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)

Recent clinical studies using neutralizing antibodies point to a key role for tumor necrosis factor-alpha (TNF-alpha) in chronic inflammatory diseases. Antisense technique is a recent approach aiming at inhibition of single proteins. Previously, we described nonspecific induction of TNF by phosphorothioate oligonucleotides. In this study, we established an in vitro model that allows specific inhibition of TNF synthesis, bypassing TNF induction. Freshly isolated human monocytes were incubated with oligonucleotides and the cationic lipid lipofectin in different ratios. TNF synthesis was stimulated with lipopolysaccharide and quantified by a specific radioimmunoassay (RIA). Among all sequences tested, one of the antisense oligonucleotides complementary to the translation initiation region of TNF mRNA (5'-CAT GCT TTC AGT CAT-3') revealed highest efficacy. At 2 microM, the antisense oligonucleotide inhibited TNF synthesis by up to 79%. A concentration as low as 250 nM of the antisense oligonucleotide was effective. Scrambled controls and controls with different, defined degrees of mismatches confirmed a sequence-specific action. Examination with confocal fluorescence microscopy showed a marked difference comparing lipofectin-mediated vs. spontaneous uptake. This study defines criteria that from the prerequisite necessary for design and application of antisense oligonucleotides against TNF in vivo.
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PMID:Specific suppression of human tumor necrosis factor-alpha synthesis by antisense oligodeoxynucleotides. 901 65

To understand the possible mechanism of nitric oxide (NO)-mediated cytotoxicity, we investigated the effect of NO on the endogenous antioxidant enzymes (AOEs) catalase, glutathione peroxidase (GPX), and CuZn- and Mn-superoxide dismutases (SODs) in rat C6 glial cells under conditions in which these cells expressed oligodendrocyte-like properties as evidenced by the expression of 2',3'-cyclic-nucleotide 3'-phosphohydrolase. The 24-h treatment with S-nitroso-N-acetylpenicillamine (SNAP), a NO donor, decreased the activities and the protein levels of catalase, GPX, and Mn-SOD in a dose-dependent manner. Alternatively, the activity and the protein level of CuZn-SOD were increased. 2-Phenyl-4,4, 5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO), a NO scavenger, blocked the effect of SNAP. Moreover, the treatment of C6 cells with sodium nitroprusside, another NO donor, or with a combination of lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma), which induce excessive production of NO, also significantly modulated the AOE activities in a manner similar to that seen with SNAP treatment. The compounds/enzymes that inhibit the production of NO (e.g., N-nitro-L-arginine methyl ester hydrochloride, arginase, and PTIO) blocked the effects of LPS and IFN-gamma on the activities of AOEs. Treatment with SNAP and a combination of LPS and IFN-gamma also modulated the mRNA levels of AOEs, parallel to the changes in their protein levels and activities, except for Mn-SOD where the combination of LPS and IFN-gamma markedly stimulated the mRNA expression. In spite of the stimulation of mRNA level, LPS and IFN-gamma significantly inhibited the activity of Mn-SOD within the first 24 h of incubation; however, Mn-SOD activity gradually increased with the increase in time of incubation. These results suggest that alterations in the status of AOEs by NO may be the basis of NO-induced cytotoxicity in disease states associated with excessive NO production.
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PMID:Modulation of endogenous antioxidant enzymes by nitric oxide in rat C6 glial cells. 910 15

The human platelet-activating factor receptor gene exists as a single copy on chromosome 1. Two 5'-noncoding exons (Exon 1 and 2) has distinct transcription initiation sites and promoters. These exons are alternatively spliced to a common splice acceptor site on exon 3 that contains a total coding regions. The transcript 1 is expressed ubiquitously with an emphasis of differentiated eosinophilic cell line (Eol-1), and leukocytes. On the other hand, the transcript 2 is expressed tissue-specifically. The latter is not expressed in leukocytes or brain. The transcript 1 has three tandem repeats of NF-kappa B, and SP-1 site, and responded to various inflammatory reagents including PAF itself, lipopolysaccharide, or phorbol ester. By northern blotting of tissue or cells with various nutritional or hormonal treatments, the PAF receptor messages are up-regulated. Estrogen increased the expression of the PAF receptor in human endometrial glandular cells, and vitamin A (retinoic acid) or thyroid hormone treatment up-regulates the PAF receptor expression only tissues with transcript 2 By various in vivo and in vitro transcriptional assays (CAT reporter assay, gel mobility shift assay), we identified estrogen responsible element, and hormone responsive element. The PAF receptor hormone responsive element is composed of three direct repeated TGACCT-like hexamer motifs with 2 and 4 bp spaces, and the two upstream and two downstream motifs were identified as response elements for RA and T.
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PMID:Platelet-activating factor receptor. Gene structure and tissue-specific regulation. 913 Nov 30

Transient transfection assays with various deletion mutants of the mouse inducible nitric oxide synthase (iNOS) promoter linked to a CAT reporter gene demonstrated that, besides the downstream NF-kappaB site, the region from -973 to -925 which contains a potential binding site for NF-kappaB (upstream NF-kappaB site) also mediated lipopolysaccharide (LPS)-inducibility in mouse macrophage cell line RAW 264.7. Site-specific mutation of three conserved nucleotides within the upstream NF-kappaB site abolished additional induction by LPS as well as maximal expression of iNOS by IFN-gamma plus LPS. In contrast, site-specific mutation of the downstream NF-kappaB site caused almost all reduction in expression of the reporter gene by LPS or LPS plus IFN-gamma. Electrophoretic mobility shift assays with the two NF-kappaB sites showed LPS-induced NF-kappaB binding to both probes and its higher affinity to the upstream NF-kappaB site. Taken together, these suggest that the upstream NF-kappaB site having enhancer function, besides the downstream NF-kappaB site as a core promoter, is essential for maximal expression of the iNOS gene.
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PMID:Upstream NF-kappaB site is required for the maximal expression of mouse inducible nitric oxide synthase gene in interferon-gamma plus lipopolysaccharide-induced RAW 264.7 macrophages. 924 8

Although certain factors appear to predispose the host to infection by Helicobacter pylori, clearly the bacterium possesses a well-defined battery of virulence factors that allow the organism to: (1) colonize the gastric mucosa (urease, flagella, adhesins, acid-inhibitory protein, iron acquisition proteins, and heat shock proteins); (2) evade host defense (shedding of surface proteins, catalase, superoxide dismutase, and poorly reactive lipopolysaccharide); and (3) damage host tissue (vacuolating cytotoxin, protease, CagA-related factors, inducers of cytokines, and chemotaxins). Together these factors allow H. pylori to persist in the host, establishing a chronic infection. Although many of these virulence factors are produced by all strains of H. pylori, there are also well-defined pathogenicity islands (contiguous stretches of chromosomal DNA) present in some strains that encode additional proteins including CagA that potentiate virulence. Strains possessing these "virulence cassettes" are isolated more frequently from patients with the more serious clinical manifestations associated with duodenal ulcer than from patients with gastritis alone or nonulcer dyspepsia.
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PMID:Helicobacter pylori factors associated with disease development. 939 56

The present study investigated the effect of lipopolysaccharide (LPS; from Escherichia coli, 2 mg/kg body wt ip) on selected aspects of the antioxidant status in Kupffer and sinusoidal endothelial cells. Cells were isolated 18 h after the injection of saline or LPS. In fresh suspension cultures, cellular reduced glutathione (GSH) and H2O2 were determined by monochlorobimane, and 2',7'-dichlorofluorescein diacetate, respectively, using a fluorescence plate reader. LPS injection increased GSH content two- to threefold in Kupffer cells compared with cells from control rats. Cellular GSH content was higher in endothelial than Kupffer cells. However, LPS did not increase GSH content in endothelial cells. Addition of H2O2 (40-200 microM) to Kupffer or endothelial cells caused a transient decrease in GSH, which was more pronounced in cells from control rats (approximately 45% drop) than in LPS-exposed cells (approximately 25% drop). Depleted GSH levels were accompanied by a proportional increase in cellular H2O2. After inhibition of catalase by 3-amino-1,2,4-triazole, the presence of 0.2 mM H2O2 depleted GSH content by 75% and 40% in Kupffer cells from saline- or LPS-injected rats, respectively. The same treatments caused a similar 50% decrease in both activated and control endothelial cells. LPS decreased catalase activity by 45% in Kupffer cells, whereas it had no effect on catalase in endothelial cells. Glutathione reductase activity was not altered by LPS in either cell type. These data show that in activated Kupffer cells the elevated level of cellular glutathione plays an augmented role in the protection against reactive oxygen species, whereas the contribution of catalase to H2O2 detoxification is attenuated. In LPS-stimulated endothelial and Kupffer cells, the efficient maintenance of GSH is consistent with upregulated production of reducing power through the hexose phosphate shunt observed previously.
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PMID:Role of glutathione and catalase in H2O2 detoxification in LPS-activated hepatic endothelial and Kupffer cells. 943 55

1. The mechanisms involved in mediating bacterial endotoxin lipopolysaccharide (LPS)-induced injury in the colon of neonatal rat pups aged 10-12 days was examined. 2. Administration of LPS (3 mg kg(-1), i.p.) caused a time-related increase in the plasma concentration of rat mast cell protease-II (RMCP-II) which was attenuated dose-dependently, by the non-selective mast cell stabilizer doxantrazole (0.05-5 mg kg(-1), i.p.). The selective connective tissue mast cell stabilizer ketotifen (5-25 mg kg(-1), i.p.) was without effect at the lower dose and had only a limited inhibitory effect at the higher dose. 3. In addition, doxantrazole (5 mg kg(-1), i.p.) inhibited mast cell degranulation in response to LPS in sections of neonatal rat colon, but ketotifen (5 mg kg(-1), i.p.) was without effect. 4. The increase in plasma RMCP-II concentration in response to LPS treatment preceded increases in tissue myeloperoxidase (MPO) activity, inducible nitric oxide synthase (iNOS) activity and tissue lipid peroxidation. These events were all attenuated by pretreatment with doxantrazole (5 mg kg(-1), i.p.), antineutrophil serum (100 microl kg(-1), i.p.), dexamethasone (2 mg kg(-1), i.p.) and the selective iNOS inhibitor, aminoguanidine (25 mg kg(-1), i.p.). 5. In addition, lipid peroxidation was inhibited by pre-administration of the antioxidant enzymes superoxide dismutase (2000 u kg(-1), i.p.) and catalase (2000 u kg(-1), i.p.), the xanthine oxidase inhibitor allopurinol (100 mg kg(-1), i.p.) and the peroxyl scavenger deferoxamine (10 mg kg(-1), i.p.), suggesting the involvement of reactive oxygen metabolites in the colonic injury. 6. These findings suggest that the sequence of events resulting in colonic damage in the neonatal rat following administration of LPS include mast cell degranulation, neutrophil infiltration, elevation in iNOS activity and subsequent lipid peroxidation.
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PMID:Role of mast cells, neutrophils and nitric oxide in endotoxin-induced damage to the neonatal rat colon. 948 51

This study investigated whether short-term exposure to Escherichia coli lipopolysaccharide (LPS) elicits vasomotor dysfunction in skeletal muscle in vivo and, if so, whether perivascular mast cell proteases partly modulate this response. With intravital microscopy, we found that suffusion of E. coli LPS on the in situ hamster spinotrapezius muscle for 60 min elicits immediate vasoconstriction followed by vasodilation. Vasoconstriction is abrogated by SK&F 108566, a selective, nonpeptide angiotensin II (AT II) subtype 1 receptor antagonist, chymostatin and soybean trypsin inhibitor. These compounds also attenuate E. coli LPS-induced vasodilation. By contrast, superoxide dismutase, catalase and indomethacin attenuate only E. coli LPS-induced vasodilation. Endothelin receptor antagonists, lisinopril, leupeptin, Bestatin and DL-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid are ineffective. Histochemical analysis of the spinotrapezius muscle reveals abundant perivascular mast cells with chymostatin-inhibitable chymase-like activity. Pretreatment of hamsters with compound 48/80 for 4 days curtails E. coli LPS-induced vasoconstriction and converts vasodilation to vasoconstriction. On balance, these data indicate that E. coli LPS stimulates perivascular mast cells in the in situ hamster spinotrapezius muscle to release an AT II-producing chymase-like protease(s). AT II thus produced elicits local vasoconstriction and elaborates reactive oxygen species which, in turn, generate vasodilator prostaglandins.
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PMID:Mast cell chymase-like protease(s) modulates Escherichia coli lipopolysaccharide-induced vasomotor dysfunction in skeletal muscle in vivo. 949 78

To investigate the role of nitric oxide (NO) and its interaction with oxygen radicals in fever, we injected conscious rabbits intravenously (i.v.) with 1 microgram/kg bacterial lipopolysaccharide (LPS) and measured body temperatures, and circulatory and respiratory parameters. We estimated plasma levels of antidiuretic hormone (ADH); nitrate as a measure of NO metabolism under aerobic conditions; prostaglandin E2 (PGE2) and prostaglandin PGF2 alpha (PGF2 alpha); and tumor necrosis factor alpha (TNF alpha). We studied the effects of LPS before and after treatment with oxygen radical scavengers superoxide dismutase and catalase (SOD/CAT), before and after treatment with NG-monomethyl-L-arginine (L-NMMA), a specific blocker of nitric oxide synthase (NOS), before and after treatment with methylene blue (MB). N-methyl-D-aspartate (NMDA) receptors were blocked with ketamine. LPS increased core temperature by 1.1 +/- 0.1 degree C within 3 h, associated with a rapid increase of plasma TNF alpha, PGE2 and PGF2 alpha, and a fall of nitrate. The decrease of nitrate following LPS was augmented in rabbits pretreated with SOD/CAT, associated with a rise of core temperature of 1.6 +/- 0.1 degree C within 3 h. The lowest levels of nitrate were observed in rabbits pretreated with L-NMMA, associated with a rise of core temperature of 3.0 +/- 0.1 degree C within 3 h. Treating the same rabbits with a continuous i.v. infusion of 5 mg/kg/h MB, starting 30 min before injection of LPS, caused an immediate increase in nitrate and completely prevented fever. The rise of TNF alpha and ADH after LPS, however, was not significantly different from the control fever, and plasma PGE2 levels were nearly twice as elevated. MB also prevented fever in NMMA-treated rabbits, but only as long as nitrate levels remained elevated. MB induced an immediate rise of core temperature in ketamine-treated rabbits. We conclude that an undisturbed or elevated synthesis of NO in the central nervous system prevents fever, possibly via positive feedback action of NO on presynaptic glutaminergic neurons.
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PMID:Antipyretic role of nitric oxide during endotoxin-induced fever in rabbits. 950 19

Endotoxin lipopolysaccharide (LPS) and streptozotocin-induced diabetes are known to cause oxidative stress in vivo. There is some evidence that a sublethal dose of LPS provides protection against subsequent oxidative stress. Because of its wide use as a diabetogenic agent, this study was undertaken to determine if streptozotocin can likewise provide a protective effect against further oxidative stress in rats. Female Sprague-Dawley rats were given streptozotocin (50 mg/kg intraperitoneally once) prior to exposure to either bacterial endotoxin from Salmonella abortus equii (5 mg/kg intraperitoneally) or three additional daily doses of streptozotocin (50 mg/kg intraperitoneally). One week after LPS or streptozotocin treatments, oxidative stress was determined by measuring changes in antioxidant activity (glutathione peroxidase, glutathione reductase, superoxide dismutase, catalase, glutathione S-transferase, and gamma-glutamyltranspeptidase) and in concentrations of glutathione, nitrite, and thiobarbituric acid reactants in liver, kidney, intestine, and spleen. High levels of some antioxidants in the LPS-control and streptozotocin-control rats, in contrast to normal levels found in diabetes + LPS and multidose-streptozotocin rats, suggest that streptozotocin, like LPS, may confer a protective effect against subsequent oxidative stress.
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PMID:Streptozotocin may provide protection against subsequent oxidative stress of endotoxin or streptozotocin in rats. 952 73


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