Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human immunodeficiency virus type 1 (HIV-1) infection is frequently associated with concurrent infection by opportunistic pathogens, against which production of nitric oxide by host macrophages provides a first line of defence. We have investigated whether regulatory HIV-1 proteins, such as Tat, can modulate the activity of the inducible nitric oxide synthase (iNos) gene when expressed in stable transfectant lines of RAW264.7 cells. A bioassay for Tat, based on transactivation of an HIV-1 LTR-CAT reporter gene, allowed selection of Tat-expressing cells. Parental and Tat-expressing macrophages accumulated identical levels of nitrite following lipopolysaccharide (LPS) stimulation. Interferon gamma (IFN-gamma) stimulation however, resulted in reduced levels of nitrite accumulation as a direct consequence of Tat expression. Conditioned media from Tat-expressing cells reduced the level of nitrite accumulation in parental cells following IFN-gamma stimulation but not stimulation with LPS. These results implicate HIV-1 Tat as a modulator of the IFN-gamma-specific signal transduction pathways leading to iNos expression.
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PMID:The human immunodeficiency virus type 1 regulatory protein Tat inhibits interferon-induced iNos activity in a murine macrophage cell line. 876 Apr 10

This study investigates the effects of either a high-fat diet or endotoxin on peroxisome metabolism as assessed by measuring catalase activity, catalase mass, and peroxisomal beta-oxidation. Three mouse strains C3H/HeJ, BALB/c, and C57BL/6J were fed either a low-fat or a high-fat diet and injected intraperitoneally with 1 microg Escherichia coli lipopolysaccharide. These parameters were not different in C3H/HeJ mice fed a high-fat diet compared with controls fed a low-fat diet. Total liver catalase activity and peroxisomal beta-oxidation were higher in BALB/c mice fed high-fat diet compared with low-fat controls. Total liver catalase activity, catalase mass and peroxisomal beta-oxidation increased to the greatest extent in C57BL/6J mice fed a high-fat diet. Endotoxin treatment did not alter any of the parameters in mice fed a low-fat diet. Among mice fed a high-fat diet, endotoxin did not affect hepatic catalase or peroxisomal beta-oxidation in the C3H/HeJ mice, decreased catalase activity in BALB/c mice (28%), and greatly decreased both catalase (66%) and peroxisomal beta-oxidation (69%) in C57BL/6J mice. The decrease in catalase activity in C57BL/6J mice was apparently because of an inactivation of the enzyme as determined by the activity/mass ratio. Thus, endotoxin is showed to inhibit both catalase and peroxisomal beta-oxidation in mice and the sensitivity to endotoxin is greatest in C57BL/6J mice fed a high-fat diet.
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PMID:Influence of dietary fat on the effect of endotoxin on murine hepatic peroxisomes. 878 30

Nitric oxide release is induced in many cells, including vascular endothelium, as part of the host response to inflammation. Nitric oxide synthase activity is increased in patients with sepsis, associated with increased oxidant demands and decreased antioxidant protection. We used a human vascular endothelial cell line to investigate the influence of antioxidants on nitric oxide synthase activity. Cells were cultured to confluence and incubated with interferon gamma, tumor necrosis factor, and lipopolysaccharide in the combined presence of the antioxidants ascorbic acid, Trolox, catalase, or superoxide dismutase, singly and in combination, for 48 h. Additionally, some cells were incubated with hypoxanthine-xanthine oxidase or a nitric oxide donor. Nitric oxide synthase activity was upregulated by cytokine exposure (p < .0005). Ascorbic acid and superoxide dismutase/ catalase resulted in decreased enzyme activity (p < .05). Superoxide anion release from xanthine oxidase caused increased activity (p < .05) and exogenous nitric oxide tended to suppress synthase activity. We suggest that antioxidants scavenge superoxide anion, enabling feedback inhibition of nitric oxide synthase activity by nitric oxide, and thus reducing enzyme activity. Exogenous nitric oxide also has a similar effect. Superoxide generation suppresses this feedback inhibition. This study has important implications in patients with sepsis in whom nitric oxide synthase inhibitor therapy is currently under investigation.
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PMID:Regulation of nitric oxide synthase activity in cultured human endothelial cells: effect of antioxidants. 879 Oct 97

The inducible isoform II of nitric-oxide synthase (iNOS) was recently cloned from brain and identified in astroglial cells. Induced nitric oxide biosynthesis occurs in brain cells only if extracellular cerebrospinal fluid contains -arginine. This study demonstrates for the first time that induced iNOS activity is strictly dependent on concomitant induction of an alternatively spliced transcript of the cat-2 gene encoding high affinity -arginine transporter System y+ in cultured rat astrocytes. Inhibition profiles of radiolabeled -arginine and -leucine uptake identified the dominance of Na+-independent transport System y+ serving cationic amino acids, with insignificant activities of Systems y+L, bo,+, or Bo,+. A reverse transcription-polymerase chain reaction/sequencing/cloning strategy was used to identify a single 123-base nucleotide sequence coding the high affinity domain of alternatively spliced CAT-2 (not CAT-2a) in astrocytes activated by lipopolysaccharide/interferon-gamma. Using this sequence as a cDNA probe, it was determined that CAT-2 mRNA, iNOS mRNA, and System y+ activity were concomitantly and strongly induced in astrocytes. Constitutive CAT-1 mRNA was weakly present in neurons and astrocytes, was not inducible in either cell type, and contributed <3% to total System y+ activity. Although astroglial iNOS Km approximately 10 microM L-arginine for intracellular substrate, hyperbolic kinetics of inducible iNOS activity measured as a function of extracellular L-arginine concentration gave Km approximately 50 microM L-arginine with intact cells. The same Km approximately 50 microM was obtained for induced membrane transport System y+ activity. iNOS activity was reduced to zero in the absence of extracellular L-arginine uptake via System y+. These findings expand the current understanding of NO biosynthesis modulation and implicate a coordinated regulation of intracellular iNOS enzyme activity with membrane L-arginine transport in brain.
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PMID:Induced nitric oxide synthesis is dependent on induced alternatively spliced CAT-2 encoding L-arginine transport in brain astrocytes. 879 37

Reactive oxygen metabolites (ROMs) are thought to play a key role in the pathogenesis of the adult respiratory distress syndrome (ARDS). Accordingly, the use of ROM scavengers, such as N-acetyl-cysteine or dimethylthiourea, as therapeutic adjuncts to prevent oxidant-mediated damage to the lung have been evaluated extensively in animal models of ARDS. Results with this approach have been quite variable among studies. Another strategy that has been examined in animal models of ARDS is the administration of various enzymes, particularly superoxide dismutase (SOD) or catalase (CAT), in an effort to promote the conversion of ROMs to inactive metabolites. In theory, this strategy should be more effective than the use of ROM scavengers since a single molecule of a catalytically active molecule can neutralize a large number of molecules of a reactive species, whereas most scavengers act in a stoichiometric fashion to neutralize radicals on a mole-for-mole basis. This notion is supported by studies showing that prophylactic treatment with CAT provides impressive protection against acute lung injury induced in experimental animals by the administration of lipopolysaccharide (LPS). Results with SOD have been more variable. Recently, we have utilized a porcine model of LPS-induced ARDS to investigate the therapeutic potential of EUK-8, a novel, synthetic, low molecular salen-manganese complex that exhibits both SOD-like and CAT-like activities in vitro. Using both pre- and post-treatment designs, we have documented that treatment with EUK-8 significantly attenuates many of the features of LPS-induced acute lung injury, including arterial hypoxemia, pulmonary hypertension, decreased dynamic pulmonary compliance, and pulmonary edema. These findings support the view that salen-manganese complexes warrant further evaluation as therapeutic agents for treatment or prevention of sepsis-related ARDS in humans.
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PMID:Role of oxidant stress in the adult respiratory distress syndrome: evaluation of a novel antioxidant strategy in a porcine model of endotoxin-induced acute lung injury. 882 94

Proteases are known to be involved in regulation of macrophage activation and killing. We examined the effect of a serine protease inhibitor, 4-(2-aminoethyl)-benzenesulfonyl fluoride (AEBSF), on lysis of leukemic cells by human macrophages. Monocytes, isolated by Histopaque gradients and centrifugal elutriation, were cultured for 5 days in RPMI-1640 medium with 5% AB serum, and then activated with interferon-gamma (IFN-gamma; 100 U/mL) and lipopolysaccharide (LPS) (5 ng/mL), with or without AEBSF, for 2 days. On day 7, macrophages were washed, fresh medium without AEBSF added, and target cells added for 2 days. Lytic activity against two leukemic cell lines (K562 and HL-60) was assessed by an 111indium-releasing assay. Macrophages treated with IFN-gamma + LPS lysed K562 and HL-60 cells. AEBSF (50-150 microM) blocked the killing of these leukemic cells in a concentration-dependent manner. Other protease inhibitors were not effective. AEBSF was nontoxic at the concentrations used, and did not inhibit tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) secretion from the macrophages. The lytic activity against leukemic cells was inhibited by anti-TNF-alpha antibody, but not by anti-IL-1 beta, nor by superoxide dismutase or catalase. However, the leukemic cells were resistant to being killed by recombinant TNF-alpha alone in the absence of macrophages, indicating that TNF-alpha was required for killing, but that other factors that were inhibited by AEBSF were also required. Serum-free culture supernatant of activated macrophages had significant cytotoxic activity against leukemic cells. This cytotoxic activity was not altered by addition of AEBSF to the culture supernatant, suggesting that AEBSF affected macrophage activation, rather than inhibiting cytotoxic proteases secreted by the macrophages, or affecting the target cells themselves. Thus, a protease, which is susceptible to AEBSF, might be involved in the activation of macrophages, and might regulate the secretion of antitumor effector molecules other than TNF-alpha.
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PMID:Lysis of leukemic cells by human macrophages: inhibition by 4-(2-aminoethyl)-benzenesulfonyl fluoride (AEBSF), a serine protease inhibitor. 883 Jul 89

Subversion of mitochondrial electron transport to the production of O2.- has been proposed as a mechanism of tumor necrosis factor (TNF)-mediated cell killing and to a lesser extent interleukin-1 (IL-1) and lipopolysaccharide (LPS) cytotoxicity. We utilized the O2.- -sensitive aconitases to measure changes in steady-state 02.- levels in the mitochondrial matrix and cytoplasm of cultured mammalian cells in response to these inflammatory mediators. TNF alpha did not measurably affect aconitase activity, and thus mitochondrial 02.- production, in either cultured human A549 cells or murine L929 cells while TNF alpha clearly caused cytotoxicity as revealed by impaired mitochondrial respiration. IL-1 alpha and Escherichia coli LPS also failed to affect the aconitase activity in A549 cells. Neither the O2.- scavenger Mn(III) TMPyP nor the H2O2 scavenger catalase protected L929 cells against the cytotoxicity of TNF alpha. In conclusion, TNF, IL-1, and LPS do not appear to exert cytotoxicity, or MnSOD gene induction effects, by eliciting mitochondrial O2.- production.
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PMID:Failure of tumor necrosis factor and interleukin-1 to elicit superoxide production in the mitochondrial matrices of mammalian cells. 883 51

The effects of urban air and diesel particles on inflammatory cytokine gene expression, tumor necrosis factor alpha (TNF-alpha) in particular, were studied in rat alveolar macrophages. TNF-alpha, interleukin (IL)-1, IL-6, cytokine-induced neutrophil chemoattractant (CINC), and macrophage inflammatory protein (MIP)-2 gene expression and TNF-alpha secretion were increased in cells treated with 50 to 200 micrograms/mL of urban air particles in a concentration-related manner. There was no cytokine induction by diesel particles at any of the concentrations tested. Cytokine expression was not related to reactive oxygen species since antioxidants, such as catalase, TMTU, or DMSO, had no effect on TNF-alpha secretion. However, cytokine induction by urban air particles was completely prevented by polymyxin B, an antibiotic capable of neutralizing bacterial lipopolysaccharide (LPS) activities. Furthermore, LPS was detected on the urban air particles, but not on diesel particle. These results suggest that activation of cytokine gene expression and secretion in rat alveolar macrophages by urban air particles is due to the presence of endotoxin on the particles.
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PMID:Role of endotoxin in tumor necrosis factor alpha expression from alveolar macrophages treated with urban air particles. 888 60

Natural killer-enhancing factor (NKEF) was identified and cloned on the basis of its ability to increase NK cytotoxicity. Two genes, NKEF-A and -B, encode NKEF proteins and sequence analysis presented suggests that each belongs to a highly conserved family of antioxidants. To examine the antioxidant potential of NKEF, we transfected the coding region of NKEF-B cDNA into the human endothelial cell line ECV304. The stable transfectant, B/1, was found to overexpress NKEF-B gene transcript and protein. We subjected B/1 to oxidative stress by either culturing them with glucose oxidase (GO), which continuously generates hydrogen peroxide, or by direct addition of hydrogen peroxide. We found that B/1 cells were more resistant than control cell lines. Resistance to hydrogen peroxide was originally thought to be mediated mainly by catalase and the glutathione cycle. Therefore, we used inhibitors to block the two pathways and found that B/1 cells were more resistant to oxidative stress than control cells when we used inhibitors to preblock either pathway. We also examined the cellular inflammatory responses to oxidized low-density lipoprotein (LDL) and bacterial lipopolysaccharide (LPS) by measuring monocyte adhesion to endothelial cells in vitro and found that B/1 cells were resistant to such responses. Lastly, we found that B/1 cells were more resistant to a novel chemotherapeutic agent CT-2584, which appears to kill tumor cells by stimulating production of reactive oxygen intermediates in mitochondria. These results demonstrate that the NKEF-B is an antioxidant that protects cells from oxidative stress, chemotherapy agents, and inflammation-induced monocyte adhesion. Furthermore, its expression may mediate cellular responses to proinflammatory molecules.
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PMID:Endogenous natural killer enhancing factor-B increases cellular resistance to oxidative stresses. 898 Oct 42

Helicobacter pylori colonises the gastric mucosa of humans and causes both antral gastritis and duodenal ulcer disease. Exactly how H. pylori causes disease is not known but several pathogenic determinants have been proposed for the organism. These include adhesins, cytotoxins and a range of different enzymes including urease, catalase and superoxide dismutase. Surface molecules of H. pylori such as flagella, lipopolysaccharide, the urease enzyme and outer membrane proteins are putative adhesin molecules. While phosphatidylethanolamine and the Lewis(b) blood group antigen have been proposed as receptor molecules for the organism the exact mechanism by which H. pylori adheres to the gastric mucosa has still to be identified. Characterisation of the adhesins of H. pylori could lead to the development of adhesin analogues for use in the inhibition of colonisation and improved therapy for ulcer disease. In vivo studies with isogenic mutants which are incapable of adhering to the gastric mucosa would greatly clarify the significance of adherence. Such mutants could possibly be useful as a vaccine against infection with wild-type organisms.
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PMID:Cell envelope characteristics of Helicobacter pylori: their role in adherence to mucosal surfaces and virulence. 898 94


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