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)

Macrophage inflammatory and immune functions were characterised in red deer (cervus elaphus), for use as a model for natural infection with bovine tuberculosis. Highly enriched populations of deer macrophages were obtained from 14 day cultures of plastic-adherent peripheral blood mononuclear cells. Cervine macrophages produced superoxide anion in response to respiratory burst stimuli (serum-opsonised zymosan and phorbol myristic acetate), but nitric oxide production could not be detected under the conditions tested. The lysosomal enzymes acid phosphatase and lysozyme were detected at the intercellular and extracellular level. Stimulation with bacterial lipopolysaccharide extract (Escherichia coli LPS) enhanced the production of superoxide and acid phosphatase with a peak increase in activity observed after 2h. Production of interleukin 1 (IL-1) and tumour necrosis factor (TNF), determined using cytokine-sensitive cell lines and mRNA analysis (Northern blotting), indicated maximal secretion of both cytokines after 24 h stimulation with LPS, preceded by a peak in message accumulation at 2-6 h post-stimulation. Cervine macrophages stimulated proliferative responses in T cell-enriched lymphocyte populations derived from the peripheral blood of autologous animals that had been primed to mycobacterial antigens (Mycobacterium bovis Bacille Calmette-Guerin, BCG). Macrophages were able to stimulate responses after pulsing with particulate (BCG) or soluble (purified protein derivative) mycobacterial antigens. These results indicate that macrophage inflammatory and immune responses in red deer are similar to those in other mammalian species, and that macrophages may play an important role in resistance to mycobacterial infection.
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PMID:Macrophage function in deer. 867 37

1. The effects of the selective and potent novel platelet-activating factor (PAF) antagonist, UR-12633 (1-(3,3-diphenylpropionyl)-4-(3-pyridylcyanomethyl)piperidin e) on several markers of endotoxic shock syndrome were evaluated in rats and mice. 2. UR-12633, administered 60 min after E. coli lipopolysaccharide (LPS), reversed the LPS-induced sustained hypotension in rats at doses of 0.01 to 1 mg kg-1, i.v. The reference compound WEB-2086 (1 mg kg-1) also reversed the LPS-induced hypotension. UR-12633 (1 mg kg-1), administered 10 min before LPS, almost fully inhibited sustained hypotension. The immediate hypotension (within 1 min) caused by LPS was not prevented by either UR-12633 or WEB-2086. 3. Pretreatment with 10 mg kg-1, i.v. of either UR-12633 or WEB-2086 inhibited the increase in disseminated intravascular coagulation markers, such as activated partial thromboplastin time (55 and 74% inhibition, respectively), and prothrombin time (22 and 72% inhibition) and prevented the decrease in plasma fibrinogen content (100 and 29% inhibition). 4. Increases in acid phosphatase (ACP) plasma activity, a marker of lysosomal activation, and in lactate dehydrogenase (LDH), a marker of tissue damage, were inhibited by pretreatment with 10 mg kg-1, i.v. of either UR-12633 or WEB-2086 (100% and 69% inhibition, ACP; 62 and 48% inhibition, LDH). Hyperglycaemia (71 and 46%) and hyperlactacidaemia (92 and 56%) were also inhibited. 5. UR-12633, but not WEB-2086, inhibited the LPS-induced increase in vascular permeability in rats, as shown by prevention of haemoconcentration and, to a lesser degree, the increase in Evans blue dye extravasation. 6. In a series of nine reference compounds and UR-12633, we found a high correlation (P < 0.001) between PAF antagonist activity, measured as the inhibition of PAF-induced rabbit platelet aggregation or PAF-induced mortality in mice and the inhibition of LPS-induced mortality. 7. In spite of the multifactorial nature of endotoxic shock, in which many mediators may be involved, the new potent PAF antagonist, UR-12633, proved effective in protecting against changes in most shock markers. These data strongly suggest a key role for PAF in the pathogenesis of endotoxic shock in rodents.
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PMID:Effects of UR-12633, a new antagonist of platelet-activating factor, in rodent models of endotoxic shock. 881 47

1. During in vitro culture in 10% human AB serum, human peripheral blood monocytes acquire a macrophage-like phenotype. The underlying differentiation was characterized by increased activities of the macrophage marker enzymes unspecific esterase (NaF-insensitive form) and acid phosphatase, as well as by a down-regulation in surface CD14 expression. 2. In parallel, a dramatic change in the phosphodiesterase (PDE) profile became evident within a few days that strongly resembled that previously described for human alveolar macrophages. Whereas PDE1 and PDE3 activities were augmented, PDE4 activity, which represented the major cyclic AMP-hydrolysing activity of peripheral blood monocytes, rapidly declined. 3. Monocytes and monocyte-derived macrophages responded to lipopolysaccharide (LPS) with the release of tumour necrosis factor-alpha (TNF). In line with the change in CD14 expression, the EC50 value of LPS for induction of TNF release increased from approximately 0.1 ng ml-1 in peripheral blood monocytes to about 2 ng ml-1 in macrophages. 4. Both populations of cells were equally susceptible towards inhibition of TNF release by cyclic AMP elevating agents such as dibutyryl cyclic AMP, prostaglandin E2 (PGE2) or forskolin, which all led to a complete abrogation of TNF production in a concentration-dependent manner and which were more efficient than the glucocorticoid dexamethasone. 5. In monocytes, PDE4 selective inhibitors (rolipram, RP73401) suppressed TNF formation by 80%, whereas motapizone, a PDE3 selective compound, exerted a comparatively weak effect (10-15% inhibition). Combined use of PDE3 plus PDE4 inhibitors resulted in an additive effect and fully abrogated LPS-induced TNF release as did the mixed PDE3/4 inhibitor tolafentrine. 6. In monocyte-derived macrophages, neither PDE3- nor PDE4-selective drugs markedly affected TNF generation when used alone (< 15% inhibition), whereas in combination, they led to a maximal inhibition of TNF formation by about 40-50%. However, in the presence of PGE2 (10 nM), motapizone and rolipram or RP73401 were equally effective and blocked TNF release by 40%. Tolafentrine or motapizone in the presence of either PDE4 inhibitor, completely abrogated TNF formation in the presence of PGE2. Thus, an additional cyclic AMP trigger is necessary for PDE inhibitors to become effective in macrophages. 7. Finally, the putative regulatory role for PDE1 in the regulation of TNF production in macrophages was investigated. Zaprinast, at a concentration showing 80% inhibition of PDE1 activity (100 micromol l-1), did not influence TNF release. At higher concentrations (1 mmol l-1), zaprinast became effective, but this inhibition of TNF release can be attributed to a significant inhibitory action of this drug on PDE3 and PDE4 isoenzymes. 8. In summary, the in vitro differentiation of human peripheral blood monocytes to macrophages is characterized by a profound change in the PDE isoenzyme pattern. The change in the PDE4 to PDE3 ratio is functionally reflected by an altered susceptibility towards selective PDE inhibitors under appropriate stimulating conditions.
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PMID:In vitro differentiation of human monocytes to macrophages: change of PDE profile and its relationship to suppression of tumour necrosis factor-alpha release by PDE inhibitors. 915 31

A crude polysaccharide fraction (DAP-1) was prepared from roots of Dipsacus asperoides by hot water extraction and EtOH precipitation, and tested for anti-complementary activity, mitogenic activity of lymphocytes, and effects on acid phosphatase and phagocytic activities of macrophages. DAP-1 showed not only anti-complementary activity but also a stimulating effect on the mitogenic activity of lymphocytes. DAP-1 also significantly suppressed the phagocytic activity of macrophages. Although DAP-1 directly stimulated the mitogenecity of lymphocytes, it had no effect on lipopolysaccharide- or concanavalin A-induced mitogenic activity of lymphocytes. Periodate oxidation and pronase digestion suggested that the polysaccharide moiety in DAP-1 contributed to the expression of its anti-complementary and mitogenic activities and that the protein moiety in DAP-1 was responsible for its effect on phagocytosis. DAP-1 gave three polysaccharide fractions (DAP-2, 3, and 4) by fractionation using cetyltrimethylammonium bromide. All the fractions had potent anti-complementary activity, but showed different stimulating or suppressive effects on the proliferation of lymphocytes, phagocytosis, or acid phosphatase activity. Three potent anti-complementary polysaccharides (DAP-4I-1a, DAP-4I-1b, and DAP-4IIa-1) were purified from DAP-4 by anion-exchange chromatography, gel filtration, and HPLC. DAP-4I-1a, I-1b, and IIa-1 consisted of Ara, Rha, Xyl, Gal, Glc and GlcA in a molar ratio of 1.0:0.7:1.0:18.6:22.2:nil; 1.0:0.1:0.3:19.3:26.8:nil; and 3.7:trace:0.6:26.3:5.5:1.0; respectively. Among the polysaccharides, only DAP-4IIa-1 reacted with beta-glucosyl-Yariv antigen. Methylation analysis indicated that DAP-4I-1a mainly comprised 4-linked Gal and 3-, 4-, and 6-linked Glc, whereas DAP-4IIa-1 consisted mainly of terminal Araf, 3-linked Glc, and 3,6-branched Gal.
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PMID:Fractionation and chemical properties of immunomodulating polysaccharides from roots of Dipsacus asperoides. 934 40

We have established a cell line cloned from primary-cultured microglia obtained from p53-deficient mice. The cell line, MG5, could be grown in astrocyte-conditioned medium and has been maintained for more than a year. MG5 cells are immunocytochemically positive for Mac-1 and F4/80 antibody and express the major histocompatibility complex (MHC) class I antigen, leukocyte function-associated antigen-1, leukocyte common antigen, and intercellular adhesion molecular-1 mRNA. Interferon-gamma enhanced the expression of MHC class II antigen mRNA in MG5 cells. We previously identified a novel calcium-binding protein, Iba1 (ionized calcium-binding adapter molecule 1), which is highly and specifically expressed in cultured microglia. Iba1 protein was also immunocytochemically demonstrated in MG5 cells. The cells retained non-specific esterase activity, 5'-nucleotidase activity, acid phosphatase activity, and phagocytic ability. Like primary cultured microglia from wild-type mice, MG5 cells released nitric oxide in response to lipopolysaccharide, and actively proliferated in the presence of mitogenic factors such as macrophage-colony stimulating factor (M-CSF), granulocyte/macrophage-CSF (GM-CSF), and interleukin-3 (IL-3). Tyrosine-phosphorylation of M-CSF receptor in MG5 cells was induced by the addition of M-CSF or astrocyte-conditioned medium. These findings indicate that MG5 cells preserve the morphological, biochemical, and physiological properties of primary-cultured microglia well. The MG5 cell line will be a useful tool for studying microglial function.
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PMID:Generation and characterization of a microglial cell line, MG5, derived from a p53-deficient mouse. 938 38

The effect of genistein on bone resorption in vitro was investigated. Femoral-metaphyseal tissues obtained from elderly female rats were cultured for 48 hr in Dulbecco's modified Eagle's medium (high glucose, 4.5%) supplemented with antibiotics and bovine serum albumin. The experimental cultures contained 10(-7) to 10(-3) M genistein. The bone-resorbing factors parathyroid hormone (1-34) (PTH; 10(-7) M), prostaglandin E2 (PGE2; 10(-5) M), and lipopolysaccharide ( 10 microg/mL) caused a significant decrease in bone calcium content. The decrease in bone calcium content induced by bone-resorbing factors was inhibited completely by genistein (10(-7) to 10(-5) M). In addition, this isoflavonoid (10(-5) M) completely inhibited the PTH (10(-7) M)- or PGE2 (10(-5) M)-induced increase in medium glucose consumption and lactic acid production by bone tissues. Moreover, genistein (10(-5) M) blocked both PTH (10(-7) M)-increased acid phosphatase and -decreased alkaline phosphatase activities of bone tissues. The inhibitory effect of genistein (10(-5) M) on PTH (10(-7) M)-stimulated bone resorption was clearly prevented by the presence of 10(-6) M tamoxifen, an anti-estrogen reagent. Genistein (10(-5) M) did not further enhance the inhibitory effect of estrogen (10(-9) M) on PTH-stimulated bone resorption. These findings indicate that genistein has a direct inhibitory effect on bone resorption in tissue culture in vitro.
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PMID:Inhibitory effect of genistein on bone resorption in tissue culture. 941 32

UR-12670 is a novel and potent PAF antagonist, eg., it displaces [3H]WEB-2086 from PAF receptors in rabbit platelet membranes (Ki = 0.6 nM) and inhibits PAF-induced increase in vascular permeability in rat trachea (100%), thymus (44%), seminal vesicles (100%) and stomach (54%) at a dose of 0.01 mg/kg i.v. Since PAF is thought to be an important mediator in endotoxic shock, the effect of pretreatment with UR-12670 on changes in vascular permeability, disseminated intravascular coagulation (DIC) and plasma biochemical parameters were determined in a rat model of acute endotoxemia. UR-12670 and the reference PAF antagonist, lexipafant (10 mg/kg i.v.), strongly inhibited lipopolysaccharide (LPS, 25 mg/kg i.v.)-induced plasma leakage in the trachea (49 and 100%, respectively) and seminal vesicles (81 and 100%), as assessed by the Evans blue extravasation method. Only lexipafant inhibited the increase in vascular permeability in the thymus (36%). Neither PAF antagonist was effective in the stomach. Both UR-12670 and lexipafant at 10 mg/kg i.v. attenuated the LPS-induced variation of some DIC markers, such as activated partial thromboplastin time increase (56 and 58%, respectively) and the fibrinogen concentration decrease (53 and 31%), whereas the increase in prothrombin time was not affected. Increased plasma acid phosphatase (ACP, a lysosomal activation marker) and lactate dehydrogenase (LDH, a tissue damage marker) activity elicited by LPS was attenuated by pretreatment with 10 mg/kg i.v. of either UR-12670 or lexipafant (ACP: 55 and 48%; LDH: 50 and 33%). LPS-induced hyperglycemia (46 and 37%) and hyperlactacidemia (100% both) were also inhibited. UR-12670 protected against several shock symptoms, confirming the role of PAF in the pathogenesis of rodent endotoxemia.
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PMID:Effects of a new platelet-activating factor antagonist, UR-12670, on several endotoxic shock markers in rats. 951 29

Tilmicosin is a semi-synthetic macrolide antibiotic, currently approved for veterinary use in cattle and swine respiratory disease. As the concentrations of tilmicosin are generally low in swine lung tissue, the interaction of tilmicosin with three types of swine phagocytes (monocyte-macrophages, alveolar macrophages, and neutrophils) was evaluated to provide an understanding of clinical efficacy. After incubation with radiolabelled tilmicosin, uptake was determined and expressed as the ratio of the intracellular (Ci) to the extracellular (Ce) drug concentration (Ci/Ce). Tilmicosin was avidly accumulated by the swine phagocytes (Ci/Ce 48-69 at 4 h incubation) with 51 to 85% localized in the lysosomes. Uptake was dependent on cell viability, temperature and pH, but was not influenced by the metabolic inhibitors, sodium cyanide or potassium fluoride. However, lipopolysaccharide (LPS) exposure increased tilmicosin uptake by the swine phagocytes. In neutrophils, upon removal of extracellular tilmicosin, 60% of the intracellular tilmicosin was effluxed within the first 30 min, but after 4 h of incubation in drug-free medium, 25% remained cell-associated. In contrast, after 4 h of incubation in drug-free medium, 60% and 45% of tilmicosin remained cell-associated, within alveolar macrophages and monocyte-derived macrophages, respectively. Tilmicosin uptake was observed to increase lysosomal enzyme (acid phosphatase, lysozyme and beta-glucuronidase) production. Finally, neutrophils were shown to transport and efflux bioactive tilmicosin in a test system measuring both neutrophil chemotaxis under agarose and a bioassay measuring inhibition of bacterial growth in the presence of antibiotic in agar. These in vitro interactions of tilmicosin with swine phagocytes suggest an integral role in effecting clinical efficacy.
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PMID:Intracellular accumulation, subcellular distribution and efflux of tilmicosin in swine phagocytes. 973 47

Administration of lipopolysaccharide (LPS) at 3 mg/kg, i.p. in rats resulted in reduced food intake, febrile hyperthermia, decreased body weight and reduced muscle performance in treadmill tests. It also induced some biochemical changes like increased serum levels of transaminases, acid phosphatase, pseudocholinesterase, free fatty acids and decreased blood glucose and liver glycogen levels. Rhinax (RHX), a herbal formulation, at 160 mg/kg, p.o. improved muscle performance but had no effect on the elevated temperature or the reduced body weight of rats weakened by LPS. It also normalised various biochemical alterations induced by LPS. The results of these studies indicate efficacy of RHX as an antifatigue agent to improve muscular performance.
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PMID:Effect of rhinax on bacterial lipopolysaccharide induced endotoxemia in rats. 975 66

Although the physiological role of neurotrophins in neuronal development and survival has been extensively investigated, their role in glial cell physiology remains to be elucidated. In the present study, we investigated the effects of neurotrophins on cultured microglia from newborn rat brain. All of the neurotrophins tested nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4), increased the secretion of plasminogen and urokinase type-plasminogen activator and specific activity of acid phosphatase, but suppressed the release of constitutively-produced and lipopolysaccharide-stimulated nitric oxide (NO) from microglia. The reverse transcription-polymerase chain reaction, immunocytochemical staining, and Western blotting revealed that cultured microglia express Trk A, B, and C, and low-affinity NGF receptor, LNGFRp75. Neurotrophin was found to phosphorylate Trk A and B, and the neurotrophin-induced enhancement of plasminogen-secretion was suppressed by protein kinase inhibitor, K252a. Furthermore, neurotrophins caused an activation of transcription factor, NF-kappaB. These results indicate that the neurotrophin family regulate the function of microglia through Trk and/or LNGFRp75-mediated signal transduction.
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PMID:Neurotrophins regulate the function of cultured microglia. 977 79


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