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 show that the stimulation of human immunodeficiency virus (HIV) brought about by tumor necrosis factor alpha and phorbol 12-myristate 13-acetate can be inhibited by adding N-acetyl-L-cysteine (NAC). NAC, which replenishes intracellular glutathione, effectively inhibits the tumor necrosis factor alpha- or phorbol ester-stimulated replication of HIV in acutely infected cell cultures. NAC also inhibits the cytokine-enhanced HIV long terminal repeat-directed expression of beta-galactosidase in in vitro HIV model systems. These results show that intracellular thiol levels influence HIV production. Furthermore, because NAC reverses tumor necrosis factor alpha toxicity both in cells and in animals and is a well-known drug that can be administered orally without known toxicity in humans, these results suggest that NAC is a possible therapeutic agent in AIDS.
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PMID:Cytokine-stimulated human immunodeficiency virus replication is inhibited by N-acetyl-L-cysteine. 211 50

A cytokine preparation from rat peritoneal exudate cells was studied. The preparation was pronase sensitive and heat labile, but was insensitive to trypsin treatment. Administration to rats resulted in elevated serum levels of alpha 1-acid glycoprotein, sialyltransferase activities and cortisol, but depressed serum albumin levels; in addition, hepatic sialyltransferase activities were increased and hepatic beta-galactosidase and beta-N-acetylhexosaminidase activities were depressed.
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PMID:Studies on rat cytokines as mediators of the acute phase response. 634 Jun 81

Mice with a secondary Listeria monocytogenes infection eliminate the bacteria much faster and more efficiently from their organs than mice with a primary infection. During the course of a secondary infection, serum concentrations of interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF) are higher than during a primary infection. The aim of the present study was to determine whether these cytokines are involved in the acquired resistance to L. monocytogenes during a secondary infection in mice. In order to neutralize cytokines, alginate-encapsulated cells, which form anti-cytokine monoclonal antibodies, were injected into the nuchal region of mice during a Listeria infection. Mice recovered from a sublethal primary Listeria infection, which acquired cell-mediated immunity, received a subcutaneous injection of anti-IFN-gamma-forming cells, or anti-TNF-forming cells, and 4 days later received an intravenous injection with 10 50% lethal dose (LD50) L. monocytogenes. The number of bacteria recovered from the liver and spleen of immune mice treated with anti-IFN-gamma-forming cells was slightly larger (approximately 1 log10) than that found for immune mice treated with anti-beta-galactosidase-forming cells, called immune control mice. The organs of immune mice treated with anti-TNF-forming cells yielded significantly more (approximately 4 log10) bacteria than those of immune control mice, more than those of immune mice treated with anti-IFN-gamma-forming cells, and comparable numbers to those of non-immune mice. Taken together, these results demonstrate that TNF is essential in acquired resistance to L. monocytogenes during a secondary infection in mice, while IFN-gamma plays a minor role.
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PMID:Tumour necrosis factor, but not interferon-gamma, is essential for acquired resistance to Listeria monocytogenes during a secondary infection in mice. 749 Jan 27

Treatment of human endothelial cells with cytokines such as interleukin-1, tumor necrosis factor-alpha (TNF-alpha) or interferon-gamma induces the expression of specific leukocyte adhesion molecules on the endothelial cell surface. Interfering with either leukocyte adhesion or adhesion protein upregulation is an important therapeutic target as evidenced by the potent anti-inflammatory actions of neutralizing antibodies to these ligands in various animal models and in patients. In the present study we report that cotreatment of human endothelial cells with certain hydroxyflavones and flavanols blocks cytokine-induced ICAM-1, VCAM-1, and E-selectin expression on human endothelial cells. One of the most potent flavones, apigenin, exhibited a dose- and time-dependent, reversible effect on adhesion protein expression as well as inhibiting adhesion protein upregulation at the transcriptional level. Apigenin also inhibited IL-1 alpha-induced prostaglandin synthesis and TNF-alpha-induced IL-6 and IL-8 production, suggesting that the hydroxyflavones may act as general inhibitors of cytokine-induced gene expression. Although apigenin did not inhibit TNF-alpha-induced nuclear translocation of NF-kappa B(p50(NFKB1)/p65(RelA)) we found this flavonoid did inhibit TNF-alpha induced beta-galactosidase activity in SW480 cells stably transfected with a beta-galactosidase reporter construct driven by four NF-kappa B elements, suggesting an action on NF-kappa B transcriptional activation. Adhesion of leukocytes to cytokine-treated endothelial cells was blocked in endothelial cells cotreated with apigenin. Finally, apigenin demonstrated potent anti-inflammatory activity in carrageenan induced rat paw edema and delayed type hypersensitivity in the mouse. We conclude that flavonoids offer important therapeutic potential for the treatment of a variety of inflammatory diseases involving an increase in leukocyte adhesion and trafficking.
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PMID:Flavonoids inhibit cytokine-induced endothelial cell adhesion protein gene expression. 763 22

Rat superior cervical ganglion neurons require the presence of nerve growth factor (NGF) to develop and survive in culture. If NGF is removed from the culture medium, then the neurons die of programmed cell death. We investigated the potential role of Ca2+ and reactive oxygen species in this process. We found that overexpression of human wild-type copper/zinc-superoxide dismutase in cultured superior cervical ganglion neurons, using an adenovirus-based vector, substantially protected the cells from the effects of NGF withdrawal, although overexpression of the Ca(2+)-binding protein calbindin D28k or the enzyme beta-galactosidase did not. We also observed that treatment of the cells with the cytokine transforming growth factor-beta 1, which has been shown to protect neurons against oxidative injury, delayed cell death produced by NGF withdrawal. These data suggest a role for reactive oxygen species in triggering programmed cell death of rat sympathetic neurons upon growth factor withdrawal.
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PMID:Expression of human copper/zinc-superoxide dismutase inhibits the death of rat sympathetic neurons caused by withdrawal of nerve growth factor. 760 46

We have previously shown that the signal peptideless cytokine interleukin 1 alpha (IL-1 alpha) may play a role as an intracellular regulator of human endothelial cell senescence (J. A. M. Maier, P. Voulalas, D. Roeder, and T. Maciag, Science 249:1570-1574, 1990). To investigate the potential intracellular function of IL-1 alpha, transformed endothelial cells were transfected with the human cDNAs that code for the two forms of IL-1 alpha, the precursor molecule IL-1(1-271) and the mature protein IL-1(113-271). The subcellular localization of the two different polypeptides was investigated directly or by using chimeric genes constructed by fusion of different fragments of the IL-1 alpha gene and the beta-galactosidase open reading frames. The IL-1(113-271) protein was cytoplasmic, while IL-1(1-271) was nuclear. The basic cluster at the NH2 terminus of IL-1, KVLKKRR, has been shown to mediate IL-1 alpha nuclear targeting. Moreover, nuclear localization of IL-1 alpha correlates with impaired cell growth and expression of some IL-1 alpha-inducible genes. These results suggest that transport of endogenous IL-1(1-271) into the nucleus is required for it to modulate endothelial cell function.
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PMID:Endogenous interleukin 1 alpha must be transported to the nucleus to exert its activity in human endothelial cells. 811 17

In T lymphocytes, intracellular Ca2+ concentration ([Ca2+]i) rises within seconds of T-cell antigen-receptor stimulation and initiates the synthesis and secretion of interleukin 2, a cytokine essential for T-cell proliferation and the immune response. Using video-imaging techniques, we tracked [Ca2+]i signals in individual T cells and measured subsequent expression of a beta-galactosidase reporter gene (lacZ) controlled by the NF-AT element of the interleukin 2 enhancer. [Ca2+]i spikes elicited by monoclonal antibody binding to the CD3 epsilon subunit of the T-cell receptor were positively correlated with gene expression, but varied widely between individual cells and were therefore difficult to relate quantitatively to lacZ expression. The [Ca2+]i dependence of NF-AT-regulated gene expression was determined by elevating [Ca2+]i with either thapsigargin or ionomycin and then "clamping" [Ca2+]i to various, stable levels by altering either extracellular [Ca2+] or extracellular [K+]. Raising [Ca2+]i from resting levels of 70 nM to between 200 nM and 1.6 microM increased the fraction of cells expressing lacZ, with Kd approximately 1 microM. Activation of protein kinase C enhanced the [Ca2+]i sensitivity of gene expression (Kd = 210 nM), whereas stimulation of protein kinase A inhibited [Ca2+]i-dependent gene expression. The experiments described here provide single-cell measurements linking a second messenger to gene expression in individual cells.
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PMID:Intracellular calcium dependence of gene expression in single T lymphocytes. 814 3

Recent studies have suggested that the signal peptide-less cytokine, interleukin (IL)-1 alpha, may play a role as an intracellular regulator of human endothelial cell proliferation in vitro (Garfinkel, S., Haines, D. S., Brown, S., Wessendorf, J., Gillespie, D. H., and Maciag, T. (1992) J. Biol. Chem. 267, 24375-24378). In order to determine the intracellular locale of the IL-1 alpha precursor, we fused the open reading frame of the IL-1 alpha precursor to the reporter gene beta-galactosidase (Gal) and studied the cellular distribution of the chimera in NIH 3T3 cells after transfection. Immunological and enzymatic analysis demonstrated that the IL-1 alpha:beta-Gal fusion protein was associated with the nucleus. To further define the region responsible for this activity, we ligated the mature form of IL-1 alpha (IL-1 alpha 113-271) and the IL-1 alpha precursor domain (IL-1 alpha 1-112) to beta-Gal. Analysis of the intracellular distribution of these chimeric polypeptides following transfection demonstrated a differential distribution of IL-1 alpha 1-112:beta-Gal in the nucleus and IL-1 alpha 113-271:beta-Gal in the cytosol. Because the IL-1 alpha precursor domain contains a sequence that resembles a nuclear translocation signal (KVLKKRRL, residues 79-86), we prepared an IL-1 alpha precursor point mutant in which Lys82 was replaced by Glu. Transfection of NIH 3T3 cells with the IL-1 alpha precursor point mutant (IL-1 alpha 1-271 Glu82:beta-Gal) resulted in a significant reduction in the ability of the IL-1 alpha precursor to associate with the nucleus and similar data were obtained as a result of Lys82 mutagenesis in the IL-1 alpha precursor domain (IL-1 alpha 1-112 Glu82:beta-Gal). These data suggest that the IL-1 alpha precursor contains a functional nuclear localization sequence within the structure of the precursor domain and Lys82 is critical for its function.
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PMID:Identification of a nuclear localization sequence within the structure of the human interleukin-1 alpha precursor. 840 68

The use of plasmid vectors expressing the HBsAg, along with improved protocols for transfection of muscle fibers (Refs. 3-6 and Davis et al., this volume), have provided the reagents and methods with which to investigate the characteristics of the strong immune response given by this antigen after DNA-mediated immunization. Analysis of the fine specificity of the humoral response provides support for the idea that the HBsAg-bearing particles are formed such that the B and T epitopes are presented to the immune system in a way resembling that of the natural viral or subviral particles. As shown here and elsewhere, DNA-mediated immunization with the HBsAg-expressing plasmid vectors induces strong CTL responses as well as a dominant Th1 phenotype among the splenic lymphocytes of immunized mice. The Th1 cytokine profile can be obtained in two different strains of mice and with two types of proteins, HBsAg and beta-galactosidase. One important line of investigation in the future will be to determine the mechanism of this generic Th1 response to DNA-based immunization. Circumstantial evidence, discussed by Pisetsky et al. (this volume), suggests that the chemical nature of DNA may play a role as an adjuvant (see also Ref. 31), and this hypothesis to explain the cytokine profiles observed after DNA-mediated immunization must now be taken seriously. All the questions raised by this novel method of immunization are of interest for the design of future vaccines, even if DNA itself is ultimately not the vaccinating moiety. The question of antigen presentation is particularly intriguing, since the small amounts of protein produced by DNA-mediated immunization (on the order of nanograms) are capable of inducing strong immune responses at the level of B and T cells. Although initially it seemed obvious that endogenous protein synthesis in cells transfected with plasmid DNA would account for the observed induction of CTL activity, this idea must be examined in light of two well established sets of experimental results. First, the primary events in activation of CD8+ (as well as CD4+) T lymphocytes normally require professional APC capable of furnishing co-stimulatory signals to supplement the consequences of interaction of the T-cell receptor with MHC surface molecules. Second, endogenous synthesis and processing is not the only mechanism of class I epitope presentation, and numerous examples are now known whereby particulate exogenous proteins, such as HBsAg, can be taken up and processed in such a way as to allow class I presentation of peptides. Consideration of these two points suggests that a major contribution to the observed CTL induction afforded by DNA-mediated immunization could come from the sustained presence of the antigenic protein in interstitial spaces or in the circulation, coupled with the ability of the exogenous protein to be processed for class I presentation. This could be true for many other proteins in addition to the HBsAg. This hypothesis eliminates the inconvenient notion that muscle fibers (or other nonleukocyte cells) present antigen in a way compatible with primary activation of T cells. However, muscle tissue can be an important reservoir of the antigen because of the potential for prolonged synthesis of the protein; this could therefore explain the immune entrainment observed after DNA-mediated immunization. Muscle fibers or other cells could also serve to present class I epitopes for the purpose of restimulating and thus expanding the pool of activated CD8+ T lymphocytes. These explanations, though certainly plausible, will require experimental investigation. The small numbers of the transfected cells in vivo, as well as the potential mobility of transfected cells other than muscle fibers, may well render such experimentation difficult. DNA-mediated immunization clearly offers opportunities for obtaining novel insights into immunological mechanisms and immunization processes. It is also likely to promote vacc
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PMID:DNA-mediated immunization to the hepatitis B surface antigen. Activation and entrainment of the immune response. 854 14

Among the various parameters which may contribute to Mycobacterium bovis BCG vaccination efficiency, the choice of the vaccine strain may play an important role. In the present study, we therefore compared the immunogenicity of five different BCG strains that are commonly used for BCG vaccine production (Glaxo 1077, Japanese 172, Pasteur 1173P2, Prague, and Russian strains). The comparison of the growth capacity of these BCG strains in BALB/c and C3H mice demonstrated that a great difference exists between the capacity of various BCG strains to multiply and persist in target organs. A much lower recovery of BCG could be shown in mice immunized with Prague and Japanese BCG strains. T-cell responses of BCG-immunized mice were also examined by analyzing T-cell proliferative responses, cytokine production, delayed-type hypersensitivity responses, and cytotoxic activity. All these assays demonstrated that BCG immunization induced strong CD4+ T-cell responses, mostly of the Th1 type, as demonstrated by interleukin-2 and gamma interferon production. These studies also demonstrated that there are differences between BCG strains in stimulating these T-cell responses. A lack of induction of cytotoxic activity was observed following immunization with the Japanese strain. Lower anti-purified protein derivative antibody responses were also observed after intravenous or oral immunization with this BCG strain. Finally, the protective activity of these BCG strains was tested by measuring the capacity of immunized mice to eliminate recombinant Pasteur and Japanese BCG strains which expressed beta-galactosidase. The results of these experiments clearly demonstrated that the Prague and Japanese strains were unable to protect mice against a second mycobacterial challenge whereas mice immunized with the Glaxo, Pasteur, or Russian strain eliminated the recombinant BCG very efficiently. Altogether, the results of the present study strongly support the view that there are considerable differences in the immunogenicity of various BCG vaccine strains and that these differences may play a major role in BCG vaccination efficiency.
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PMID:Comparison of immune responses of mice immunized with five different Mycobacterium bovis BCG vaccine strains. 855 24


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