Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is no doubt that acute renal failure (ARF) is associated with enhanced protein breakdown. It has been shown that protein split products can be measured in plasma samples of these patients. On the other hand, ARF frequently occurs in conditions of increased metabolic stress which leads to enhanced protein catabolism. Muscle wasting, loss of lean body weight, and a negative nitrogen balance result in malnutrition which considerably increases morbidity and mortality. Besides the accumulation of uremic toxins, several other factors are involved in the accelerated proteolysis in ARF. Metabolic acidosis appears to be one of the major catabolic factors in chronic renal failure, and probably in ARF as well. Insulin resistance, which is commonly attributed to uremia, also increases protein degradation. However, this derangement of carbohydrate metabolism is not directly accessible to therapy, in contrast to acidosis, which can be easily corrected by bicarbonate administration. There is further evidence that glucocorticoid excess contributes to the enhanced muscle proteolysis in ARF. Moreover, several studies have demonstrated that only in the presence of both glucocorticoids and acidosis could proteolysis occur. Investigation of the cellular mechanism by which muscle proteins are degraded indicates the importance of the cytosolic, soluble ATP- and ubiquitin-dependent proteolytic system. Successful treatment of various catabolic conditions with recombinant human growth hormone and insulin-like growth factor-I seems to be a promising strategy in severely catabolic patients with ARF. Anticytokine therapy appears to be another promising treatment in the course of catabolic illness due to sepsis; however, clinical application is still in its infancy.
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PMID:Protein catabolism in acute renal failure. 938 14

The phosphorylation of Ca(2+)-transport ATPase of rat liver endoplasmic reticulum (ER) during early and late septic shock induced by cecum ligation and puncture (CLP) was investigated by determining incorporation of [gamma-32P] ATP into Ca(2+)-ATP phosphoprotein intermediate. Hepatic endoplasmic reticulum was isolated by differential centrifugation with sucrose density gradient. The Ca(2+)-ATPase phosphoprotein intermediate was identified by SDS-PAGE. The results showed that the phosphorylation of Ca(2+)-ATPase (115 kD) was decreased respectively by 15-23% (P < 0.05) and 17-27% (P < 0.05) at 9 h (early sepsis) and 18 h (late sepsis), following the CLP in the rough, intermediate and smooth ER preparations. Kinetic analysis using rough ER showed that the Vmax for Ca2+ and for ATP for the phosphorylation of Ca(2+)-ATPase were decreased dramatically during early and late sepsis, but without changes in the K(m) values. These results demonstrate that the phosphorylation of the phosphoprotein intermediate of Ca(2+)-ATPase in rat liver was impaired during different phases of sepsis.
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PMID:[Impairment in the phosphorylation of Ca(2+)-transport ATPase of rat liver endoplasmic reticulum during sepsis]. 938 79

Changes in protein kinase C (PKC) (calcium- and phospholipid-dependent protein kinase) activity in rat liver during different metabolic phases of sepsis were studied. Sepsis was induced by cecal ligation and puncture (CLP). Experiments were divided into three groups: control, early sepsis, and late sepsis. Early and late sepsis refers to those animals sacrificed at 9 and 18 h, respectively, after CLP. Hepatic PKC was extracted and partially purified by ammonium sulfate fractionation and DEAE-cellulose chromatography. PKC activity was assayed based on the rate of incorporation of 32p from [gamma-32P]ATP into histone. The results show that during early sepsis, both membrane-associated and cytosolic PKC activities remained relatively unaltered. During late sepsis, membrane-associated PKC was unaffected while cytosolic PKC activity was decreased by 19.5-34.4%. Kinetic analysis of the data on cytosolic PKC during late phase of sepsis reveals that the Vmax values for ATP, histone, Ca2+, phosphatidylserine, and diacylglycerol were decreased by 23.4, 22.1, 19.5, 25, and 34.4%, respectively, with no changes in their Km values. These data indicate that cytosolic PKC activity was inactivated in rat liver during late hypoglycemic phase of sepsis. Since PKC-mediated phosphorylation plays an important role in regulating hepatic glucose metabolism, an inactivation of cytosolic PKC may contribute to the development of hypoglycemia during late phase of sepsis.
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PMID:Inactivation of protein kinase C in rat liver during late hypoglycemic phase of sepsis. 956 54

Streptococcus pneumoniae is the major cause of bacterial pneumonia, and it is also responsible for otitis media and meningitis in children. Apart from the capsule, the virulence factors of this pathogen are not completely understood. Recent technical advances in the field of bacterial pathogenesis (in vivo expression technology and signature-tagged mutagenesis [STM]) have allowed a large-scale identification of virulence genes. We have adapted to S. pneumoniae the STM technique, originally used for the discovery of Salmonella genes involved in pathogenicity. A library of pneumococcal chromosomal fragments (400 to 600 bp) was constructed in a suicide plasmid vector carrying unique DNA sequence tags and a chloramphenicol resistance marker. The recent clinical isolate G54 was transformed with this library. Chloramphenicol-resistant mutants were obtained by homologous recombination, resulting in genes inactivated by insertion of the suicide vector carrying a unique tag. In a mouse pneumonia model, 1.250 candidate clones were screened; 200 of these were not recovered from the lungs were therefore considered virulence-attenuated mutants. The regions flanking the chloramphenicol gene of the attenuated mutants were amplified by inverse PCR and sequenced. The sequence analysis showed that the 200 mutants had insertions in 126 different genes that could be grouped in six classes: (i) known pneumococcal virulence genes; (ii) genes involved in metabolic pathways; (iii) genes encoding proteases; (iv) genes coding for ATP binding cassette transporters; (v) genes encoding proteins involved in DNA recombination/repair; and (vi) DNA sequences that showed similarity to hypothetical genes with unknown function. To evaluate the virulence attenuation for each mutant, all 126 clones were individually analyzed in a mouse septicemia model. Not all mutants selected in the pneumonia model were confirmed in septicemia, thus indicating the existence of virulence factors specific for pneumonia.
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PMID:Large-scale identification of virulence genes from Streptococcus pneumoniae. 982 34

Purpose. The purpose of this study was to investigate the relationship between hepatic energy status and liver injury during sepsis, using transgenic mice which express creatine kinase in the liver catalyzing the phosphocreatine/creatine system. Methods. Creatine kinase transgenic mice were fed with normal rodent chow or chow containing 10% creatine for 5 days. Lipopolysaccharide (0.2 mg/kg) combined with d-galactosamine (600 mg/kg) was administered intraperitoneally. Results. Eighty percent of the creatine-fed transgenic mice had survived at 48 h post-d-galactosamine and lipopolysaccharide administration, compared with none of the normally fed transgenic mice. Hepatic phosphocreatine and ATP levels in the normally fed transgenic mice were significantly lower than those in the creatine-fed transgenic mice before and after lipopolysaccharide combined with d-galactosamine was administered. Massive hepatic hemorrhagic necrosis with apoptosis was seen in response to d-galactosamine and lipopolysaccharide in normally fed transgenic mice. These results are consistent with a significant increase in serum aminotransferase at 8 h. In contrast, there were faint necrotic changes in the liver with minimal cellular infiltration in creatine-fed transgenic mice. Conclusions. Maintenance of hepatic ATP levels protects from sepsis-induced liver injury and mortality.
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PMID:The beneficial effect of phosphocreatine accumulation in the creatine kinase transgenic mouse liver in endotoxin-induced hepatic cell death. 987 18

These serial clinical and experimental studies were designed to clarify the pathogenesis of postburn MODS. Both animal and clinical studies were performed. In animal experiments, 46 male cross-bred dogs were cannulated with Swan-Ganz catheters and 39 of them were inflicted with 50% TBSA third degree burns (7 were used as controls). The burned dogs were randomly divided into 4 groups: immediate infusion, delayed infusion, delayed fast infusion and delayed fast infusion combined with ginsenosides. All dogs were kept under constant barbiturate sedation during the whole study period. Hemodynamics, visceral MDA, mitochondrial respiratory control rate (RCR) and ADP/O ratio, ATP, succinic dehydrogenase (SDH), organ water content as well as light and electron microscopy of visceral tissues were determined. In the clinical study, 61 patients with extensive deep burns were chosen, of which 16 sustained MODS. Plasma TXB2/6-keto-PGF1alpha ratio, TNF, SOD, MDA, circulatory platelet aggregate ratio (CPAR), PGE2, interleukin-1, total organ water content and pathological observations of visceral tissues from patients who died of MODS were carried out. Results demonstrated that ischemic-reperfusion damage due to severe shock, sepsis and inhalation injury are three main causes of postburn death. All inflammatory mediators increased markedly in both animals and patients who sustained organ damage or MODS. SDH, RCR, ADP/O and ATP decreased significantly. These findings suggested that ischemic damage and systemic inflammatory response syndrome (SIRS) initiated by mediators or cytokines might be important in the pathogenesis of postburn MODS.
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PMID:Serial experimental and clinical studies on the pathogenesis of multiple organ dysfunction syndrome (MODS) in severe burns. 991 70

Oxygen metabolites formed during reperfusion of ischemic kidneys prevent recovery of renal function after short periods of renal ischemia. The administration of ATP-MgCl2 is beneficial to the survival of animals after hemorrhagic shock, severe burns, septicemia-peritonitis, post-ischemic hepatic failure, bowel ischemia, and endotoxic shock. In this study, the effect of ATP-MgCl2 on lipid peroxidation and its curative effect were evaluated by measuring the decomposition products of lipid peroxidation, detected as thiobarbituric-acid reactive substances in homogenized kidney tissues in ischemic and reperfused rabbit kidneys. Ischemia was performed by clamping the right renal artery for 60 minutes followed by 30 minutes of reperfusion. Thirty-six rabbits were classified into 6 groups containing 6 rabbits in each. In the first group, no renal ischemia-reperfusion (I-R) was designed (Sham group), the right kidney was removed 90 minutes later. In the second group, I-R was established but nothing given. Saline 0.25 cc/kg was given into the right renal artery in group 3 two minutes before ischemia, and in group 4 two minutes before reperfusion. ATP-MgCl2 17.5 mumol/kg (0.25 cc/kg) was given two minutes before ischemia in group 5, and before reperfusion in group 6. The right kidneys of the rabbits were removed and thiobarbituric-acid reactive substances in the homogenates were measured. In addition, histopathological evaluation was performed. High lipid peroxidation products were recorded in groups 2-5, whereas in group 6, these levels were low similar to those obtained in Sham group (76.72 +/- 1.01 nmol/g tissue). On histopathological evaluation, a considerable cell damage resulting from I-R trauma especially in proximal tubules was observed. In groups which were under saline effect, no histopathological damage was found. Histophatological preservation was better in group 6 rather than in group 5. The results of this study indicate that ATP-MgCl2 is remarkably effective for preventing the lipid peroxidation if given before reperfusion but not before ischemia in experimental I-R injury in rabbit kidneys.
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PMID:The effect of ATP-MgCl2 on lipid peroxidation in ischemic and reperfused rabbit kidney. 1020 3

Insulin plays a major role in the regulation of skeletal muscle protein turnover but its mechanism of action is not fully understood, especially in vivo during catabolic states. These aspects are presently reviewed. Insulin inhibits the ATP-ubiquitin proteasome proteolytic pathway which is presumably the predominant pathway involved in the breakdown of muscle protein. Evidence of the ability of insulin to stimulate muscle protein synthesis in vivo was also presented. Many catabolic states in rats, e.g. streptozotocin diabetes, glucocorticoid excess or sepsis-induced cytokines, resulted in a decrease in insulin action on protein synthesis or degradation. The effect of catabolic factors would therefore be facilitated. In contrast, the antiproteolytic action of insulin was improved during hyperthyroidism in man and early lactation in goats. Excessive muscle protein breakdown should therefore be prevented. In other words, the anabolic hormone insulin partly controlled the 'catabolic drive'. Advances in the understanding of insulin signalling pathways and targets should provide information on the interactions between insulin action, muscle protein turnover and catabolic factors.
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PMID:Insulin action on skeletal muscle protein metabolism during catabolic states. 1022

During the last years many investigations have shown that a major catalyst within the mechanism of skeletal muscle wasting occurring under conditions like sepsis, injuries, trauma, cancer cachexia, chronic acidosis, fasting, glucocorticoid treatment, and insulinopenia is the ubiquitin-proteasome system. Evidence for this was obtained by findings that the rate of ATP-dependent protein degradation is increased, that m-RNA concentrations of several proteasome subunits and ubiquitin are increased and the amount of ubiquitin-protein conjugates is elevated under these conditions. Additionally, the enhanced protein breakdown was shown to be suppressed by proteasome inhibitors. In the present report we show that most but not all of the proteolytic activities of partially purified 20S/26S proteasomes from skeletal muscle of rats increase after induction of Diabetes mellitus. This finding suggests that part of the mechanism of acceleration of muscle protein breakdown is due to changes in proteasome activities.
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PMID:Alterations of proteasome activities in skeletal muscle tissue of diabetic rats. 1036 52

Catabolism of lean body mass (particularly muscle) occurs in sepsis and other forms of critical illness despite apparently adequate nutritional support. The determination of the optimal balance of carbohydrate and fat intake in this circumstance should be based on the resulting effect on the maintenance of lean body mass, and the nature and extent of any side effects. The general stress response involves a disruption in normal glucoregulation, in that hepatic glucose production is accelerated and the normal blood glucose lowering action of insulin is diminished. Nonetheless, the capacity to oxidize glucose once inside the cells is not impaired. Lipolysis, or the breakdown of peripheral triglycerides to free fatty acids (FFA) and glycerol, is accelerated in critical illness, to a greater extent than fat oxidation. Provision of exogenous fat maintains fat stores, but has minimal effect on the direct oxidation of plasma FFA. From the results of oxidation studies, it seems that about 5 mg kg x min of glucose can be readily oxidized, and the balance of energy will be supplied by the oxidation of fat, either endogenous or exogenous. However, an additional consideration in determining the optimal caloric substrate is that insulin is a potent anabolic hormone and stimulates muscle protein synthesis. Consequently, provision of exogenous insulin enhances retention of muscle. This procedure dictates that almost all non-protein calories be provided as carbohydrate to avoid hypoglycemia. Preliminary studies suggest this may be the optimal approach in critically ill patients. Glucose and fatty acids are the major energy substrates in the body. The oxidative metabolism of these substrates provides the ATP needed for physiological function, including protein synthesis. Over the past 20 y, development of new techniques in nutritional support have made it possible to provide large amounts of carbohydrate and fat to critically-ill patients, along with protein or amino acids. However, despite providing such patients with what should be more than adequate caloric and protein intake, critically ill patients lose lean body mass (Streat et al, 1987), largely because of persistent muscle catabolism (Sakurai et al, 1995). The general relation between energy substrate metabolism and maintenance of lean body mass has been recognized for many years (Calloway & Spector, 1954), so it is important to examine the alterations in energy substrate metabolism that occur in response to critical illness that may play a role in causing the persistent catabolism of muscle protein.
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PMID:Sepsis as a modulator of adaptation to low and high carbohydrate and low and high fat intakes. 1036 91


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