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 11-amino-acid amphipathic synthetic peptide homologous to a helical region on helix 1 of human lactoferrin HLP-2 exhibited bactericidal activity against Escherichia coli serotype O111, whereas an analogue synthesized with Pro substituted for Met, HLP-6, had greatly reduced antimicrobial activity. The bactericidal activity of HLP-2 was 10-fold greater than that of HLP-6 in both buffer and growth medium by time-kill assays. These assays also showed a pronounced lag phase that was both concentration and time dependent and that was far greater for HLP-2 than for HLP-6. Both peptides, however, were shown to be equally efficient in destabilizing the outer membrane when the hydrophobic probe 1-N-phenylnaphthylamine was used and to have the same lipopolysaccharide (LPS) binding affinity, as shown by polymyxin B displacement. Circular dichroism (CD) spectroscopy was used to study the structure and the organization of the peptides in solution and upon interaction with E. coli LPS. In the presence of LPS, HLP-2 and HLP-6 were found to bind and adopt a beta-strand conformation rather than an alpha-helix, as shown by nonimmobilized ligand interaction assay-CD spectroscopy. Furthermore, this assay was used to show that there is a time-dependent association of peptide that results in an ordered formation of peptide aggregates. The rate of interpeptide association was far greater in HLP-2 LPS than in HLP-6 LPS, which was consistent with the lag phase observed on the killing curves. These results allow us to propose a mechanism by which HLP-2 folds and self-assembles at the outer membrane surface before exerting its activity.
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PMID:Structure and association of human lactoferrin peptides with Escherichia coli lipopolysaccharide. 1515 21

Previous studies have shown that oral treatment with lactoferrin (LF) restores the immune response in cyclophosphamide (CP) immunocompromised mice. The aim of the present investigation was to determine the regulatory ability of LF on the production of interleukin 6 (IL-6) in peritoneal and alveolar cells, derived from CP-treated mice. CBA mice were injected with a single, intraperitoneal (i.p.) dose of CP (350 mg/kg body weight) followed by LF administered in drinking water (0.5% solution) for 21 days. The control counterparts were given water. Peritoneal and alveolar cells were isolated from mice and the production of IL-6, both spontaneous and lipopolysaccharide (LPS) induced, was determined in 24h cell cultures using a bioassay. The results showed increased production of IL-6 in both CP-treated mice and in mice given, in addition, LF. The administration of LF alone led also to an increase in IL-6 production by the cell cultures. Intravenous (i.v.) administration of LPS resulted in a significant increase in IL-6 serum levels in CP and CP/LF but not in LF-treated mice. Analysis of cell type composition in the peritoneal cavity revealed a strong increase in mastocyte and neutrophil content in CP and CP/LF-treated groups. Our findings suggest that enhanced IL-6 production in CP and CP/LF-treated mice may contribute to reconstitution of immune system function in immunocompromised mice.
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PMID:Effects of lactoferrin on IL-6 production by peritoneal and alveolar cells in cyclophosphamide-treated mice. 1521 55

Previous studies on cyclophosphamide (CP)-immunocompromised mice showed accelerated reconstitution of immune system function following oral treatment with lactoferrin (LF). The aim of this investigation was to evaluate the ability of mice, treated with a sublethal dose of CP and given LF, to combat bacterial infections. Mice were injected with a single, intraperitoneal dose of CP (350 mg/kg body weight). One group of CP-treated mice was also given LF in drinking water (0.5% solution) for 14 days. Untreated and LF-treated mice served as controls. On day 15 following CP administration, mice were infected intravenously with 10(8) Escherichia coli or 5 x 10(7) Staphylococcus aureus. Twenty-four hours later, the number of colony-forming units (CFU) in spleens and livers were determined. Phenotypic analysis of blood leukocytes was determined, as well as the ability of splenic and peritoneal cells to produce IL-6 spontaneously and in the presence of lipopolysaccharide (LPS). Treatment with CP, or with CP and LF, led to profound reduction of E. coli CFU in the liver and the spleen; treatment with LF alone had significant inhibitory effects on organ enumerated CFU. S. aureus CFUs were also significantly reduced in spleens of mice treated with CP or CP/LF and, to a lesser degree, after LF alone. These effects were also significantly reduced in the livers. Analysis of blood cellular phenotype revealed total number of peripheral leukocytes was lower in the CP-treated group (52.6%) but not significantly different from control values in CP/LF and LF-treated groups (90.7% and 104.6%, respectively). Conversely, percentage of blood neutrophils was markedly elevated in CP and CP/LF groups--62% and 42.5% vs. 18.4% in controls. These findings were accompanied by production of IL-6 by splenic and peritoneal cells which was significantly increased in CP- and CP/LF-treated groups. It was concluded that the increased clearance of bacteria in the organs of mice treated with CP and CP/LF may result from a rise in the number of neutrophils infiltrating the organs and contributing to accelerated clearance of bacteria. The study also suggests that the ability of cells from CP- and CP/LF-treated mice to produce significantly more IL-6 may also contribute to increased resistance to infections. Lastly, together with our previous data, this study indicates that LF used to reconstitute the antigen-specific immune response in CP-treated mice does not impair their resistance to infection.
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PMID:Enhanced clearance of Escherichia coli and Staphylococcus aureus in mice treated with cyclophosphamide and lactoferrin. 1525 Nov 11

Though lactoferrin (LF) is a glycoprotein that is involved in immunomodulation, its action mechanism has not been fully elucidated. Previous studies have suggested that lipopolysaccharide (LPS) activity is inhibited by direct binding between LPS and LF. However, here we show that when LPS and purified LF was mixed, and formed a complex (termed as LF-LPS), it was found to induce production of inflammatory mediators in macrophages to some extent, rather than inhibit LPS activity. Moreover, when macrophages were pretreated with LF-LPS, cells were rendered a tolerant state to LPS challenge. These macrophage-activating effects were mediated by Toll-like receptor 4 (TLR4)-NF-kappaB pathway. Comparative studies with C3H/HeN and C3H/HeJ mice demonstrated the strong dependency of the LF-LPS signal on TLR4. These findings suggest that the immunomodulatory properties of LF could be due, in part, to LPS binding.
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PMID:Lactoferrin works as a new LPS-binding protein in inflammatory activation of macrophages. 1525 Nov 14

The effect of bovine lactoferrin (Lf) was studied in experimental Escherichia coli mastitis, using enrofloxacin as a comparator. Mastitis was induced in six clinically healthy primiparous dairy cows by infusing 1500 colony-forming units of E. coli into a single udder quarter. The challenge was repeated into a contralateral quarter of the same cows 3 weeks later. At the first challenge, three cows were treated with 1.5 g of bovine lactoferrin intramammarily three times (12, 20 and 36 h postchallenge, PC), and the other three cows received 5 mg/kg of enrofloxacin (Baytril) parenterally (12, 36 and 60 h PC). Flunixin meglumine (2.2 mg/kg) was administered to all cows twice at 24-h intervals. During the second challenge, the treatments for the two groups were reversed. Intramammary challenge with E. coli produced clinical mastitis in all cows, but the severity of the disease varied markedly. No statistically significant differences between treatment groups were observed in clinical signs such as rectal temperature, rumen motility and general attitude. Milk somatic cell count, daily milk yield and bacterial counts in cows treated with Lf and those receiving enrofloxacin also did not differ significantly. However, a trend for a more rapid elimination of bacteria was seen in the cows treated with enrofloxacin. Milk NAGase activity also decreased significantly faster in the group treated with enrofloxacin. The concentration of lipopolysaccharide in milk compared with the number of bacteria was significantly lower in Lf than in enrofloxacin-treated cows (20 h PC).
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PMID:The efficacy of bovine lactoferrin in the treatment of cows with experimentally induced Escherichia coli mastitis. 1530 47

The innate immune system plays a critical role in the defense of areas exposed to microorganisms. There is an increasing body of evidence indicating that antimicrobial peptides and proteins (APs) are one of the most important weapons of this system and that they make up the protective front for the respiratory tract. On the other hand, it is known that pathogenic organisms have developed countermeasures to resist these agents such as reducing the net negative charge of the bacterial membranes. Here we report the characterization of a novel mechanism of resistance to APs that is dependent on the bacterial capsule polysaccharide (CPS). Klebsiella pneumoniae CPS mutant was more sensitive than the wild type to human neutrophil defensin 1, beta-defensin 1, lactoferrin, protamine sulfate, and polymyxin B. K. pneumoniae lipopolysaccharide O antigen did not play an important role in AP resistance, and CPS was the only factor conferring protection against polymyxin B in strains lacking O antigen. In addition, we found a significant correlation between the amount of CPS expressed by a given strain and the resistance to polymyxin B. We also showed that K. pneumoniae CPS mutant bound more polymyxin B than the wild-type strain with a concomitant increased in the self-promoted pathway. Taken together, our results suggest that CPS protects bacteria by limiting the interaction of APs with the surface. Finally, we report that K. pneumoniae increased the amount of CPS and upregulated cps transcription when grown in the presence of polymyxin B and lactoferrin.
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PMID:Capsule polysaccharide mediates bacterial resistance to antimicrobial peptides. 1555 34

Treatment of Gram-negative bacterial infections with antimicrobial agents can cause release of the endotoxin lipopolysaccharide (LPS), the potent initiator of sepsis, which is the major cause of mortality in intensive care units worldwide. Structural information on peptides bound to LPS can lead to the development of more effective endotoxin neutralizers. Short linear antimicrobial and endotoxin-neutralizing peptide LF11, based on the human lactoferrin, binds to LPS, inducing a peptide fold with a "T-shaped" arrangement of a hydrophobic core and two clusters of basic residues that match the distance between the two phosphate groups of LPS. Side chain arrangement of LF11 bound to LPS extends the previously proposed LPS binding pattern, emphasizing the importance of both electrostatic and hydrophobic interactions in a defined geometric arrangement. In anionic micelles, the LF11 forms amphipathic conformation with a smaller hydrophobic core than in LPS, whereas in zwitterionic micelles, the structure is even less defined. Protection of tryptophan fluorescence quenching in the order SDS>LPS>DPC and hydrogen exchange protection indicates the decreasing extent of insertion of the N terminus and potential role of peptide plasticity in differentiation between bacterial and eukaryotic membranes.
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PMID:Structural origin of endotoxin neutralization and antimicrobial activity of a lactoferrin-based peptide. 1568 91

PEP1261, a tetrapeptide derivative used in this study, corresponds to residues 39-42 of human lactoferrin. The parent protein lactoferrin is known to exhibit antinociceptive activity and it regulates many aspects of inflammation. This study is aimed to evaluate the antinociceptive and antipyretic activities of PEP1261 in rats. PEP1261 exhibits a significant dose dependent antinociceptive activity with optimal effect at 40 mg/kg body weight (b.w.) (i.p.) in both tail-flick model and acetic acid induced writhing in rats. PEP1261 at the doses of 20 and 40 mg/kg b.w. (i.p.) is also observed to exhibit notable antipyretic effect in lipopolysaccharide-induced pyrexia in rats. In conclusion, the results suggest that PEP1261 possesses antinociceptive and antipyretic activities better than the control peptide KRDS.
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PMID:Antinociceptive and antipyretic effects of a derivatized tetrapeptide from lactoferrin in rats. 1575 76

The concentration of lactoferrin in bovine milk is dramatically increased in response to infection. The high levels of lactoferrin may have a role in the prevention of microbial infection of the mammary gland. However, molecular mechanisms of how the lactoferrin gene is regulated in the mammary gland in response to infection remain unknown. In this study, we isolated and characterized the 5' flanking region of the bovine lactoferrin gene. An 8.2 kilobase (kb) fragment of the bovine lactoferrin gene, containing 4.4 kb of 5' flanking region, exon 1, intron 1, and exon 2, was isolated from a bovine genomic library on two overlapping bacterial artificial chromosome (BAC) clones. Sequence analysis of the isolated lactoferrin gene revealed that the promoter region contains a high GC content, a non-canonical TATA box, multiple stimulating protein 1 (SP1)/GC elements, and other putative binding sites for transcription factors including nuclear factor-kappaB (NF-kappaB), activator protein 1 (AP1), signal transducer and activator of transcriptions 3 and 5 (STAT3 and STAT5), and steroid hormone receptors. To demonstrate that the isolated promoter is functional, 4.4 kb of 5' flanking region was inserted upstream from the firefly luciferase gene and the chimeric construct was transiently transfected into murine mammary epithelial cells. Transfection studies showed that the basal promoter activity is quite potent, being similar in strength to that of the simian virus 40 (SV40) promoter/enhancer. In addition, a 24-h treatment with Escherichia coli lipopolysaccharide (LPS) significantly stimulated its activity up to 2.3-fold in a dose-dependent manner. Furthermore, promoter deletion analysis indicated that the sequence up to -543 was sufficient for basal activity, whereas the sequence up to -1029 was required for maximal basal activity. The basal activity of the promoter is affected by both positive regulatory regions (-2462/-1879 and -1029/-75) and a negative regulatory region (-1407/-1029). LPS-responsive regions of the promoter were localized to the region from -1029 to -543 containing one STAT3 site and two NF-kappaB sites, and the region from -4355 to -2462 containing three AP1 sites and six NF-kappaB sites. Taken together, our findings suggested that the lactoferrin promoter responds to infection via the NF-kappaB pathway.
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PMID:Characterization of the infection-responsive bovine lactoferrin promoter. 1593 71

Bovine and possum macrophages were infected in vitro with a virulent strain of Mycobacterium bovis, and mycobacterial replication was measured in the infected macrophages cultured under a variety of conditions. Virulent M. bovis replicated substantially in alveolar possum macrophages as well as in bovine blood monocyte-derived macrophages. Addition of recombinant bovine interferon-gamma (IFN-gamma) with low concentrations of lipopolysaccharide (LPS) rendered bovine macrophages significantly more resistant to M. bovis replication. Disruption of iron levels in infected macrophages by addition of apotransferrin or bovine lactoferrin blocked replication of M. bovis in both bovine and possum macrophages. On the other hand, addition of exogenous iron, either in the form of iron citrate or iron-saturated transferrin, rendered macrophages of both species much more permissive for the replication of M. bovis. The impact of iron deprivation/loading on the mycobacteriostatic activity of cells was independent of nitric-oxide release, as well as independent of the generation of oxygen radical species in both possum and bovine macrophages. Exogenous iron was shown to reverse the ability of IFN-gamma/LPS pulsed bovine macrophages to restrict M. bovis replication. When autologous possum lymphocytes from animals vaccinated with M. bovis strain BCG were added to infected macrophages, they rendered the macrophages less permissive for virulent M. bovis replication. Loading the cells with iron prior to this macrophage-lymphocyte interaction, reversed this immune effect induced by sensitized cells. We conclude that, in two important animal species, intracellular iron level plays an important role in M. bovis replication in macrophages, irrespective of their activation status.
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PMID:Iron modulates the replication of virulent Mycobacterium bovis in resting and activated bovine and possum macrophages. 1599 92


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