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)

An extracellular lethal toxin produced by Aeromonas salmonicida was purified by fast-protein liquid ion-exchange chromatography. The toxin is composed of glycerophospholipid:cholesterol acyltransferase (GCAT) (molecular mass, 25 kilodaltons) aggregated with lipopolysaccharide (LPS), the GCAT/LPS complex having a molecular mass of about 2,000 kilodaltons, estimated by gel filtration chromatography. The toxin is lethal for Atlantic salmon (Salmo salar L.) at a concentration of 0.045 micrograms of protein per g of body weight. The toxin is a hemolysin (T-lysin, active on fish erythrocytes), leukocytolysin, and cytotoxin. Antiserum to the purified toxin neutralized the lethal toxicity of the crude extracellular toxins, indicating this toxin to be the major lethal factor produced by A. salmonicida. In the crude extracellular products, small amounts of free GCAT were also present. This has been purified, and its activities and properties have been compared with those of the GCAT/LPS complex. The presence of LPS did not influence the GCAT activity of the enzyme with egg yolk or phosphatidylcholine (lecithin) as a substrate, but the specific hemolytic activity and lethal toxicity was about eightfold higher in the complexed form. Furthermore, the free GCAT was more susceptible to proteolytic and heat inactivation than was the GCAT/LPS complex. Recombination of LPS (phenol extracted from extracellular products of A. salmonicida) with free GCAT enhanced the hemolytic activity, lethal toxicity, and heat stability of the latter but did not influence its lecithinase activity. In native polyacrylamide gel electrophoresis, the GCAT/LPS complex and the recombined GCAT-LPS both showed a high-molecular-mass band which did not enter the gel, while the free GCAT produced a single band with low molecular mass. In isoelectric focusing gels, the GCAT/LPS and recombined GCAT-LPS produced a nonfocusing smear with pIs from pI 5.0 to 5.8, while the free GCAT produced a single band with pI 4.3. These data show that free GCAT can combine with LPS to produce a high-molecular-mass complex with enhanced toxicity and heat stability compared with those of free GCAT, similar to the preexisting GCAT/LPS complex, and indicate that the LPS moiety of the toxin plays an active role in toxicity.
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PMID:Glycerophospholipid:cholesterol acyltransferase complexed with lipopolysaccharide (LPS) is a major lethal exotoxin and cytolysin of Aeromonas salmonicida: LPS stabilizes and enhances toxicity of the enzyme. 239 87

The effects of different serum components alone and in conjunction with each other on Escherichia coli B were investigated. In general, the viability, turbidity, and electron microscope results were compatible with the following conclusions. The most efficient killing and destruction of E. coli B occurred when beta-lysin, lysozyme, and the antibody-complement system functioned in cooperation with each other at the serum concentration in isotonic solutions. The addition of sucrose protected the bacteria from the lethal and lytic action of these agents. Elimination of lysozyme from serum had the least effect on bactericidal activity, even though lysozyme treatment caused the cell wall to separate from the cytoplasmic membrane and caused clear areas to appear in the inner granular layer of the cell wall. Beta-lysin removal had an intermediate effect on the serum bactericidal activity. Beta-lysin treatment caused cell walls to collapse, allowed cytoplasmic contents to leak out of the cells, and stopped the separation of cell wall and cytoplasmic membrane, which normally takes place in 0.5 M sucrose solution. Inactivation of the complement eliminated the serum bactericidal activity against E. coli B. After treatment with antibody and complement, the cell walls became thick and indistinct, a portion of the cytoplasmic contents escaped, and patches of the middle layer of the cell wall appeared in freeze-etch preparations. Beta-lysin damaged the cytoplasmic membrane, lysozyme damaged the inner peptidoglycan layer of the cell wall, and the antibody-complement system damaged both the middle lipopolysaccharide layer of the cell wall and the cytoplasmic membrane.
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PMID:Interrelationship between serum beta-lysin, lysozyme, and the antibody-complement system in killing Escherichia coli. 460 6

NK lysin is a 9-kDa polypeptide that was originally isolated from porcine intestinal tissue based on its antibacterial activity. It is produced by cytolytic lymphocytes and is cytolytic against a number of different types of tumor cells. Here we report the binding of NK lysin to lipopolysaccharide (LPS) and its anti-LPS activity. NK lysin binds to matrix-coated LPS from Escherichia coli, Pseudomonas aeruginosa, and different strains of Salmonella enterica. Lipid A and polymyxin B inhibited the binding, demonstrating a preferential interaction of NK lysin with the lipid part of LPS. Chromium-labeled lymphoma cells were lysed by NK lysin, and LPS dose-dependently inhibited the cytolysis at equimolar amounts. In the same manner, NK lysin inhibited certain LPS-stimulated effects on mouse bone marrow cells as well as LPS binding to mouse granulocytes. These results suggest that NK lysin may be a another natural LPS-binding protein from lymphocytes that may participate in the endogenous defense response associated with elevated concentrations of LPS.
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PMID:Interaction of NK lysin, a peptide produced by cytolytic lymphocytes, with endotoxin. 986 16

By virtue of its binding to cyclophilin, the cellular receptor for cyclosporine (CsA), we could identify a new compound D-43787 [N-[(1-tert-butyloxycarbonyl)-indolin-2-(S)-carbonyl]-indolin-2-(S)-carbonacid-[N-epsilon-benzyloxycarbonyl)-2-(S)-lysin methylester]-amide] exhibiting immunomodulating properties. It inhibited cell proliferation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA)/ionomycin and anti-CD3/CD28 with an IC(50) of 0.3 microM. The protein phosphatase calcineurin, which is the target of the CsA-cyclophilin complex, is not inhibited by D-43787. It inhibited T helper cell (Th) 2 cytokines interleukin (IL)-4, -5, and -13 more effectively than the Th1 cytokine interferon (IFN)-gamma in human primary T cells. The IC(50) for IL-5 and IL-13 in TPA/ionomycin-stimulated peripheral blood mononuclear cells (PBMC) is 0.7 +/- 0.1 and 0.5 +/- 0.1 microM, respectively, whereas the IC(50) for IFN-gamma is 2.0 +/- 0.4 microM. When PBMC were stimulated with anti-CD3/CD28, the IC(50) for IL-4, -5, and -13 were 1.5 +/- 0.2, 1.8 +/- 0.2, and 1.9 +/- 0.4 microM, respectively. IFN-gamma was only partially inhibited under these conditions. This effect was even more pronounced in pure CD4(+) T cells. Pretreatment of human monocytes with D-43787 inhibited lipopolysaccharide-induced proinflammatory cytokines IL-6 and TNFalpha with an IC(50) of 1.2 +/- 0.1 and 4.7 +/- 0.9 microM, respectively. In vivo, D-43787 potently inhibited late-phase eosinophilia in actively sensitized and challenged guinea pigs (10 mg/kg, i.p.: 51%) and Brown-Norway rats (1 mg/kg, intrapulmonary: 66% 30 mg/kg, i.p.: 50%). In adjuvant-induced arthritis, D-43787 (10-40 mg/kg, b.i.d., i.p.) dose dependently reduced edema development on both hind paws. The potency of D-43787 was comparable with that of indomethacin and dexamethasone. In conclusion, we characterized a novel Th2 selective immunosuppressive drug with possible anti-asthmatic/anti-inflammatory effects. Its mode of action is distinct from that of CsA.
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PMID:Anti-inflammatory effects of a cyclosporine receptor-binding compound, D-43787. 1196 Oct 80

Amoebapores from protozoan parasite Entamoeba histolytica and NK-lysin of porcine cytotoxic lymphocytes belong to the same family of saposin-like proteins. In addition to the structural similarity, amoebapores and NK-lysin are both highly effective against prokaryotic and eukaryotic target cells in that they permeabilize the target cell membranes. Here, we have investigated in detail the protein/lipid interaction for the three isoforms of amoebapore and NK-lysin. Results obtained from electrical measurements on planar bilayer membranes, including reconstitution models of the lipid matrix of the outer membrane of Escherichia coli and phospholipid membranes, fluorescence energy transfer spectroscopy with liposomes, and monolayer measurements on a Langmuir trough, provided information on lipid preferences, pH dependences, and membrane interaction mechanisms. The three amoebapores led to the formation of transient pores with similar characteristics in conductance, sublevels, and lifetime for the different isoforms. The conductance of the pores was dependent on the polarity of the applied clamp voltage, and the distribution of the sublevels was affected by the value of the clamp voltage. The size of the pores and distribution of conductance sublevels differed between symmetric phospholipid and asymmetric lipopolysaccharide/phospholipid bilayers. Notably, NK-lysin caused the formation of well-defined pores, which were lipid- and voltage-dependent, and their characteristics differed from those induced by amoebapores; e.g., the protein concentration necessary to induce pore formation was 20 times higher. The biophysical data give important information on the mode of action of these small effector proteins, which may further lead to a better understanding of peptide-membrane interactions in general.
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PMID:Interaction of amoebapores and NK-lysin with symmetric phospholipid and asymmetric lipopolysaccharide/phospholipid bilayers. 1291 24

NK-2, a membrane-acting antimicrobial peptide, was derived from the cationic core region of porcine NK-lysin and consists of 27 amino acid residues. It adopts an amphipathic, alpha-helical secondary structure and has been shown to interact specifically with membranes of negatively charged lipids. We therefore investigated the interaction of NK-2 with lipopolysaccharide (LPS), the main, highly anionic component of the outer leaflet of the outer membrane of gram-negative bacteria, by means of biophysical and biological assays. As model organisms and a source of LPS, we used Salmonella enterica strains with various lengths of the LPS carbohydrate moiety, including smooth LPS, rough LPS, and deep rough LPS (LPS Re) mutant strains. NK-2 binds to LPS Re with a high affinity and induces a change in the endotoxin-lipid A aggregate structure from a cubic or unilamellar structure to a multilamellar one. This structural change, in concert with a significant overcompensation of the negative charges of LPS, is thought to result in the neutralization of the endotoxic LPS activity in a cell culture system. Neutralization of LPS activity by NK-2 as well as its antibacterial activity against the various Salmonella strains strongly depends on the length of the sugar chains of LPS, with LPS Re being the most sensitive. This suggests that a hydrophobic peptide-LPS interaction is necessary for efficient neutralization of the biological activity of LPS and that the long carbohydrate chains, besides their function as a barrier for hydrophobic drugs, also serve as a trap for polycationic substances.
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PMID:Biophysical characterization of endotoxin inactivation by NK-2, an antimicrobial peptide derived from mammalian NK-lysin. 1510 10

Antimicrobial peptides are widely believed to exert their effects by nonspecific mechanisms. We assessed the extent to which physicochemical properties can be exploited to promote discriminative activity by manipulating the N-terminal sequence of the 13-mer dermaseptin derivative K(4)-S4(1-13) (P). Inhibitory activity determined in culture media against 16 strains of bacteria showed that when its hydrophobicity and charge were changed, P became predominantly active against either gram-positive or gram-negative bacteria. Thus, conjugation of various aminoacyl-lysin moieties (e.g., aminohexyl-K-P) led to inactivity against gram-positive bacteria (MIC(50) > 50 microM) but potent activity against gram-negative bacteria (MIC(50), 6.2 microM). Conversely, conjugation of equivalent acyls to the substituted analog M(4)-S4(1-13) (e.g., hexyl-M(4)-P) led to inactivity against gram-negative bacteria (MIC(50) > 50 microM) but potent activity against gram-positive bacteria (MIC(50), 3.1 microM). Surface plasmon resonance experiments, used to investigate peptides' binding properties to lipopolysaccharide-containing idealized phospholipid membranes, suggest that although the acylated derivatives have increased lipophilic properties with parallel antibacterial behavior, hydrophobic derivatives are prevented from reaching the cytoplasmic membranes of gram-negative bacteria. Moreover, unlike modifications that enhanced the activity against gram-positive bacteria, which also enhanced hemolysis, we found that modifications that enhanced activity against gram-negative bacteria generally reduced hemolysis. Thus, compared with the clinically tested peptides MSI-78 and IB-367, the dermaseptin derivative aminohexyl-K-P performed similarly in terms of potency and bactericidal kinetics but was significantly more selective in terms of discrimination between bacteria and human erythrocytes. Overall, the data suggest that similar strategies maybe useful to derive potent and safe compounds from known antimicrobial peptides.
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PMID:Physicochemical properties that enhance discriminative antibacterial activity of short dermaseptin derivatives. 1687 Jul 56

The NK-lysin cDNA of Japanese flounder, Paralichthys olivaceus, consists of 657bp, containing an open reading frame (ORF) of 444bp, which encodes 147 amino acid residues. The amino acid sequence of Japanese flounder NK-lysin has 21% identity to porcine NK-lysin and bovine NK-lysin, 23% to equine NK-lysin, and 46% to zebrafish NK-lysin-like protein. Multiple alignments of Japanese flounder NK-lysin and other known saposin-like proteins revealed that the six cysteine residues important for structural folding are completely conserved. The Japanese flounder NK-lysin gene is approximately 2kb and consists of five exons and four introns. Japanese flounder NK-lysin mRNA constitutive expression was mainly detected in gills, heart, head kidney, intestines, peripheral blood leukocytes (PBLs), spleen and trunk kidney, and was detected at low levels in liver, muscle and ovary. However, expression was not detected in brain, skin and stomach of apparently healthy Japanese flounder. Gene expression of Japanese flounder NK-lysin was not inducible by lipopolysaccharide (LPS) treatment. A synthesized NK-lysin peptide, consisting of 27 amino acid residues, showed antimicrobial activity against Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Photobacterium damselae subsp. piscicida.
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PMID:Characterization of Japanese flounder (Paralichthys olivaceus) NK-lysin, an antimicrobial peptide. 1704 82

A basic challenge in the treatment of septic patients in critical care units is the release of bacterial pathogenicity factors such as lipopolysaccharide (LPS, endotoxin) from the cell envelope of Gram-negative bacteria due to killing by antibiotics. LPS aggregates may interact with serum and membrane proteins such as LBP (lipopolysaccharide-binding protein) and CD14 leading to the observed strong reaction of the immune system. Thus, an effective treatment of patients infected by Gram-negative bacteria must comprise beside bacterial killing the neutralization of endotoxins. Here, data are summarized for synthetic compounds indicating the stepwise development to very effective LPS-neutralizing agents. These data include synthetic peptides, based on the endotoxin-binding domains of natural binding proteins such as lactoferrin, Limulus anti-LPS factor, NK-lysin, and cathelicidins or based on LPS sequestering polyamines. Many of these compounds could be shown to act not only in vitro, but also in vivo (e.g. in animal models of sepsis), and might be useful in future clinical trials and in sepsis therapy.
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PMID:Mechanisms of endotoxin neutralization by synthetic cationic compounds. 1705 90

Two M5.1 and M15.2 B complex congenic lines of Fayoumi chickens were evaluated for body weight loss and faecal oocyst counts as parameters of avian coccidiosis. M5.1 chickens exhibited resistance to E. maxima compared with M15.2. To correlate the differential responses of the M5.1 and M15.2 lines to E. maxima infection with cellular immune responses, the expression levels of mRNAs encoding 14 immune-related molecules were measured by quantitative RT-PCR in intestinal intraepithelial lymphocytes (IELs) and splenocytes at 0, 3, 4, and 5 days following parasite infection. Intestinal IELs from M5.1 chickens expressed higher levels of transcripts encoding interferon gamma (IFNG), interleukin-lbeta (1L1B), IL6, IL8, IL12, IL15, IL17A, inducible nitric oxide synthase (iNOS), and lipopolysaccharide-induced tumour necrosis a factor (LITAF), and lower levels of mRNAs for IFNA, IL10, IL17D, NK-lysin (NKL), and tumour necrosis factor superfamily 15 (TNFSF15) at 3 days post infection, compared with the M15.2 line. In the spleen, E. maxima infection was associated with higher expression levels of IFNA, and IL15 and lower levels of IL6, IL17D, and IL12 in M5.1 compared to M15.2 birds. Using an intestinal IEL cDNA microarray, the differential dynamics of gene expression in the gut of M5.1 and M15.2 chickens following experimental coccidiosis were evident. In particular, the genes encoding lymphotactin and parathymosin were expressed at significantly higher levels in M5.1 compared with M15.2 line chickens. In conclusion, genetic determinants within the chicken major histocompatibility complex (MHC) B complex influence resistance to E. maxima infection by controlling the local and systemic expression of immune-related cytokine and chemokine genes.
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PMID:Differential immune-related gene expression in two genetically disparate chicken lines during infection by Eimeria maxima. 1881 95


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