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)

Hepatocellular dysfunction, as a result of sepsis or endotoxemia, plays a critical role in the pathogenesis of multiple systems organ failure. Conventional methods to assay hepatic ATP require large tissue samples, making repeat measurements in the same animal impossible, and are unable to detect the minimal changes in metabolism consistent with early or reversible cellular injury. 31P NMR is a modality available for the in vivo measurement of high energy phosphates. Inorganic phosphate (Pi) and phosphomonoester (PME) ratios (markers of cellular metabolism and viability) as well as fractionated ATP may be repeatedly quantitated. To assess the early effects of endotoxemia on hepatic function, phosphorus spectra of the liver were obtained using a 1.7-cm surface coil in six rats after the ip administration of 4 mg/kg Escherichia coli lipopolysaccharide. Conventional assay was performed on 24 matched controls. Pi, PME, alpha-, beta-, and gamma-ATP peaks (expressed as percentage total signal area) were collected over 20 min, integrated, and analyzed. Pi/beta-ATP decreased over time until 6 hr reflecting ongoing uptake of inorganic phosphate and continued cellular metabolism. PME/beta-ATP ratios, which indicate cellular viability, became significantly elevated at 6 hr. Using 31P NMR, beta-ATP best reflected the early subtle energy changes present prior to cell death and subsequent organ failure with significant decreases at 2, 4, and 6 hr. Conventional assay for ATP confirmed similar trends. We conclude that 31P NMR is a valuable tool for the study of reversible hepatic energy changes during early endotoxemia.
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PMID:In vivo [31P]NMR assessment of early hepatocellular dysfunction during endotoxemia. 161 20

The active component of the exoantigens of malarial parasites which stimulates macrophages to secrete tumour necrosis factor (TNF) has been shown to depend upon a phospholipid, the activity of which was blocked by phosphatidylinositol (PI) and inositol monophosphate (IMP) in competitive inhibition studies. Antisera made against the exoantigens of Plasmodium yoelii, which inhibited their induction of TNF, were found by an ELISA assay to contain antibody against several other phospholipids. However, the inhibitory antibody was removed specifically by adsorption with liposomes containing PI, but not other phospholipids. Furthermore, PI was the only phospholipid in non-liposomal form which induced the production of inhibitory antisera. Mice immunized with IMP, but not inositol, also produced inhibitory antisera. When incorporated into liposomes several other phospholipids did give rise to inhibitory antibodies but, in contrast to the antisera against parasite exoantigens, PI and IMP, the inhibitory activity was removed by adsorption with heterologous phospholipid liposomes, suggesting that it was directed against a common determinant, presumably the phosphate ester head group. Inhibitory antibodies in the antisera tested were predominantly IgM and titres were not increased after repeated injections. Antisera raised against PI, IMP or the cross-reacting phospholipid liposomes also inhibited TNF secretion by macrophages stimulated by exoantigens of the human parasites P. falciparum and P. vivax, but not by bacterial lipopolysaccharide. These findings confirm our conclusion that exoantigens from these different species contain phosphate bound to inositol in their TNF-inducing moiety.
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PMID:Antibodies against phosphatidylinositol and inositol monophosphate specifically inhibit tumour necrosis factor induction by malaria exoantigens. 162 98

Lipid X, a precursor in the biosynthesis of lipid A, has been claimed to possess most of the immunostimulatory activity but none of the toxicity of endotoxin. However, recent work shows that synthetic lipid X can be contaminated with small amounts of N,O-acylated disaccharide-1-phosphate (H. Aschauer, A. Grob, J. Hildebrandt, E. Schuetze, and P. Steutz, J. Biol. Chem. 265:9159-9164, 1990). Because the impurities themselves exhibit immunostimulatory properties, it was necessary to establish whether chemically pure synthetic lipid X exhibits any of the endotoxinlike biological activities previously attributed to the native compound extracted from the Escherichia coli MN7 mutant. In the present study, two batches of synthetic lipid X were used: batch A contained the contaminating disaccharide, and batch B was pure lipid X. Batch A, previously believed to be pure on the basis of spectroscopic and microanalysis data, induced murine peritoneal macrophages to secrete tumor necrosis factor, interleukin-1, and prostaglandin E2 at a minimal dose of 10 micrograms/ml in vitro. Batch B, further purified by Sephadex LH 20 chromatography, was found virtually inactive in these in vitro assays. Furthermore, batch A was pyrogenic in rabbits at a dose of 0.05 mg/kg, whereas batch B was not pyrogenic at doses of up to greater than or equal to 2 mg/kg. However, both batches were equally tolerated by galactosamine-loaded mice at doses of up to 100 mg/kg. Surprisingly, while only batch A protected neutropenic mice against lethal infection with Pseudomonas aeruginosa (50% effective dose, 12.4 mg/kg), both batches were equally protective against infection with herpes simplex virus type 1 in mice and guinea pigs, even when lipid X was administered therapeutically. Interestingly, both batches of lipid X blocked endotoxin-induced expression of monocyte procoagulant activity and priming of human neutrophils for superoxide anion release. Similarly, both batches protected galactosamine-sensitized mice from otherwise lethal endotoxemia when administered prophylactically or simultaneously with the lipopolysaccharide challenge. Thus, our findings suggest that chemically pure lipid X (batch B) is devoid of the immunostimulatory properties of lipid A or endotoxin. Rather, it behaves as a competitive inhibitor of lipopolysaccharide. We conclude, therefore, that previous studies which attributed immunostimulatory activities to any batch of synthetic lipid X should be interpreted with caution.
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PMID:Immunostimulatory, but not antiendotoxin, activity of lipid X is due to small amounts of contaminating N,O-acylated disaccharide-1-phosphate: in vitro and in vivo reevaluation of the biological activity of synthetic lipid X. 164 70

The chemical structure of the saccharide portion of Vibrio parahaemolyticus serotype 012 lipopolysaccharide was studied. Using chemical degradation and modification, as well as methylation analysis in combination with GLC-MS, laser-desorption mass spectrometry and 1H-NMR and 13C-NMR spectroscopy, the carbohydrate backbone of the lipopolysaccharide was characterized as a branched decasaccharide with the following structure: (formula; see text) In the native lipopolysaccharide two additional phosphate groups are present and 3-deoxy-D-threo-hexulosonic acid and D-galacturonic acid are bound via acid-labile linkages.
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PMID:Chemical structure of the carbohydrate backbone of Vibrio parahaemolyticus serotype 012 lipopolysaccharide. 165 25

The chemical structure of the 2-keto-3-deoxyoctonate (KDO) region of the lipopolysaccharide (LPS) isolated from O1 V. cholerae NIH 41R (Ogawa) was elucidated by dephosphorylation, periodate oxidation and methylation analysis. Methylation analysis of KDO in the dephosphorylated LPS revealed the presence of 5-O-acetyl-1,2,4,6,7,8-hexa-O-methyl-3-deoxy-octitol and 2-keto-3-deoxy-heptulosonic acid was detected in the methanolysate of the periodate-oxidized and dephosphorylated LPS. These results indicated that the site of binding of KDO to the core oligosaccharide is position C5 as in enteric gram-negative bacterial LPS, while only one molecule of the KDO residue carrying phosphate on position C4 is present in the inner core region of the LPS in contrast to enteric gram-negative bacterial LPS in which one molecule of KDO carrying KDO or KDO2----4KDO disaccharide instead of the phosphate group at position C4 is present in its main chain.
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PMID:Chemical structure of the 2-keto-3-deoxyoctonate (KDO) region of the lipopolysaccharide isolated from O1 Vibrio cholerae NIH 4IR (Ogawa). 166 65

Routes of quinolone permeation in Pseudomonas aeruginosa were investigated by using sparfloxacin as a prototype compound. [14C]sparfloxacin cell labeling was 13 to 28% lower in three protein D2-deficient mutants resistant to imipenem than in their imipenem-susceptible counterparts. In four impermeability-type quinolone-resistant strains isolated from pefloxacin-treated animals, we observed two- to fourfold-greater resistance to imipenem, reduced protein D2 expression in the outer membrane according to Western blotting (immunoblotting), and 25 to 29% decreased cell labeling with imipenem. In a protein D2-producing strain but not in its protein D2-deficient isogenic mutant, uptake of [14C]sparfloxacin was strongly inhibited by L-lysine and imipenem, which act as substrates for protein D2. Conversely, binding of [14C]imipenem in a porin D2-positive strain was reduced by sparfloxacin but not by the nonamphoteric quinolone nalidixic acid. Sparfloxacin, imipenem, and lysine possess a carboxyl group and a potentially protonated nitrogen separated from each other by 0.64 to 1.07 nm as calculated by computer. Hence, protein D2 may catalyze facilitated diffusion for sparfloxacin, as it does for imipenem. In addition, pefloxacin-selected isolates contained 41 to 113% more 3-deoxy-D-mannooctulosonic acid than their quinolone-susceptible counterparts, with MIC increases of 2- to 4-fold for WIN-57273 (n-octanol-phosphate buffer partition coefficient, 13.139), 4- to 8-fold for difloxacin (partition coefficient, 3.093) and sparfloxacin (partition coefficient, 0.431), and 8- to 16-fold for norfloxacin (partition coefficient, 0.059) and ciprofloxacin (partition coefficient, 0.056). Thus, we hypothetize that in quinolone-selected strains, increased amounts of lipopolysaccharide form a permeability barrier that acts preferentially against hydrophilic quinolones.
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PMID:Role of protein D2 and lipopolysaccharide in diffusion of quinolones through the outer membrane of Pseudomonas aeruginosa. 166 23

The uncoupler 2,4-dinitrophenol prevents in vivo synthesis of O antigen in Salmonella typhimurium by inhibiting the first reaction of the pathway, formation of galactosyl-pyrophosphoryl-undecaprenol. Inhibition was observed only in intact cells; dinitrophenol had no effect on activity of the synthase enzyme in isolated membrane fractions. In vivo inhibition could not be explained by changes in intracellular nucleotide pools or a shift in the equilibrium of the reaction and appeared to be specific for the first step in the pathway. Neither the subsequent mannosyl transferase, which catalyzes formation of the trisaccharide-lipid intermediate, mannosyl-rhamnosyl-galactosyl-pyrophosphoryl-undecaprenol, nor O-antigen polymerase was inhibited. In addition, incorporation of galactose into core lipopolysaccharide was only modestly inhibited under conditions in which O-antigen synthesis was abolished. The results suggest that maintenance of proton motive force is required for access of substrate, UDP-galactose and/or undecaprenyl phosphate, to the active site of the galactosyl-pyrophosphoryl-undecaprenol synthase enzyme.
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PMID:Energy dependence of O-antigen synthesis in Salmonella typhimurium. 170 61

Combined effects of chemically synthesized lipid A analogs, the compound A-171 (acylglucosamine-4-phosphate with (R)-3-hydroxytetradecanoyl and (R)-3-hydroxytetradecanoyloxy]tetradecanoyl group at the C-2 and C-3 positions), or the compound A-172 (with (R)-3-hydroxytetradecanoyloxy]tetradecanoyl and (R)-3-tetradecanoyloxytetradecanoyl group at the C-2 and C-3 positions), and muramyl dipeptide (MDP) on antitumor activity against Meth A fibrosarcoma, were examined. Meth A fibrosarcoma cells (5 X 10(5)) were inoculated intradermally into BALB/c mice on day 0, compound A-172 and/or MDP were administered intravenously (i.v.) on day 7. Although the antitumor activity by single i.v. injection of A-172 (50 micrograms/mouse) with MDP (10 micrograms) was weaker than that of 50 micrograms of synthetic lipid A analogs (506), or 10 micrograms of bacterial lipopolysaccharide (LPS) with MDP, A-172 alone and with MDP exhibited tumor inhibition rates of 49.0 and 70.6%, respectively. When A-171 (50 micrograms) with MDP (10 micrograms) was administered i.v. twice (days 7 and 10) into mice inoculated Meth A fibrosarcoma, two of five mice caused complete tumor regression. Furthermore, L929 cell lysis by the combination of A-171, A-172 with MDP was higher than that by the analogs or MDP alone, suggesting that the lipid A analogs of monosaccharide type as well as LPS are able to enhance the production of tumor necrosis factor in the presence of MDP.
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PMID:Combined effects of synthetic lipid A analogs and muramyl dipeptide on antitumor activity against Meth A fibrosarcoma in mice. 178 74

The molecular mechanisms surrounding the toxicity and high mortality rate that accompany the release of bacterial lipopolysaccharide (LPS) are unclear, although its potent activity suggests that an amplification system is involved. Because previous studies suggest that a guanine-nucleotide-binding protein (G-protein) may participate in LPS action, we have evaluated the effects of LPS on GTPase activity in membranes isolated from macrophage (RAW 264.7) and fibroblast (B82L) cell lines. LPS induced substantial GTPase activation (200-300% above basal), and kinetic analyses indicated that the maximal LPS-stimulated increase in velocity is observed within 15 min, that it is a low-Km (for GTP) activity, that it can be enhanced by ammonium sulphate, and that it appears to be pertussis toxin-insensitive. Moreover, the LPS-enhanced GTPase activity was not antagonized by phosphatase/ATPase inhibitors such as p-nitrophenyl phosphate, ouabain, bafilomycin or N-ethylmaleimide, and in fact was potentiated by the addition of ATP or ADP. Conversely, the LPS precursor, lipid X, which can decrease the lethal effects of LPS, was found to dose-dependently inhibit the LPS-mediated stimulation of GTPase activity. Half-maximal inhibition was seen at the same lipid X/LPS ratio known to be effective in vivo, i.e. 1:1(w/w). These effects appear to be specific because other phospholipids, detergents and glycosides neither stimulated basal, nor inhibited LPS-induced, GTPase activity. These data suggest the involvement of a GTPase in LPS action, and indicate that lipid X may act to directly antagonize LPS at this level.
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PMID:Bacterial lipopolysaccharide-stimulated GTPase activity in RAW 264.7 macrophage membranes. 185 66

1. The modulation of the spontaneous increase in contractile responses to des-Arg9-bradykinin (des-Arg9-BK) of rabbit aortic strips incubated in vitro was studied. Rapid hypotensive responses to exogenous kinins were also measured in rabbits anaesthetized 5 h following pretreatment. 2. Continuous exposure to the protein synthesis inhibitors cycloheximide (71 microM) or anisomycin (3.8 microM) profoundly inhibited the sensitization to des-Arg9-BK in incubated aortic strips. However, temporary (3 h) inhibition of protein synthesis in vitro followed by further incubation (3 h) of tissues without inhibitor, paradoxically enhanced both the maximal contractile responses to des-Arg9-BK (1.7 microM) and the apparent affinity of the kinin without affecting contractions to noradrenaline (NA, 100 nM) at 6.5 h. 3. The stimulatory activity of the short treatment (pulse) with cycloheximide was abolished in the presence of dexamethasone sodium phosphate (100 microM throughout the incubation). The function of receptors for kinins did not appear to be altered directly by the steroid treatment. 4. Interleukin-1 beta (IL-1 beta), applied at low concentrations (100-250 pg ml-1) on aortic strips between 3 h and 6.5 h of incubation time, mimicked the selective stimulatory effect of the cycloheximide pulse on responses to des-Arg9-BK. Higher concentrations of IL-1 beta (0.5-5 ng ml-1) did not further amplify the responses to des-Arg9-BK but decreased the contractile responses to NA. 5. The modulation by IL-1 beta of vascular sensitivity to des-Arg9-BK and to NA was prevented by blockade of protein synthesis. 6. The induction in vivo by IL-1 beta (5 micrograms kg-1) or by cycloheximide (10 mg kg-1) of cardiovascular responsiveness to des-Arg9-BK was demonstrated with a blood pressure assay of exogenous kinins or with tissues isolated ex vivo 5 h after pretreatment of animals. Evidence of active disposition of cycloheximide in vivo was also obtained. 7. We propose the production of endogenous IL-1 as a possible mechanism for the enhancement of responsiveness to des-Arg9-BK observed in tissues pulsed with a protein synthesis inhibitor and for the inducing effect of cycloheximide or E. coli lipopolysaccharide in vivo. These results suggest that effects mediated by the BK1 receptor for kinins are potentially present in pathological conditions associated with IL-1 production.
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PMID:Pulse exposure to protein synthesis inhibitors enhances vascular responses to des-Arg9-bradykinin: possible role of interleukin-1. 187 45


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