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)

Epidemiological studies have shown an increased incidence of coronary artery disease in patients with chronic infections and inflammatory disorders. Because oxidative modification of lipoproteins plays a major role in atherosclerosis, the present study was designed to test the hypothesis that the host response to infection and inflammation induces lipoprotein oxidation in vivo. Lipoprotein oxidation was measured in 3 distinct models of infection and inflammation. Syrian hamsters were injected with bacterial lipopolysaccharide (LPS), zymosan, or turpentine to mimic acute infection, acute systemic inflammation, and acute localized inflammation, respectively. Levels of oxidized fatty acids in serum and lipoprotein fractions were measured by determining levels of conjugated dienes, thiobarbituric acid-reactive substances, and lipid hydroperoxides. Our results demonstrate a significant increase in conjugated dienes and thiobarbituric acid-reactive substances in serum in all 3 models. Moreover, LPS and zymosan produced a 4-fold to 6-fold increase in conjugated diene and lipid hydroperoxide levels in LDL fraction. LPS also produced a 17-fold increase in LDL content of lysophosphatidylcholine that is formed during the oxidative modification of LDL. Finally, LDL isolated from animals treated with LPS was significantly more susceptible to ex vivo oxidation with copper than LDL isolated from saline-treated animals, and a 3-fold decrease occurred in the lag phase of oxidation. These results demonstrate that the host response to infection and inflammation increases oxidized lipids in serum and induces LDL oxidation in vivo. Increased LDL oxidation during infection and inflammation may promote atherogenesis and could be a mechanism for increased incidence of coronary artery disease in patients with chronic infections and inflammatory disorders.
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PMID:Infection and inflammation induce LDL oxidation in vivo. 1084 52

Dopamine-beta-hydroxylase (DbetaH) is a copper-containing enzyme that uses molecular oxygen and ascorbate to catalyze the addition of a hydroxyl group on the beta-carbon of dopamine to form norepinephrine. While norepinephrine causes vasoconstriction following reflex sympathetic stimulation, nitric oxide (NO) formation results in vasodilatation via a guanylyl cyclase-dependent mechanism. In this report, we investigated the relationship between NO and DbetaH enzymatic activity. In the initial in vitro experiments, the activity of purified DbetaH was inhibited by the NO donor, diethylamine/NO (DEA/NO), with an IC(50) of 1 mm. The inclusion of either azide or GSH partially restored DbetaH activity, suggesting the involvement of the reactive nitrogen oxide species, N(2)O(3). Treatment of human neuroblastoma cells (SK-N-MC) with diethylamine/NO decreased cellular DbetaH activity without affecting their growth rate and was augmented by the depletion of intracellular GSH. Co-culture of the SK-N-MC cells with interferon-gamma and lipopolysaccharide-activated macrophages, which release NO, also reduced the DbetaH activity in the neuroblastoma cells. Our results are consistent with the hypothesis that nitrosative stress, mediated by N(2)O(3), can result in the inhibition of norepinephrine biosynthesis and may contribute to the regulation of neurotransmission and vasodilatation.
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PMID:Inhibitory effects of nitric oxide and nitrosative stress on dopamine-beta-hydroxylase. 1088 4

Copper (Cu) deficiency suppresses macrophage activities in animals and humans. Our previous studies indicated that the induction of Cu deficiency in differentiated U937 monocytic cells impairs respiratory burst and bactericidal activities and lipopolysaccharide-mediated secretion of inflammatory mediators. The current investigation examined the roles of Cu in the monocytic differentiation process. Human U937 promonocytic cells were exposed to a high affinity Cu chelator (5 microM 2,3,2-tetraamine [tet]) for 24 hr before inducing differentiation by treatment with 1,25-dihydroxyvitamin D3 plus interferon-gamma (DI). This procedure decreased cell Cu by 55% without compromising cellular Zn, Fe, or general metabolic activities. Lower Cu status significantly attenuated the expression of maturation markers Mac-1 (CD11b), ICAM-1 (CD54), and LPS-R (CD14). This change was associated with a marked suppression in respiratory burst activity and killing of Salmonella. To examine if the adverse effect of inadequate Cu on the DI-induced differentiation represented a more general defect, U937 cells were treated with phorbol 12-myristate 13-acetate (PMA). Lower Cu status also suppressed PMA-mediated differentiation of U937 cells. Supplemental Cu, but not Zn or Fe, blocked the tet-induced declines in cell Cu, expression of maturation markers, and respiratory burst and bactericidal activities. These results demonstrate that Cu is essential for the monocytic differentiation process that contributes to the competency of the host's defense system.
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PMID:Differentiation of human U937 promonocytic cells is impaired by moderate copper deficiency. 1136 Oct 41

2-Mercaptomethyl-4-(4-methylphenyl)-4-oxobutanoic acid (KE-758), which is the active metabolite of 2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid (KE-298), is a novel sulphydryl anti-rheumatic drug. In this study we analyzed the effect of KE-758 on the proliferation of murine lymphocytes, and on the production of nitric oxide (NO) by RAW264.7 murine macrophage cells. We compared its effect with other sulphydryl drugs such as D-penicillamine, bucillamine and auranofin. The proliferation of lymphocytes was measured by 3H-thymidine incorporation assay. Nitrite was measured using Griess Reagent. In the absence of copper ions, KE-758, D-penicillamine and bucillamine rarely affected the proliferation of concanavarin A (ConA) activated murine splenocytes. However, in the presence of copper, pharmacological concentrations of KE-758 but not D-penicillamine and bucillamine suppressed the proliferation of murine splenocytes through a hydrogen peroxide-dependent mechanism. Auranofin markedly suppressed the proliferation regardless of the presence of copper ions by reducing the cellular viability. Furthermore, only KE-758 markedly suppressed the proliferation of phorbol myristate acetate (PMA) plus ionomycin activated murine whole blood lymphocytes (WBL) even in the absence of exogenous copper ions by a hydrogen peroxide-independent mechanism. Meanwhile, lipopolysaccharide (LPS) or LPS plus interferon-gamma (IFN-gamma) induced NO production by RAW264.7 cells were suppressed by KE-758 and auranofin but not by D-penicillamine and bucillamine. In conclusion, KE-758 is a novel immunosuppressive drug, which inhibits both lymphocyte and macrophage functions and its unique anti-rheumatic profile is distinct from that of D-penicillamine, bucillamine and auranofin.
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PMID:Effects of KE-758; an active metabolite of the new anti-rheumatic drug KE-298, D-penicillamine, bucillamine and auranofin on the proliferation of murine lymphocytes, and the production of nitric oxide by murine macrophages. 1137 39

We used cDNA arrays to investigate differentially expressed genes in astrocytes challenged with lipopolysaccharide (LPS). Astrocyte cultures were prepared from 1-day-old rat brains. Purified astrocytes were treated with LPS (1 microg/ml) for 2, 8 and 48 h. Differentially expressed genes in these astrocytes were examined with Atlas rat cDNA arrays. At all the three time points studied, three genes were found consistently up-regulated: I-kappaB alpha chain, NF-kappaB, and interferon induced protein. In addition to these three, six other genes were also up-regulated at 2 and 8 h. They were genes encoding vascular cell adhesion protein 1 (VCAM-1), interferon regulatory factor 1 (IRF-1), mitochondrial hydroxymethylglutaryl-CoA synthase (HMG-CoA synthase), aldehyde dehydrogenase 2, macrophage inflammatory protein 1 (MIP-1) and neurotensin receptor 2. At these two time points, three genes were down-regulated: copper-zinc-containing superoxide dismutase 1 (SOD-1), insulin-like growth factor binding protein 1 (IGFBP-1), and insulin-like growth factor binding protein 3 (IGFBP-3). Expression of several differentially expressed genes in cDNA array (I-kappaB, VCAM-1 and MIP-3) were further confirmed by reverse transcription polymerase chain reaction study. The prominently modulated genes could be classified into three categories: nuclear transcription factors, pro-inflammatory cytokines/chemokines and metabolic enzymes. Application of pyrrolidine dithiocarbamate, an inhibitor of nuclear factor-kB (NF-kappaB), prior to LPS stimulation not only prevented up-regulation of NF-kappaB gene expression, but also completely blocked up-regulation of pro-inflammatory cytokine genes (TNF-alpha and interleukin-1beta) and two chemokine genes: CXC chemokine LIX and CC chemokine MIP-3 alpha. These results indicate that both up-regulation of inflammatory cytokine expression and down-regulation of growth factor expression are probably involved in the response of astrocytes upon exposure to LPS.
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PMID:Analysis of genes differentially expressed in astrocytes stimulated with lipopolysaccharide using cDNA arrays. 1157 93

Chylomicrons play a role in atherosclerosis, however, because the mechanisms involved in the cell uptake of these particles are not fully understood, investigations were carried out using a radioactively labeled protein-free triacylglycerol-rich emulsion incubated with peritoneal macrophages obtained from normal and apoE-knockout mice. Experiments were done in the presence of substances that inhibit several endocytic processes: EDTA for low density lipoprotein receptor, fucoidan for scavenger receptor, cytochalasin B for phagocytosis, and a lipopolysaccharide for lipoprotein lipase. In addition, triacylglycerol-rich emulsions were also prepared in the presence of native or modified radioactively labeled low density lipoprotein particles that are known to accumulate in the arterial intima. Probucol was also used to prevent the possible role played by an antioxidant in triacylglycerol-rich emulsion uptake. We have shown that triacylglycerol-rich emulsion alone is taken up by a coated-pit-dependent mechanism, mediated by macrophage secretion of apolipoprotein E. Furthermore, native, aggregated, acetylated, and moderately macrophage-oxidized low density lipoprotein stimulate the uptake of a triacylglycerol-rich emulsion through several mechanisms such as an actin-dependent pathway, scavenger receptors, and lipolysis mediated by lipoprotein lipase. On the other hand, in spite of the interaction of low density lipoprotein forms with a triacylglycerol-rich emulsion, the cellular triacylglycerol-rich emulsion uptake is impaired by copper-oxidized low density lipoprotein, possibly due to its diminished affinity towards lipoprotein lipase. We have also shown that macrophages take up aggregated low density lipoprotein better than the acetylated or oxidized forms of low density lipoprotein.
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PMID:Macrophages take up triacylglycerol-rich emulsions at a faster rate upon co-incubation with native and modified LDL: An investigation on the role of natural chylomicrons in atherosclerosis. 1178 60

We have previously shown that iron-containing human lactoferrin (LF) purified from breast milk is able to form both in vitro and in vivo a complex with ceruloplasmin (CP), the copper-containing protein of human plasma. Here we present evidence that the CP-LF complex is dissociated by high concentrations of NaCl, CaCl2, or EDTA, or by decreasing the pH to 4.7. In addition, DNA, bacterial lipopolysaccharide, and heparin can displace CP from its complex with LF. Antibodies to either of the two proteins also cause dissociation of the complex.
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PMID:Studies of the ceruloplasmin-lactoferrin complex. 1190 41

The mechanisms by which lipopolysaccharide (LPS) activates cells have been the subject of intense investigation for many years. Whereas much information on this process has been collected for mammalian species, little is known about the signalling path-ways operative in other animals. One general mode of cellular activation that has been recently pro-posed for pathways independent of the primary mammalian LPS receptor, CD14, involves reactive oxygen species (ROS) as intermediates in LPS-induced signalling pathways. Therefore, we used 2',7'-dichlorodihydrofluorescein, a fluorogenic probe of redox activity, to examine LPS-induced oxidative responses of a macrophage-like cell line from the rainbow trout, RTS11. Lipopolysaccharide dose-dependently increased oxidation of this probe by RTS11 cells, and a variety of other cell lines. This process was inhibited by catalase, superoxide dismutase and NG-methylarginine citrate, an inhibitor of nitric oxide synthases, suggesting the involvement of a diverse assortment of cellular ROS. More careful dissection of this phenomenon led us to conclude that the increase in oxidation was, in fact, due almost entirely to metals, particularly copper, in some LPS preparations, which is something to consider when experimenting with LPS.
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PMID:Redox-active metals in commercial preparations of lipopolysaccharide: implications for studies of cellular responses to bacterial products. 1267 81

Intravenous administration of copper (up to a final concentration of ca. 35 micromol/l in the plasma) led to a progressive, dramatic fall of mean arterial pressure in rats. Copper-induced pressure changes were comparable to those elicited by 2 mg/kg LPS, and were greatly prevented by previous infusion of the inducible NOS (NOS-II) inhibitors aminoguanidine or l-N(6)-(L-imino-ethyl)lysine. RT-PCR analysis showed a significant transcriptional induction of NOS-II in a number of tissues, including aorta, liver, and lungs. Immunohistochemistry revealed that NOS-II was massively synthesized in these tissues upon copper or LPS treatment. The protein was active, as revealed by enzymatic assays on lung homogenates and by the large increase of nitrite/nitrate levels in the plasma. Copper-challenged rats displayed elevated plasma levels of TNFalpha. Extensive formation of nitrotyrosines, indicative of peroxynitrite production, was accompanied by marked morphological changes in examined tissues. Our results clearly show that copper can act as a proinflammatory agent through activation of the nitric oxide pathway, leading to the same pathological frame induced by bacterial lipopolysaccharide.
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PMID:Copper induces type II nitric oxide synthase in vivo. 1272 13

Soil, water, and amphibian tissues collected between 1995 and 1999 from 15 study sites in Bermuda were analysed for pesticides and heavy metals. The most abundant pesticide residue in soil was p,p'-dichlorodiphenyldichloroethylene (DDE) which was found at all sites in concentrations ranging from 0.003 to 4.023 p.p.m. No pesticide residues were found in water. DDE was also recovered from the livers and fat bodies of marine toads (Bufo marinus) and whistling frogs (Eleutherodactylus johnstonei). Analyses of food sources consumed by these anuran species revealed residue levels of p, p'-DDE ranging from 0.05 to 0.217 p.p.m. Other soil residues included dichlorodiphenyltrichloroethane (DDT) at eight study sites, Dicofol(kelthane) at eight sites, dieldrin at five sites, and polychlorinated biphenyls (PCBs) as Arochlor 1254 and Arochlor 1260 at seven sites. Analyses of toad livers revealed significant concentrations of cadmium, chromium, copper and zinc. Livers of Bermuda toads exhibited altered hepatocytic morphology and an increased number of melanomacrophages and possible granulomas, while spleens showed a marked decrease in white pulp. Spleen cells from Bufo marinus collected at one site having high levels of cadmium exhibited a decreased B cell response to lipopolysaccharide. The incidence of trematode infection in Bufo marinus increased from 53.8% in 1995 to 90% in 1999. Deformity rates in the limbs of subadult and adult toads ranged between 15 and 25%. Examination of 1,995 newly-metamorphosed toads revealed deformity rates as high as 47%. The current comprehensive study suggests that environmental pollutants may account for immunosuppression, increased susceptibility to infections, limb malformations and possible decline in amphibian populations from Bermuda.
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PMID:Role of environmental pollutants on immune functions, parasitic infections and limb malformations in marine toads and whistling frogs from Bermuda. 1274 35


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