectin-3 expression was examined immunohistochemically in 154 patients with esophageal squamous carcinoma, who had undergone surgery without preoperative supplemental therapy at the Department of Surgery II in the Hospital of the Faculty of Medicine, Oita University, between 1990 and 2000. The cases with > or =30% nuclear-stained cancer cells were considered high nuclear expression cases. In contrast, the cases with > or =45% cytoplasm-stained cancer cells were considered high cytoplasm expression cases. Twenty-three of 154 ESCC cases were regarded as high nuclear expression (14.9%) and 72 of 154 cases were regarded as high cytoplasm-expression (46.5%). High expression of galectin-3 in the nuclei inversely correlated with vascular invasion (p=0.030) and histological differentiation (p=0.0064). In contrast, cytoplasmic expression of galectin-3 revealed no significant impact on clinicopathological factors. Neither nuclear nor cytoplasmic expression of galectin-3 was a prognostic indicator in ESCC. Elevated expression of galectin-3 in the nuclei but not the cytoplasm may be an important biological parameter related to histological differentiation and vascular invasion in patients with ESCC.
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PMID:Impact of nuclear galectin-3 expression on histological differentiation and vascular invasion in patients with esophageal squamous cell carcinoma. 1564 4

A major challenge for gene therapy is to be able to deliver efficiently the gene of interest to specific cell types. Here we describe a safe and simple effective naked DNA gene delivery method, via inferior vena cava (IVC) injection, to the recipient's kidneys. It was further demonstrated that gene expression was concentrated in the proximal tubular epithelial cells of the cortico-medullary region of the kidney. Confocal microscopy analyses demonstrated the presence of the exogenous DNA in the renal cell membrane 10 min postgene delivery. However, it was only by 30 min that the presence of the exogenous DNA could be detected in the cell cytoplasm and in the nuclei of the renal cells. Stable expression of the beta-galactosidase gene could be detected for up to 35 days and no toxicity or any adverse pathological effect associated with the delivery method could be observed. Importantly, this IVC gene delivery method could promote the targeting of genes to carcinoma established in the kidney of SCID mice. These results provide the first evidence to support that stable gene expression could be achieved in the renal cells of kidney and the established carcinoma in the kidneys following in vivo gene delivery with naked DNA and could therefore provide the potential to design protocols for the gene therapy of the kidney diseases.
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PMID:Systemic administration of naked DNA with targeting specificity to mammalian kidneys. 1564 68

HIV is transmitted sexually through mucosal surfaces where IgA Abs are the first line of immune defense. In this study, we used paired IgA and IgG mAbs against HIV gp160 to study intraepithelial cell neutralization and inhibition of HIV replication. African green monkey kidney cells, Vero C1008, polarizable epithelial cells transfected to express the polymeric Ig receptor (pIgR), were transfected with HIV proviral DNA, and intracellular neutralization mediated by the mAbs was assessed. D47A and D19A IgA, which neutralized HIV in a conventional assay, potently inhibited intracellular HIV replication as assessed by infecting HeLa-CD4-long terminal repeat/beta-galactosidase cells (human cervical carcinoma cell line) and CEMx174 cells (human T cell line) with apical supernatant, basolateral medium, and cell lysate from transfected cells. D47A also inhibited the production of virus as assessed by direct assay of p24. In contrast, D47 and D19 IgG, sharing the same V regions, but which were not transcytosed by the pIgR, did not inhibit intracellular HIV replication, nor did D47A and D19A IgA in pIgR- cells, incapable of transcytosing IgA. Confocal immunofluorescence microscopy showed prominent colocalization of HIV protein and D47A, in agreement with the intracellular neutralization data. D10A, which did not neutralize HIV in the conventional assay, and irrelevant IgA did not show intracellular neutralization or colocalization. Control studies with two kinds of conditioned medium confirmed that HIV neutralization had indeed occurred inside the cells. Thus, during its transcytosis through epithelial cells, HIV-specific IgA can neutralize HIV replication.
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PMID:Intraepithelial cell neutralization of HIV-1 replication by IgA. 1581 9

Peripheral myelin protein 22 (PMP22) is a tetraspan membrane glycoprotein, the misexpression of which is associated with hereditary demyelinating neuropathies. Myelinating Schwann cells (SCs) produce the highest levels of PMP22, yet the function of the protein in peripheral nerve biology is unresolved. To investigate the potential roles of PMP22, we engineered a novel knock-out (-/-) mouse line by replacing the first two coding exons of pmp22 with the lacZ reporter. PMP22-deficient mice show strong beta-galactosidase reactivity in peripheral nerves, cartilage, intestines, and lungs, whereas phenotypically they display the characteristics of tomaculous neuropathy. In the absence of PMP22, myelination of peripheral nerves is delayed, and numerous axon-SC profiles show loose basal lamina, suggesting altered interactions of the glial cells with the extracellular matrix. The levels of beta4 integrin, a molecule involved in the linkage between SCs and the basal lamina, are severely reduced in nerves of PMP22-deficient mice. During early stages of myelination, PMP22 and beta4 integrin are coexpressed at the cell surface and can be coimmunoprecipitated together with laminin and alpha6 integrin. In agreement, in clone A colonic carcinoma cells, epitope-tagged PMP22 forms a complex with beta4 integrin. Together, these data indicate that PMP22 is a binding partner in the integrin/laminin complex and is involved in mediating the interaction of SCs with the extracellular environment.
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PMID:Peripheral myelin protein 22 is in complex with alpha6beta4 integrin, and its absence alters the Schwann cell basal lamina. 1643 5


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