Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gut fuel utilisation has several unique features. Arterial and luminal fuels provide nutrition for the enterocyte, the former being of more importance. This factor, and the heterogeneity of cell types within the gut makes it difficult to define its fuel utilisation. Metabolic control logic suggests that modulation of the maximal activity of any pathway resides in those enzymes that operate in vivo at rates far below their maximal capacity and that catalyse non-equilibrium reactions. On this basis, although enterocyte hexokinase activity is much higher than in other 'glycolytic' cells (for example, brain), potentially high rates of glucose utilisation are modulated by substrate cycling of glucose 6-phosphate back to glucose through glucose 6-phosphatase. Glutamine metabolism proceeds by glutaminase to produce glutamate, which may then be transaminated (aspartate-aminotransferase and alanine-amino transferase) to produce alpha-ketoglutarate, alanine, and aspartate. The end products of glutamine metabolism by incubated gut preparations in vitro (mainly alanine), suggests that enterocytes, not immune cells, are responsible for most gut glutamine metabolism. High flux rates of glucose and glutamine metabolism in the enterocyte may result from the need for de novo synthesis of purines and pyrimidines and ribose sugars for nucleic acid synthesis. Sepsis reduces rates of glucose and glutamine metabolism, perhaps to preserve the increased consumption of these fuels by activated lymphocytes and macrophages in the gut wall.
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PMID:Quantitative aspects of glucose and glutamine metabolism by intestinal cells. 812 83

Dichloroacetate has been shown to have therapeutic effects on sepsis and endotoxin shock and to reduce liver damage in rats intoxicated with ethanol or carbon tetrachloride. In this study, the effect of dichloroacetate on endotoxin hepatitis was investigated. Endotoxin hepatitis was induced by an intraperitoneal coadministration of 50 micrograms/kg lipopolysaccharide from Escherichia coli, and 200 mg/kg D-galactosamine in starved, male Wistar rats. This treatment induced the following changes within 24 hr: an increase in the serum aminotransferase activity, histological alterations of the liver including focal necrosis of liver cells and inflammatory infiltrates, an increase in blood pyruvate and alanine concentrations, and inhibition of starvation ketosis. The intraperitoneal administration of 250 mg/kg dichloroacetate 30 min after the administration of the toxins partially counteracted all of these changes. The administration of dichloroacetate might be useful in coping with hepatic damage as well as lacticemia and cardiovascular depression induced by endotoxins.
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PMID:The limiting effect of dichloroacetate on endotoxin-induced liver damage in starved rats. 814 37

It is believed that induction of cytokine expression by bacterial cell wall components plays a role in the development and course of sepsis. However, most attention has been focused on lipopolysaccharide (LPS). We studied the ability of N-acetylglucosaminyl-1,6-anhydro-N-acetylmuramyl-L-alanyl-D- isoglutamyl-m-diaminopimelyl-D-alanine (G(Anh)MTetra), a naturally occurring breakdown product of peptidoglycan that is produced by soluble lytic transglycosylase of Escherichia coli, to induce cytokine expression in human monocytes. G(Anh)MTetra was found to strongly induce interleukin (IL)-1 beta and IL-6 mRNA expression after 2 h and IL-1 beta and IL-6 protein secretion after 48 h of activation. The increase in mRNA accumulation was at least partly due to an increase in the transcription rates of the respective genes and was accompanied by a strong induction of nuclear factor-kappa B and activator protein-1 transcription factor expression. Experiments using inhibitors of protein kinase C, protein kinase A, and tyrosine kinase-dependent pathways revealed that G(Anh)MTetra-induced IL-1 beta and IL-6 mRNA expression involves activation of an H7-inhibitable pathway. By using the protein synthesis inhibitor cycloheximide, it was shown that G(Anh)MTetra-induced IL-6 mRNA expression depends on the synthesis of new protein, whereas G(Anh)MTetra-induced IL-1 beta mRNA accumulation does not. When responses to G(Anh)MTetra were compared with those to LPS and muramyldipeptide (MDP), it was found that the optimal response to G(Anh)MTetra induction was similar to that of LPS but significantly higher than the response to MDP. Furthermore, maximal G(Anh)MTetra-induced IL-1 beta and IL-6 mRNA expression could be enhanced by co-stimulation with LPS or MDP, suggesting that different receptors and/or transduction pathways were involved. These results indicate that G(Anh)MTetra induces IL-1 beta and IL-6 expression in human monocytes suggesting a possible role for G(Anh)MTetra in the release of cytokines during sepsis.
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PMID:G(Anh)MTetra, a natural bacterial cell wall breakdown product, induces interleukin-1 beta and interleukin-6 expression in human monocytes. A study of the molecular mechanisms involved in inflammatory cytokine expression. 830 82

This study of the plasma aminogram was done on 35 patients with a moderate to high level of stress and/or sepsis. For the criteria of illness, the SAPS (Simplified Acute Physiological Score) was used on their admission to the intensive Care Unit, and the diagnosis of sepsis was established according to the criteria of Jacobs and Boone. The stress level was calculated according to Bistrian. The plasma aminogram was determined with High Resolution Liquid Chromatography. The plasma samples were taken while nutrient units containing what is considered a standard solution of amino acids were infused. The eight essential amino acids (EAA) and 10 non-essential were quantified. The ratio of ramified to aromatic amino acids (RAA/AAA) was calculated by Fisher's criteria. An increase in AAA (phenylalanine, p < 0.001, and tyrosine, NS) and sulphur containing amino acids (methionine, p < 0.001) was found. The RAA were within normal ranges (valine) or increased (leucine, p < 0.001 and isoleucine, p < 0.001). The RAA/AAA ratio was reduced, p < 0.0001. Glycine was increased, p < 0.0001 and alanine reduced, p < 0.05. Glutamine and glutamic acid were reduced, p < 0.0001 and p < 0.01 as was arginine, p < 0.001. No difference was found in the total concentration of AA. The results confirm the standard plasma aminogram described in situations of metabolic stress and/or sepsis.
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PMID:[Plasma aminogram in critical patients]. 846 96

Classical galactosaemia, deficiency of galactose-1-phosphate uridyltransferase (GALT), is characterized by acute symptoms of hepatomegaly, jaundice, sepsis, cataracts and growth retardation. Treatment with dietary galactose restriction corrects these complications immediately; however, most of these children develop long-term complications of verbal dyspraxia, mental retardation and ovarian failure. Our previous molecular study showed that the most common mutation of the GALT gene is a missense mutation of Q188R (replacement of glutamine-188 by arginine) in approximately 60-65% of the German galactosaemic population. The coding region of GALT was amplified by the polymerase chain reaction from genomic DNA of classical galactosaemic individuals, who are negative or heterozygous for Q188R, and was further characterized by direct sequencing. Three new disease-causing mutations, two missense and a stop codon mutation, were identified in three patients from two families with mild galactosaemic variants: firstly R67C, replacement of arginine-67 by cysteine and W316X, the stop codon at tryptophan-316 in one male; secondly A330V, replacement of alanine-330 by valine in two female siblings. In the first family the patient was also heterozygous for the polymorphism N314D and in the second family both girls were compound heterozygotes for Q188R and A330V. All three galactosaemic individuals have a considerable amount of the residual GALT activity in RBC and the galactose-1-phosphate (GALP) level decreased much faster on treatment than that of other galactosaemic patients with missense mutations such as Q188R. The clinical and biochemical data of these patients were much more favourable in comparison with those of two female galactosaemic individuals, one homozygous for L195P and the other compound heterozygous for Q188R and L195P. These three missense mutations (R67C, L195P and A330V) also occur in highly conserved regions. These observations suggest that the phenotypic variation in galactosaemic individuals may be due to different molecular aetiologies.
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PMID:Mutations in the galactose-1-phosphate uridyltransferase gene of two families with mild galactosaemia variants. 859 37

Despite their beneficial effects on cardiovascular derangements in patients with severe sepsis, high doses of sympathomimetics might contribute to an impaired neutrophil function. This study was conducted to examine whether various sympathomimetics [(-)-epinephrine (EPI), dopamine (DA) and dobutamine (DOB)] differ in their potency to suppress the formation of oxygen radicals by neutrophils and whether this potency correlates with their affinity to or intrinsic activity for beta-2 adrenoceptors (beta-2 AR). Oxygen radical production of human neutrophils was induced by N-formyl-methionyl-leucyl-phenyl-alanine and detected by chemiluminescence measurements. Dose-response curves for the inhibition of chemiluminescence by sympathomimetics were measured in the absence and presence of 0.1 microM CGP 20,712 A (1-[2(3-carbamoyl-4-hydroxy phenoxy)-ethylamino]-3-[4-(1-methyl-4-trifluoromethyl-2-imidazolyl) phenoxy]-2-propanol methanesulfonate) and 0.1 microM ICI 118,551 (erythro-(+/-)-1-(7-methylindan-4-yloxy)-3 isopropylaminobutan-2-ol hydrochloride) to selectively antagonize beta-1 AR and beta-2 AR, respectively. Inhibition of chemiluminescence of neutrophils by EPI was approximately 100-fold more potent than that by DA and DOB. Only the inhibition curve by EPI exhibited two components, one at nanomolar and one at micromolar concentrations. The nanomolar component was sensitive against beta-2 AR blockade, whereas the micromolar one was insensitive against both beta AR antagonists. Dose-response curves for DA and DOB exhibited a simple hyperbolic shape at micromolar concentrations and were insensitive against both beta AR antagonists. Maximum inhibition by DA and DOB was equipotent to that by EPI. However, the EC50 for DA was much lower than its dissociation constants, KD, assayed in membrane preparations by radioligand binding, whereas the EC50 of DOB matched KD. This difference could not be explained by a different efficiency of signal transduction, which was determined in receptor-coupled adenylate cyclase activity and which only showed a slightly higher efficiency of DA (51%) than of DOB (34%). Therefore, sympathomimetics were also investigated in a cell-free system, in which chemiluminescence was generated by horseradish peroxidase with hydrogen peroxide as substrate. Surprisingly, all of the sympathomimetics suppressed chemiluminescence with micromolar concentrations. We conclude that sympathomimetics with high affinity and high intrinsic activity (EPI) inhibit neutrophil function via occupation of beta-2 AR, whereas sympathomimetics with low affinity (DA) or low intrinsic activity (DOB) may act by direct scavenging of oxygen radicals.
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PMID:Is inhibition of oxygen radical production of neutrophils by sympathomimetics mediated via beta-2 adrenoceptors? 881 92

Although a linkage between aerobic glycolysis and sodium-potassium transport has been demonstrated in diaphragm, vascular smooth muscle, and other cells, it is not known whether this linkage occurs in skeletal muscle generally. Metabolism of intact hind-leg muscles from young rats was studied in vitro under aerobic incubation conditions. When sodium influx into rat extensor digitorum longus (EDL) and soleus muscles was facilitated by the sodium ionophore monensin, muscle weight gain and production of lactate and alanine were markedly stimulated in a dose-dependent manner. Although lactate production rose in both muscles, it was more pronounced in EDL than in soleus. Monensin-induced lactate production was inhibited by ouabain or by incubation in sodium-free medium. Preincubation in potassium-free medium followed by potassium re-addition also stimulated ouabain-inhibitable lactate release. Replacement of glucose in the incubation medium with pyruvate abolished monensin-induced lactate production but exacerbated monensin-induced weight gain. Muscles from septic or endotoxin-treated rats exhibited an increased rate of lactate production in vitro that was partially inhibited by ouabain. Increases muscle lactate production in sepsis may reflect linked increases in activity of the Na+, K+-ATPase, consumption of ATP and stimulation of aerobic glycolysis.
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PMID:Linkage of aerobic glycolysis to sodium-potassium transport in rat skeletal muscle. Implications for increased muscle lactate production in sepsis. 894 58

The identification of plasma markers of the course of the acute respiratory distress syndrome (ARDS) is needed to improve its treatment and to further advance the development of new therapeutic agents. The status of markers of lung injury in ARDS is reviewed and some new potential markers are proposed. This study focused on plasma amino acids, related amino compounds, and catecholamine levels during the acute phase of endotoxin-induced lung injury in 8 sheep characterized by the onset of pulmonary edema caused by increased microvascular permeability. A number of significant changes from baseline values were found. During the sixth hour of a 12-hour period of endotoxin infusion, norepinephrine, epinephrine, and alanine levels increased whereas the isoleucine level decreased. During the sixth hour of the immediate postendotoxin period, the taurine level increased while the levels of arginine, citrulline, glycine, isoleucine, methionine, ornithine, serine, threonine, and tryptophan decreased. These findings are compared with prior studies in human subjects detailing the amino acid profile characteristic of advanced sepsis. We conclude that the present profile of catecholamine and amino acid changes during endotoxemia in sheep deserves further study in human subjects to determine its significance as a marker of the early stage of ARDS.
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PMID:A profile of amino acid and catecholamine levels during endotoxin-induced acute lung injury in sheep: searching for potential markers of the acute respiratory distress syndrome. 896 Jun 37

Branched chain amino acids (BCAAs) and glutamine are both recommended in catabolic states. The object of this study was to compare the efficacies of alanylglutamine (Ala-Gln)-enriched and BCAA-enriched total parenteral nutrition (TPN) on the protein kinetics in peritonitis. Rats were divided into Ala-Gln and BCAA groups after intraperitoneal implantation of an osmotic pump, delivering a continuous infusion of Escherichia coli. Glutamine composed 30.0% (w/v) of the total amino acids in the Ala-Gln group, and BCAA composed 30.5% (w/v) of the total amino acids in the BCAA group. The two solutions were isocaloric and isonitrogenous. Whole body protein turnover and organ fractional protein synthetic rates (FSR) were measured on days 3 and 5. Serum amino acid levels and mucosal morphology were determined. Ala-Gln group had higher rates of whole body protein turnover, and hepatic FSR on both days. Serum glutamine levels correlated with hepatic and muscle FSR. Ala-Gln TPN group had greater mucosal thickness, numbers of mitoses per crypt, and FSR in distal intestine. Ala-Gln-enriched TPN may be a useful nutritional treatment modality in sepsis.
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PMID:Alanylglutamine-enriched total parenteral nutrition improves protein metabolism more than branched chain amino acid-enriched total parenteral nutrition in protracted peritonitis. 904 98

The development of the multiorgan dysfunction syndrome, directly determining the severity of the septic process, is characterized by not only inverse ratio of the energy and plastic material, but by metabolic changes which are still unclear and cannot yet be explained. Our purpose was to detect some features of amino acid metabolism in patients with grave sepsis and septic shock. The concentrations of plasma free amino acids were measured on days 1, 3, and 5 in 37 patients with grave sepsis and septic shock. The diagnosis of grave sepsis, septic shock, and organ dysfunction was made proceeding from the criteria defined by R. Bone. The study revealed reliably increased (p < 0.05) levels of arginine, proline, alanine, and the arginine-ornithine index reflecting the direction of arginine transformation in patients with septic shock and grave organ dysfunction (for at least 3 systems). This may be explained by active degradation of endogenous proteins of skeletal muscles, which is characteristic of septic hypermetabolism. Strong correlations were revealed between arginine level and the APACHE-II score (r = 0.57), proline and the same score (r = 0.51), mean arterial pressure and the arginine-ornithine index (r = -0.72), APACHE-II score and the arginine-ornithine index (r = 0.79), arterial lactate and the arginine-ornithine index (r = 0.64). Hence, amino acid metabolism apparently mediates the effects of septic cascade mediators on the following cell.
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PMID:[Characteristics of amino acid metabolism in patients with severe sepsis and septic shock]. 917 19


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