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)

When monocytes are activated with endotoxin (lipopolysaccharide [LPS]), they make and release several mediators, including interleukin-1 beta (IL-1 beta). This study was undertaken to investigate the role of glucose in IL-1 beta production by these cells. IL-1 beta was produced in a dose-dependent manner to glucose concentration in the culture medium. The uptake of (3H)2-deoxyglucose in monocytes was stimulated by LPS 1,554% after 10 minutes, 6,095% after 2 hours, then gradually declined after 4 hours of incubation. The inhibition of the uptake of (3H)2-deoxyglucose by either 10 microM cytochalasin B or phloretin, added at the time of monocyte activation, was accompanied by significant reduction in ATP/ADP ratio and the inhibition of the production of IL-1 beta by activated monocytes. The synthesis of total protein did not change in monocytes activated in the absence of glucose in the culture medium, nor in the presence of either 10 microM cytochalasin B or phloretin. The export of IL-1 beta from LPS-activated monocytes was not inhibited by either 10 microM cytochalasin B or phloretin, nor in the absence of glucose in the culture medium. These data suggest that 1) glucose is required for LPS-induced IL-1 beta production by monocytes; 2) glucose is the major source of ATP for IL-1 beta production; 3) glucose transporter (GLUT 1) does not control the export of IL-1 beta.
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PMID:Role of glucose in interleukin-1 beta production by lipopolysaccharide-activated human monocytes. 840 38

Hypoglycemia is among the most injurious metabolic disorders caused by endotoxemia. In experimental endotoxemia with lipopolysaccharide (LPS) in animals, a marked glucose consumption is observed in macrophage-rich organs. However, the direct effect of LPS on the uptake of glucose by macrophages has not been fully understood, and the present study was undertaken to shed light on this point. The consumption and uptake of glucose, as measured with 2-deoxy-D-[3H]glucose, by murine peritoneal exudate macrophages in culture were accelerated two- to threefold by stimulation with 3 ng of LPS per ml. The rate of glucose uptake reached a plateau after 20 min of stimulation and remained at the maximum as long as LPS was present. Northern (RNA) blot analysis with cDNA probes for five known isoforms of glucose transporter (GLUT) revealed that the expression of GLUT by macrophages was restricted to the GLUT1 isoform during LPS stimulation and the amount of GLUT1 mRNA was increased by the stimulation. These results suggest that macrophage responses to LPS are supported by a rapid and sustained glucose influx via GLUT1 and that this is a participating factor in the development of systemic hypoglycemia when endotoxemia is prolonged.
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PMID:Endotoxin-induced enhancement of glucose influx into murine peritoneal macrophages via GLUT1. 855 27

The role of nitric oxide in the alterations of liver carbohydrate metabolism during septic shock has been studied in fed and starved animals injected with bacterial lipopolysaccharide (LPS). One h after LPS injection an hyperglycemic peak was observed followed by hypoglycemia when the plasma nitric oxide concentration increased. However, in animals pharmacologically treated with nitric oxide donors only hypoglycemia was observed. In isolated hepatocytes from LPS treated rats an impairment of the gluconeogenic flux was observed accompanied by a decrease in the mRNA levels of the glucose transporter GLUT-2 and phosphoenolpyruvate carboxykinase, at the time that increased the mRNA levels of the inducible form of nitric oxide synthase. These results suggest that part of the effects observed in response to LPS challenge are due to early signaling molecules (cytokines and other factors molecules) whereas other effects can be attributed to nitric oxide synthesis which in turn has specific effects on hepatic metabolism.
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PMID:Characterization of nitric oxide dependent changes in carbohydrate hepatic metabolism during septic shock. 863 9

Glucose is the primary metabolic substrate of macrophages, which are critical components of the host response to injury and infection. We have carried out a series of studies to examine macrophage glucose uptake and the status of glucose transporter 1 (GLUT1) at both the mRNA and protein level. Peritoneal macrophages that were obtained from mice undergoing sham burned (S), 15%TBSA burn (B) +/- Pseudomonas aeruginosa burn infection (B + I) and lipopolysaccharide (LPS) or tumor necrosis factor-alpha (TNF-alpha) administration. [3H]deoxyglucose uptake was significantly increased (B, 157 +/- 9%; B + I, 243 +/- 19%; S + LPS, 231 +/- 24%; S + TNF-alpha, 379 +/- 18%; B + LPS, 230 +/- 13%; and B + TNF, 305 +/- 23%, P< 0.01 vs. sham). GLUT1 mRNA and protein levels were increased as well (mRNA: B, 135 +/- 13%; B + I, 250 +/- 33%; S + LPS, 282 +/- 29%; S + TNF-alpha, 193 +/- 19%; B + LPS, 378 +/- 20%; and B + TNF-alpha, 204 +/- 16%; protein: B, 159 +/- 27%; B + I, 181 +/- 17%; S + LPS, 219 +/- 26%; S + TNF-alpha, 343 +/- 51%; B + LPS, 366 +/- 41%; and B + TNF-alpha, 415 +/- 44, P< 0.01 vs. sham). Macrophages co-cultured with LPS or TNF-alpha in vitro demonstrated a similar response pattern. Following burn injury and infection, macrophages augment their cellular glucose uptake, which is facilitated by an increased GLUT1 mRNA and protein levels. TNF-alpha elicited by LPS may mediate this enhanced carbohydrate metabolism at the point of glucose entry into the cell.
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PMID:Augmentations of glucose uptake and glucose transporter-1 in macrophages following thermal injury and sepsis in mice. 865 48

The study aimed to assess the effect of lipopolysaccharide (LPS) in vivo (from Escherichia coli, 2 mg/kg body weight intraperitoneally) on the production and elimination of hydrogen peroxide (H2O2) in rat hepatic endothelial and Kupffer cells. Twenty-two hours after the injection of LPS, hepatic cells were isolated by collagenase and pronase digestion followed by centrifugal elutriation, and cell-associated H2O2 was determined by flow cytometry analysis using 2',7'-dichloroflorescin diacetate (DCF-diacetate). LPS treatment did not alter the basal or phorbol myristate acetate-stimulated levels of H2O2-related fluorescence in endothelial cells; however, it doubled phorbol myristate acetate-stimulated fluorescence in Kupffer cells. Administration of varying concentrations of H202 (range, 10(-7) - 10(-4) mol/L) in vitro caused a significantly delayed increase in fluorescence in endothelial cells from endotoxemic rats as compared with cells from saline-injected animals. The 50% effective concentration of H202 was found at 1.1 x 10(-6) and 8.1 x 10(-6) mol/L on endothelial cells after saline and LPS treatment, respectively. No differences were detected in H2O2-stimulated fluorescence between resting and LPS-stimulated Kupffer cells. Administration of varying glucose concentrations in vitro significantly decreased the H2O2-stimulated fluorescence in endothelial and Kupffer cells from LPS-injected animals. Inhibition of nitric oxide synthase by in vitro administration of NG-monomethyl-L-arginine (L-NNMMA) did not alter the H2O2- or phorbol myristate acetate-stimulated responses in endothelial and Kupffer cells. As shown earlier, LPS stimulates the gene expression of GLUT1 glucose transporter, glucose-6-phosphate dehydrogenase (G6PD), superoxide dismutases, and glutathione peroxidase in hepatic endothelial cells. The present data indicate that the LPS-induced metabolic alterations are accompanied by an increased H2O2-detoxifying capacity in hepatic endothelial cells. This may represent a protective mechanism against exogenous oxidative stress caused by activated hepatic phagocytes during inflammation. Our observations are consistent with primed production of reactive oxygen species (ROS) in LPS-activated Kupffer cells.
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PMID:Endotoxin stimulates hydrogen peroxide detoxifying activity in rat hepatic endothelial cells. 878 44

Hypoglycemia occurs without hyperinsulinemia in suckling rats with endotoxic shock. However, tissue glucose uptake during endotoxic shock is not well known in the newborn. GLUT1 is insulin insensitive and is the predominant glucose transporter in 10 day old rats. In the adult with endotoxic shock, noninsulin-mediated glucose uptake and GLUT1 gene expression increase. Therefore, we hypothesized that tissue glucose uptake and GLUT1 mRNA abundance increased in 10 day old rats with endotoxic shock. The present study showed that whole body glucose disposal increased 3 h after a Salmonella enteritidis lipopolysaccharide injection (LD90 at 72 h). Plasma insulin concentration was not altered. Tissue glucose uptake increased in liver (2.4-fold) and fat (2.6-fold). However, changes of GLUT1 protein concentration were not detected in liver. GLUT1 mRNA abundance increased in liver (9-fold) and fat (4-fold). GLUT1 mRNA abundance but not glucose uptake increased in muscle. Neither glucose uptake or GLUT1 mRNA abundance was altered in brain. The mRNA abundance of tissue-specific glucose transporters (GLUT2 and GLUT4) was not altered. Thus, tissue glucose uptake and GLUT1 mRNA abundance increased without hyperinsulinemia during endotoxic shock in 10 day old rats.
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PMID:Tissue glucose transport and glucose transporters in suckling rats with endotoxic shock. 890 42

Reactive oxygen species (ROS) are mediators of cellular injury and play a putative role in the onset of hepatic damage during endotoxemia or sepsis. It has been suggested that induction of glucose-6-phosphate (G-6-P) dehydrogenase, the key enzyme of the hexose monophosphate shunt (HMS), may support ROS-producing or ROS-eliminating pathways in hepatic endothelial and Kupffer cells during endotoxemia. The aim of the study was to assess in vivo lipopolysaccharide (LPS)-induced alterations in rat gene expression of selected enzymes that are in functional relationship with the HMS. mRNA levels and activities of glucose transporter GLUT-1, Mn- and CuZn-dependent superoxide dismutases (Mn-SOD and CuZn-SOD), and Se-dependent glutathione peroxidase (Se-GPX) were determined. Cellular extracts were analyzed 7 or 22 h after injection of LPS (Escherichia coli, 2 mg/kg ip) or injection of saline. Exposure to LPS for 7 or 22 h caused a 10- to 25-fold increase in GLUT-1 mRNA levels in endothelial and Kupffer cells. In parenchymal cells, GLUT-1 mRNA expression was low, and LPS caused no marked changes. Cellular levels of Mn-SOD mRNA were 20-40 times greater in all hepatic cells from LPS-treated animals than in cells from control rats. LPS at 22 h increased Mn-SOD activity by 45% in endothelial cells but caused no significant changes in Kupffer or parenchymal cells. Message levels and enzyme activities of CuZn-SOD and Se-GPX were significantly elevated 22 h after LPS injection in endothelial cells only. Thus LPS results in marked upregulation of functionally related genes in hepatic cells. In endothelial cells, the simultaneous upregulation of GLUT-1, G-6-P dehydrogenase, Mn-SOD, CuZn-SOD, and Se-GPX may represent an important mechanism for accelerated elimination of ROS released from activated sinusoidal phagocytes. In Kupffer cells, upregulated GLUT-1 and G-6-P dehydrogenase, together with constitutively present SOD and lack of upregulated Se-GPX, suggest an elevated capacity to produce O2- and H2O2 that is consistent with primed bacterial killing.
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PMID:Endotoxin stimulates gene expression of ROS-eliminating pathways in rat hepatic endothelial and Kupffer cells. 892 96

During the innate immune response, excessive release of reactive oxygen species (ROS) from sequestered phagocytes and activated resident macrophages represents the predominant component of oxidative stress in the liver and other tissues. The consequence of oxidative stress is determined by the status and adaptive changes of antioxidant pathways. In this review, we present evidence that the synchronized response of hepatic sinusoidal endothelial cells, the primary sites of phagocyte attachment, plays an important role in defense against phagocyte-derived ROS. An essential component of the metabolic adaptation of hepatic sinusoidal cells to lipopolysaccharide (LPS)-induced oxidative stress is the stimulated expression of glucose-6-phosphate dehydrogenase (G6PD), the key enzyme of the pentose cycle (hexose monophosphate shunt, HMS). All major ROS-metabolic enzymes, i.e., glutathione peroxidase, glutathione reductase, catalase, superoxide dismutases, NADPH oxidase, and nitric oxide synthase, directly or indirectly depend on NADPH, which is produced in the HMS in these cells. The functional significance of up-regulated HMS within a particular cell type depends on the accompanying adaptive changes in ROS-metabolizing enzymes. In LPS-activated Kupffer cells, the elevated expression of glucose transporter GLUT1 and G6PD mainly serves primed production of superoxide anion, hydrogen peroxide, and nitric oxide. In sinusoidal endothelial cells, the LPS-induced response pattern of glucose- and ROS-metabolizing enzymes results in elevated ROS detoxifying capacity. The described studies also suggest the existence of an intercellular oxidant balance between pro-oxidant Kupffer cells and antioxidant endothelial cells in the hepatic micro-environment. Maintenance of the intercellular oxidant/antioxidant balance between phagocytes and endothelial cells may represent an important mechanism protecting the hepatic parenchyma against exogenous oxidative stress during the inflammatory response.
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PMID:Endotoxemia, pentose cycle, and the oxidant/antioxidant balance in the hepatic sinusoid. 958 96

The induction of nitric oxide (NO) synthase in astrocytes by endotoxin and/or cytokine treatment is associated with increased glucose consumption and glycolysis, but the mechanism whereby this phenomenon occurs remains obscure. In this work, we have addressed this issue and found that incubation of cultured rat astrocytes with lipopolysaccharide (LPS; 1 microg/mL) for 24 h increased the level of constitutively expressed GLUT1 glucose transporter mRNA, and triggered GLUT3 mRNA expression, which was absent in normal astrocytes. The occurrence of GLUT3 protein after LPS treatment was corroborated by western blotting and immunocytochemistry. A 4-h incubation of astrocytes in the absence of glucose, or under an oxygen-poor (3%) atmosphere also resulted in GLUT3 mRNA overexpression. Experiments performed with 2-deoxy-D-[U-14C]glucose (at 0.1 mM of D-glucose) confirmed that LPS (0.1-10 microg/mL) dose-dependently increased the rate of glucose uptake (by a factor of 1.6 at 1 microg/mL of LPS), which was paralleled with the increase in NO synthesis. Furthermore, blockade of NO synthase with 2-amino-5,6-dihydro-6-methyl-(4H)-1,3-thiazine (AMT; 50 microM) partially (by 45%) prevented the LPS-mediated increase in glucose uptake. Finally, incubation of astrocytes with the NO donor 1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA; 100 microM) increased by a factor of 1.4 the rate of glucose uptake. We conclude that the increase in GLUT3-driven glucose uptake in astrocytes would have a neuroprotective role under conditions in which NO formation is combined with hypoglycaemia, such as in brain ischemia.
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PMID:Expression of glucose transporter GLUT3 by endotoxin in cultured rat astrocytes: the role of nitric oxide. 1159 53

It has been reported in the literature that biological membranes arising from HIV-induced cell fusion, as well as syncytium formation between infected and non-infected cells and those involved in transduction, viral DNA nuclear import and virion budding from the host cell, are all made of proteins, a phospholipid (P) bilayer and cholesterol (C). However, the P/C molar ratio is higher in the retroviral envelope than in the plasma membrane where they originate, and higher than in the nuclear envelope. Mechanisms are described which elucidate this puzzling fact, as well as cholesterol-dependent leakage and pore formation during cell fusion. Fatty acylation of viral and host cell proteins is required to direct them to membranes. Detergent-insoluble microdomains enriched in cholesterol and sphingolipids, termed either DIGs (detergent-insoluble glycolipid-enriched complexes), DRMs (detergent resistant membranes), TIFFs (Triton-insoluble floating fractions) or GEMs (glycolipid-enriched membranes), function as platforms for attachment of proteins in the process of signal transduction. HIV-SUgp120 (HIV-surface glycoprotein), T-cell receptor (TCR)-CD4+ and co-receptors promote aggregation of these lipid "rafts" which concentrate the Src family tyrosine kinases SFKs (PTK, Lyn, Fyn, Lck), GPI (glycosyl phosphatidylinositol)-anchored proteins, and phosphatidylinositol kinases PI(3)K and PI(4)K, inducing cell signalling. HIV-SUgp120 transduces the activation signal and provokes the formation of polyunsaturated fatty acid (PUFA) metabolites, i.e. the prostaglandin PGE2 suppressor of immune function and inhibitor of cytotoxic T-lymphocyte (CTL) proliferation, while PGB2 activates SFKs and increases mRNA expression, as well as NFkappaB (nuclear transcription factor) translocation to nucleus. HIV nuclear import, DNA integration, chromatin template capacity may be mediated by the lipid environment. The lipid-enriched microdomains from which HIV-1 buds, may explain the high level of cholesterol and sphingolipids in the viral envelope, since host cell rafts become a viral coat. HIV-1 infection induces alteration of cellular lipids: (1) shift in phospholipid synthesis to neutral lipids associated with the viral load, polyunsaturated fatty acid (PUFA) peroxidation, and n-3 deficiency with deregulation of cytokines and PPAR-gamma (peroxisome proliferator-activated receptor-gamma), and (2) alloimmune phospholipid antibody production in which antibodies to cardiolipin and to phosphatidylserine are most prevalent, due to the destruction of mitochondrial membranes and progression of lymphocyte apoptosis. The current highly active anti-retroviral therapy, including both viral reverse transcriptase (RT) inhibitors (NRTIs and NNRTIs, nucleoside and non-nucleoside RT inhibitors) and protease inhibitors (PIs), induces side-effects in the long term. Lipodystrophy (LD), consists of peripheral lipoatrophy associated with central fat accumulation (called "crixbelly" and "buffalo hump"), insulin resistance, elevation of very low density lipoproteins, decrease in high density lipoproteins and inhibition of adipocyte differentiation. LD syndrome appears to be induced by PIs that inhibit GLUT4, glucose transporter isoform, and by NRTIs which provoke mitochondrial failure. New therapeutic strategies assessed: (1) inhibition of the viral integrase and/or HIV entry into cells through natural products or their derivatives, (2) inhibition of HIV-1 entry into macrophages pretreated with Gram-negative bacterial lipopolysaccharide, (3) vaccination with multi-lipopeptides, i.e. sequences of HIV-1 peptides with CD4+ T-cell and B-cell epitopes, modified by adding a lipid tail to one end, which produce HIV-specific CTL and multispecific immune responses in most of the vaccinated subjects and (4) stimulation of antiviral drug activity with lipid-prodrugs targeting viral RT, polymerase, integrase, or aspartyl-protease.
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PMID:Human immunodeficiency virus and host cell lipids. Interesting pathways in research for a new HIV therapy. 1169 68


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