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)

We reported a case of a 3-year-old girl with hemolytic uremic syndrome (HUS), which showed hemolytic anemia (Hemoglobin 8.2 g/dl, lactate dehydrogenase 1277 IU/l and total bilirubin 0.6 mg/dl), small purpura on the skin (platelet 7.3 x 10(4)/microliter) and slightly decreased output of urine (creatinine 0.4 mg/dl and blood urea nitrogen 27.2 mg/dl). Verotoxin producing Escherichia coli (E. coli) O157 was not isolated, but Salmonella agona and E. coli O125, which is one of the enteropathogenic E. coli, were detected from her stool culture. However, the IgM antibody against verotoxin producing E. coli (VTEC) O157 lipopolysaccharide was detected in both serum of the acute and convalescent phase by immunoblot assay. In addition verotoxin DNA was demonstrated in the stool by PCR method. Therefore, we think this HUS might be due to VTEC O157, which must have been co-infected with Salmonella agona and E. coli O125. There have been four cases including the present case of co-infection with VTEC O157 so far, and the other three cases were of the Salmonella species. Although the reason of co-infection was unknown, we may infer that food might be contaminated with some pathogens including Salmonella species or that these patients might be already infected with Salmonella species prior to VTEC infection. Even when some other pathogens were detected by a stool culture from a patient with HUS, we should pay attention to demonstrate associated of VTEC and HUS by the specific antibodies and PCR for verotoxin DNA.
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PMID:[A case of hemolytic uremic syndrome documented co-infection of vertoxin producing Escherichia coli O157 and other pathogens]. 933 32

1. An enhanced production of nitric oxide (NO) from L-arginine, related to the diffuse expression of an inducible NO synthase (iNOS), contributes to the pathogenesis of endotoxic shock. Since iNOS activity depends on extracellular L-arginine, we hypothesized that limiting cellular L-arginine uptake would reduce NO production in endotoxic shock. We investigated the effects of L-lysine, an inhibitor of L-arginine uptake through system y+, on NO production, multiple organ dysfunction and lactate levels, in normal and endotoxaemic rats. 2. Anaesthetized rats challenged with intravenous lipopolysaccharide (LPS, 10 mg kg[-1]) received a 5 h infusion of either L-lysine (500 micromol kg(-1) h(-1), n = 12) or isotonic saline (2 ml kg(-1) h(-1), n = 11). In rats treated with saline, LPS produced a large increase in plasma nitrate and L-citrulline concentrations at 5 h, both markers of enhanced NO production. LPS also caused severe hypotension, low cardiac output and marked hyperlactataemia. All these changes were significantly reduced by L-lysine administration. 3. Endotoxaemia also caused a significant rise in the plasma levels of alanine aminotransferase (ALAT), lipase, urea and creatinine, and hence, liver, pancreatic and renal dysfunction. These changes tended to be less pronounced in rats treated with L-lysine, although the differences did not reach statistical significance. 4. Similar experiments were conducted in 10 rats challenged with LPS vehicle in place of LPS and then treated with L-lysine (500 micromol kg(-1) h(-1), n = 5) or saline (2 ml kg(-1) h(-1), n = 5) for 5 h. In these animals, all the haemodynamic and metabolic variables remained stable and not statistically different between both treatment groups, except for a slight rise in ALAT, which was comparable in L-lysine and saline-treated rats. 5. In conclusion, L-lysine, an inhibitor of cellular L-arginine uptake, reduces NO production and exerts beneficial haemodynamic effects in endotoxaemic rats. L-lysine also reduces hyperlactataemia and tends to blunt the development of organ injury in these animals. Contrastingly, L-lysine has no effects in the absence of endotoxin and thus appears to act as a selective modulator of iNOS activity.
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PMID:Effect of L-lysine on nitric oxide overproduction in endotoxic shock. 937 72

Macrophage dysfunction is considered an important contributory factor for increased propensity of infections in uremia. Because nitric oxide (NO) is believed to be an effector molecule of macrophage cytotoxicity, we propose that the dysfunction may be related to impaired NO synthesis. To verify this hypothesis, we evaluated macrophage NO synthesis in the presence of urea, a compound that accumulates in renal failure and is believed by some to be a uremic toxin. Macrophages (RAW 264.7 cells) were incubated with bacterial lipopolysaccharide to induce NO synthesis, whereas the test groups had various concentrations of urea in addition. NO synthesis was measured by assaying the supernatant for nitrites and nitrates by chemiluminescence. We observed that urea consistently produced a dose-dependent reversible inhibition of inducible NO production in macrophages, whereas parathormone, another toxin retained in uremia, had no such inhibitory effects. Further studies revealed that mRNA for inducible NO synthase was not inhibited by urea. We thus conclude that urea inhibits inducible NO synthesis in macrophages by a posttranscriptional mechanism and that this may be important in macrophage dysfunction of uremia.
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PMID:Urea inhibits inducible nitric oxide synthase in macrophage cell line. 943 93

In macrophages and many other cell types, L-arginine is used as a substrate by both nitric oxide synthase (NOS) and arginase to produce nitric oxide (NO) and urea, respectively. Because the availability of L-arginine is a major determinant for NO synthesis in the activated macrophage, we hypothesized that NO production may be reduced by arginase via depleting the common substrate in this cell type. To test this hypothesis, we investigated the effect of an arginase inhibitor, L-norvaline, on NO production in J774A.1 mouse macrophages activated by lipopolysaccharide (LPS, 1.0 microgram/ml) for 22 h. In the absence of LPS, macrophages produced a low level of NO. In contrast, NO production from these cells was significantly increased in the presence of LPS. Increasing extracellular levels of L-arginine (0.01-0.8 mM) produced a concomitant increase in NO production of activated macrophages. L-Norvaline (10 mM), which specifically inhibits arginase activity (i.e., reducing urea production by 50%) without altering NOS activity, enhanced NO production (by 55%) from activated macrophages. The enhancement of NO production by L-norvaline was inversely related to the extracellular level of L-arginine. A more pronounced increase in NO production was observed at the lower level of extracellular L-arginine, i.e., a 55 vs. 28% increase for 0.05 and 0.1 mM extracellular L-arginine, respectively. When the L-arginine concentration exceeded 0.5 mM, the L-norvaline effect was abolished. These results indicate that arginase can compete with NOS for their common substrate and thus inhibit NO production. This regulatory mechanism may be particularly important when the extracellular supply of L-arginine is limited.
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PMID:Arginase modulates nitric oxide production in activated macrophages. 945 85

Nitric oxide (NO) is a multifunctional messenger in many vertebrates. In the liver, NO was found to play an important but controversial role in injury produced by toxins or sepsis. The purpose of the present investigation was to further characterize the role of NO in hepatocyte oxidative injury. A cellular system formed of immobilized and perfused rat hepatocytes was used to test the ability of the latter to produce endogenous NO after lipopolysaccharide administration in vivo (LPS, 20 mg/kg i.p.) and how hepatocyte functionality competence is modified according to NO level. This cellular system also was used to delineate a relationship between exogenously delivered NO to the perfusion medium as produced by the NO donor, sodium nitroprusside (2.0 and 0.2 mM), and any alteration in the degree of injury as evoked by anoxia/reoxygenation or cumene hydroperoxide (1.0 mM and 0.2 mM). Rat hepatocytes were immobilized in low-gelling agarose and perfused with Williams E medium. Endogenous or exogenous NO was evaluated by measuring the end products of NO (NO2- + NO3-) in the perfusion medium. Functional integrity of hepatocytes was evaluated from lactate dehydrogenase (LD) leakage, urea synthesis in the perfusion medium and lipid peroxides (LP) formation. Normal, anoxia/reoxygenation or cumene hydroperoxide injured hepatocytes did not exhibit measurable NO while LPS-treated hepatocytes produced NO. Apparently, within the present experimental conditions, it seems that there was an inverse relation between the rate of NO produced after LPS administration and the rate of lipid peroxides formed in the hepatocytes. Low concentration of sodium nitroprusside (as NO donor) significantly decreased LD leakage, increased the rate of urea synthesis and increased trypan blue exclusion by hepatocytes in anoxia/reoxygenation or cumene hydroperoxide injured (0.2 mM) cells. Lipid peroxides were decreased by NO in cumene hydroperoxide injured hepatocytes. The present data suggest that NO endogenously produced, or exogenously delivered, has an ameliorative role in mild oxidative liver injury models, but not in severe cases and that inside hepatocytes, there is a very delicate balance between the rate of NO production and its consumption. The disturbance in this balance may be responsible for injury due to the formation of more toxic oxygen species.
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PMID:Possible dual role of nitric oxide in oxidative stress injury: a study in perfused hepatocytes. 963 60

A severe acute pancreatitis was produced by intraperitoneal injection of lipopolysaccharide (LPS) in rats with preexisting hemorrhagic and necrotizing pancreatitis induced by retrograde injection of a 5% taurocholate plus 1% trypsin solution into the pancreatic duct. Mortality and time-course changes in pancreatic, hepatic, renal and pulmonary functions, and organ myeloperoxidase (MPO) levels were examined in this model. LPS at an intraperitoneal dose of 30 mg/kg, which scarcely caused death and had no marked effect on serum parameters and organ MPO levels in rats without pancreatitis, increased the mortality in rats with taurocholate plus trypsin-induced pancreatitis. Pancreatic weight and ascitic volume increased in rats with taurocholate plus trypsin-induced pancreatitis regardless of the presence or absence of LPS. Serum amylase and lipase levels were also significantly increased in rats with induced pancreatitis, but was higher in the group given LPS. Serum glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), blood urea nitrogen (BUN) and creatinine levels were significantly elevated in LPS-treated rats with induced pancreatitis, whereas levels in rats with induced pancreatitis not given LPS were only slightly elevated. Renal weight was also significantly increased in rats with induced pancreatitis despite the presence or absence of LPS. In LPS-treated rats with induced pancreatitis, the arterial oxygen pressure, pulmonary weight and pulmonary MPO level were significantly elevated. However, the MPO level in the kidney in these rats was not different from that in control rats, indicating that the renal dysfunction was not produced by the infiltration of neutrophils into the kidney. Increase in the pancreatic MPO level was observed in rats with induced pancreatitis, but combination treatment with LPS did not raise it. Protective effects of prophylactic treatment of 2-(3-methylsulfonylamino-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl)-N-( 3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (compound 1), a neutrophil elastase inhibitor, and trifluoroacetyl-L-lysyl-L-alaninanilide hydrochloride (compound 2), a pancreatic elastase inhibitor, on mortality were also examined in this model. Results were compared with that of the combined treatment of compound 1 and compound 2. In LPS-treated rats with taurocholate plus trypsin-induced pancreatitis, the combined treatment of compound 1 (2 mg/kg/h) and compound 2 (30 mg/kg/h) significantly reduced mortality, whereas single treatment of compound 1 or compound 2 did not show the beneficial effect. These results suggest that marked hepatic and renal dysfunction accompanies pancreatitis in this pancreatitis model rats, which may be good models for acute pancreatitis in humans. It is also suggested that neutrophil and pancreatic elastases may be synergistically involved in the pathogenesis of acute pancreatitis in this model.
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PMID:Protective effect of the combined treatment of pancreatic and neutrophil elastase inhibitors on acute pancreatitis elicited by lipopolysaccharide in rats given intraductal injection of taurocholate plus trypsin. 965 Aug 10

The objective of the present study was to evaluate the response of rats suffering from moderate renal insufficiency to bacterial lipopolysaccharide (LPS, or endotoxin). The study involved 48 eight-week-old male SPF Wistar rats (175-220 g) divided into two groups of 24 animals each. One group underwent 5/6 nephrectomy while the other was sham-operated. Two weeks after surgery, the animals were further divided into two subgroups of 12 animals each and were fasted for 20 h but with access to water ad libitum. One nephrectomized and one sham-treated subgroup received E. coli LPS (25 micrograms/kg, i.v.) while the other received a sterile, pyrogen-free saline solution. Gastric retention (GR) was determined 10 min after the orogastric infusion of a standard saline test meal labeled with phenol red (6 mg/dl). The gastric emptying of the saline test meal was studied after 2 h. Renal function was evaluated by measuring the plasma levels of urea and creatinine. The levels of urea and creatinine in 5/6 nephrectomized animals were two-fold higher than those observed in the sham-operated rats. Although renal insufficiency did not change gastric emptying (median %GR = 26.6 for the nephrectomized subgroup and 29.3 for the sham subgroup), LPS significantly retarded the gastric emptying of the sham and nephretomized groups (median %GR = 42.0 and 61.0, respectively), and was significantly greater (p < 0.01) in the nephrectomized rats. We conclude that gastric emptying in animals suffering from moderate renal insufficiency is more sensitive to the action of LPS than in sham animals.
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PMID:The effect of bacterial lipopolysaccharide on gastric emptying in rats suffering from moderate renal insufficiency. 969 2

At present, the physiological role of NO. synthesis in the liver is ambiguous. Studies directed to reveal the role of NO. in relation to liver function were primarily initiated by an interest in the hepatic response to infections and the consequent modulation of liver function. The purpose of the present investigation was to use perfused rat hepatocytes to test the ability of the latter to produce NO. and to delineate the relationship between exogenously delivered NO. and any alteration in the degree of injury as produced by anoxia/reoxygenation (AR) or D-galactosamine (GalN, 5 mM) intoxication. NO. production in rats was stimulated by a single dose of lipopolysaccharide (LPS, 20 mg/kg i.p.) from which hepatocytes were isolated and perfused. Exogenous NO. was delivered to the perfusate of hepatocytes that were isolated from untreated rats, by the addition of sodium nitroprusside (SNP, 2 mM and 0.2 mM). AR and GalN hepatocyte injury was followed after the addition of SNP. Rat hepatocytes were immobilized in low-gelling agarose and perfused with Williams E medium. Endogenous synthesis of NO. and exogenous NO. as produced by SNP was evaluated by estimating the end products of NO. (NO2- + NO3-) in the perfusion medium. The functional and structural integrity of hepatocytes was evaluated from lactate dehydrogenase (LD) leakage and urea synthesis in the perfusion medium. Normal, AR- and GalN-injured hepatocytes did not exhibit measurable NO. while LPS-treated hepatocytes produced NO. (80 microM NO2- + NO3-). SNP-produced NO. significantly increased or decreased LD leakage in AR at 2 mM or 0.2 mM, respectively, and also reduced or increased the rate of urea synthesis, respectively. 0.2 mM SNP increased trypan blue exclusion by hepatocytes. On the other hand, GalN toxicity was not significantly altered by SNP as demonstrated by LD leakage and the rate of urea synthesis was increased by SNP addition. The present data suggest both deleterious and beneficial role of NO. in AR liver injury model depending on the level of NO. generated.
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PMID:Effects of nitroprusside as a nitric oxide donor on anoxia/reoxygenation and D-galactosamine hepatic injuries: a study in perfused hepatocytes. 972 82

1. The intermediates of biochemical cycles are commonly utilized for biosynthetic processes; thus at least one intermediate must be replenished de novo to provide constant flux through the cycle. The utilization of L-arginine for NO synthesis in macrophages may thus reduce the concentration of intermediates of the urea cycle. It is possible that a glutamine-utilizing pathway exists in mononuclear phagocytes that may connect with the urea cycle.2. In this paper we report that mouse peritoneal resident and Bacillus Calmette-Guerin (BCG)-activated macrophages and human monocytes are capable of utilizing glutamine at high rates, contain sufficient activity of the enzymes required to convert glutamine to citrulline (and subsequently citrulline to arginine) to account for observed rates of nitrite synthesis in the absence of extracellular L-arginine, and will release nitrite when exposed to intermediates of the proposed glutamine-->arginine pathway.3. The rate of nitrite production (in the absence of extracellular arginine) was reduced by culturing macrophages or monocytes in the presence of the glutaminase inhibitor 6-diazo 5-oxo norleucine.4. The rate and extent of arginase secretion, glutamine utilization, nitrite production (basal and lipopolysaccharide-stimulated) and phosphate-dependent glutaminase activity from BCG-activated macrophages was increased compared with resident cells.5. We suggest that the elevated arginase secretion rates in activated macrophages would effectively increase the intracellular concentration of arginine available for conversion to NO via inducible nitric oxide synthase, the expression of which is known to increase on activation of macrophages or monocytes. Additionally, the rate of L-arginine biosynthesis from glutamine may be increased on immunostimulation of the macrophage.
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PMID:Importance of glutamine metabolism in murine macrophages and human monocytes to L-arginine biosynthesis and rates of nitrite or urea production. 974 15

The objective of this study was to elucidate the role and mechanism of nitric oxide (NO) synthase (NOS) in modulating the growth of the Caco-2 human colon carcinoma cell line. The two novel observations reported here are, first, that NG-hydroxy-L-arginine (NOHA) inhibits Caco-2 tumor cell proliferation, likely by inhibiting arginase activity, and, second, that NO causes cytostasis by mechanisms that might involve inhibition of ornithine decarboxylase (ODC) activity. Both arginase and ODC are enzymes involved in the conversion of arginine to polyamines required for cell proliferation. Cell growth was monitored by cell count, cell protein analysis, and DNA synthesis. NOHA (1-30 microM) and NO in the form of DETA/NO (1-30 microM) inhibited cell proliferation by 30-85%. The cytostatic effect of NOHA was prevented by addition of excess ornithine, putrescine, spermidine, or spermine to cell cultures, whereas the cytostatic effect of NO (DETA/NO) and alpha-difluoromethylornithine (ODC inhibitor) was unaffected by ornithine but was prevented by putrescine, spermidine, or spermine. The cytostatic effect of NOHA appeared to be independent of its conversion to NO, and the effect of NO appeared to be independent of cGMP. NOHA inhibited urea production by Caco-2 cells and inhibited arginase catalytic activity (85% at 3 microM), whereas NO (DEA/NO and SNAP) inhibited ODC activity (>/=60% at 30 microM) without affecting arginase activity. Coculture of Caco-2 cells with lipopolysaccharide/cytokine-activated rat aortic endothelial cells markedly slowed Caco-2 cell proliferation, and this was blocked by NOS inhibitors. These observations that NOHA and NO may inhibit sequential steps in the arginine-polyamine pathway suggest a novel biological role for NOS in the inhibition of cell proliferation of certain tumor cells and possibly other cell types.
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PMID:NG-hydroxy-L-arginine and nitric oxide inhibit Caco-2 tumor cell proliferation by distinct mechanisms. 975 58


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