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)

Catabolic conditions such as uremia, cancer, insulin-dependent diabetes and sepsis are associated with muscle atrophy resulting from activation of the ubiquitin-proteasome proteolytic pathway. Evidence for the activation of this pathway includes an increase in both proteolytic activity and capacity, as demonstrated by increased protein degradation and a higher rate of gene transcription in muscle yielding increased levels of mRNAs encoding components of the pathway. Glucocorticoids are critical but other hormones and cytokines interact to regulate the activity of this proteolytic pathway.
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PMID:Mechanisms stimulating protein degradation to cause muscle atrophy. 1056 34

Muscle protein breakdown during sepsis is associated with upregulated expression and activity of the ubiquitin-proteasome proteolytic pathway. Previous studies suggest that ubiquitination of proteins in skeletal muscle is regulated by the ubiquitin ligase E3alpha together with the 14 kDa ubiquitin-conjugating enzyme E2(14k). The E3alpha gene was cloned only recently. The influence of sepsis on the gene expression of E3alpha in skeletal muscle has not been reported. In the present study, induction of sepsis in rats by cecal ligation and puncture resulted in increased mRNA levels for E3alpha in white, fast-twitch but not in red slow-twitch muscle. Treatment with the glucocorticoid receptor antagonist RU38486 (10 mg/kg) prevented the sepsis-induced increase in E3alpha and E2(14k) mRNA levels. The present study is the first report of increased E3alpha expression in skeletal muscle during sepsis. The results lend further support to the concept that glucocorticoid-mediated upregulation of the ubiquitin-proteasome proteolytic pathway is involved in sepsis-induced muscle cachexia. Increased expression of both E3alpha and E2(14k) suggests that muscle proteins are degraded in the N-end rule pathway during sepsis.
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PMID:The gene expression of ubiquitin ligase E3alpha is upregulated in skeletal muscle during sepsis in rats-potential role of glucocorticoids. 1063 Oct 91

Sepsis-induced muscle proteolysis mainly reflects ubiquitin-proteasome-dependent protein degradation. The effect of in vivo administration of a proteasome inhibitor on muscle protein breakdown during sepsis is not known. We treated rats with the proteasome inhibitor N-benzyloxycarbonyl-Ile-Glu-(O-t-butyl)-Ala-leucinal (PSI) or corresponding volume of vehicle i.p. 2 h before sham-operation or induction of sepsis by cecal ligation and puncture. The sepsis-induced increase in total and myofibrillar muscle protein breakdown was inhibited in rats treated in vivo with PSI and a maximal effect was seen following 15 mg/kg of the proteasome inhibitor. Results from in vitro experiments in which incubated muscles were treated with 100 microM PSI suggest that the drug has a direct effect on muscle and that the effect is specific for the proteasome. The results are important because they suggest that it may be possible to prevent or improve the cachectic response in skeletal muscle during sepsis by treatment with a proteasome inhibitor.
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PMID:Sepsis-induced muscle proteolysis is prevented by a proteasome inhibitor in vivo. 1073 30

Based on the essential involvement of NF-kappaB in immune and inflammatory responses and its apoptosis-rescue function in normal and malignant cells, inhibitors of this transcription factor are potential therapeutics for the treatment of a wide range of diseases, from bronchial asthma to cancer. Yet, given the essential function of NF-kappaB in the embryonic liver, it is important to determine its necessity in the liver beyond embryogenesis. NF-kappaB is normally retained in the cytoplasm by its inhibitor IkappaB, which is eliminated upon cell stimulation through phosphorylation-dependent ubiquitin degradation. Here, we directed a degradation-resistant IkappaBalpha transgene to mouse hepatocytes in an inducible manner and showed substantial tissue specificity using various means, including a new method for live-animal imaging. Transgene expression resulted in obstruction of NF-kappaB activation, yet produced no signs of liver dysfunction, even when implemented over 15 months. However, the transgene-expressing mice were very vulnerable both to a severe immune challenge and to a systemic bacterial infection. Despite having intact immunocytes and inflammatory cells, these mice were unable to clear Listeria monocytogenes from the liver and succumbed to sepsis. These findings indicate the essential function of the hepatocyte through NF-kappaB activation in certain systemic infections, possibly by coordinating innate immunity in the liver.
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PMID:High susceptibility to bacterial infection, but no liver dysfunction, in mice compromised for hepatocyte NF-kappaB activation. 1080 15

We examined the effect of insulin-like growth factor I (IGF-I), administered in vivo, on protein turnover rates and gene expression of the ubiquitin-proteasome proteolytic pathway in skeletal muscle of septic rats. Sepsis was induced by cecal ligation and puncture. Other rats were sham-operated. Miniosmotic pumps were implanted sc, and groups of rats received IGF-I (7 mg/kg x 24 h) or saline. Protein synthesis and breakdown rates were determined in incubated extensor digitorum longus muscles. Messenger RNA levels for ubiquitin and the ubiquitin-conjugating enzyme E2(14k) were determined by Northern blot analysis. Sepsis resulted in an approximately 30% reduction of muscle protein synthesis, and this effect of sepsis was blunted in rats treated with IGF-I. In contrast, IGF-I did not prevent the sepsis-induced increase in total and myofibrillar muscle protein breakdown. Ubiquitin and E2(14k) messenger RNA levels were increased several fold in muscle from septic rats, and this effect of sepsis was abolished in IGF-I treated rats. The results suggest that administration of IGF-I may improve sepsis-induced muscle cachexia by stimulating protein synthesis. However, because muscles were resistant to IGF-I, with regard to regulation of protein breakdown, the use of IGF-I to treat muscle cachexia during sepsis remains unclear. An additional important implication of the present study is that changes in messenger RNA levels for ubiquitin and the ubiquitin-conjugating enzyme E2(14k) do not always reflect changes in muscle protein breakdown rates.
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PMID:Insulin-like growth factor I reduces ubiquitin and ubiquitin-conjugating enzyme gene expression but does not inhibit muscle proteolysis in septic rats. 1091 58

A 22-year-old man developed unconsciousness, severe quadriplegia and muscle atrophy, and had markedly elevated serum creatine kinase levels after using the high-dose steroid and nondepolarizing neuromuscular blocking agents during the course of sepsis and DIC. On neurological examination, he was lethargic. The patient had generalized muscle weakness and wasting, and diminished deep tendon reflexes. He weakly responsed to painful stimuli on the legs. The motor nerve conduction study demonstrated decreased CMAP (compound muscle action potential) amplitudes. Motor and sensory nerve conduction velocities and their distal latencies were normal. Muscle biopsy revealed marked muscle fiber atrophy predominantly in type 2 fibers and numerous basophilic and a few necrotic fibers. Some atrophic fibers had decreased to absent myosin adenosine triphosphatase activity in their center. Accordingly, he was diagnosed as having acute quadriplegic myopathy (AQM), which has been reported mainly in Western countries. The mechanism of muscle fiber degradation in this myopathy is still unknown. On immunohistochemical analysis to our patient, enzyme activities of various proteases such as calpain, cathepsin B, and proteasomes were increased in the sarcoplasm, especially in the atrophic fibers. We suggest that lysosomal cathepsin, nonlysosomal calpain, and ATP-ubiquitin-proteasome proteolytic pathways participate in muscle fiber degradation in AQM.
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PMID:[A case of acute quadriplegic myopathy]. 1108 98

Muscle catabolism is an important component of the metabolic response to stress and injury, including sepsis and burn injury. Muscle wasting and weakness in catabolic patients may adversely affect the outcome in these patients owing to delayed ambulation and involvement of respiratory muscles. An understanding of the regulation of muscle protein breakdown during sepsis and following injury therefore is of great importance from a clinical standpoint and is essential for the development of new therapeutic modalities to prevent protein loss from muscle tissue. Studies in experimental animals and in patients have provided evidence that the myofibrillar proteins actin and myosin are particularly sensitive to the effects of sepsis and injury. (Glucocorticoids, interleukin-1, and tumor necrosis factor participate in the regulation of muscle protein breakdown. Most muscle proteins are degraded by the ubiquitin-proteasome-dependent proteolytic pathway. Because the proteasome does not degrade intact myofibrils, a calcium-dependent Z-band disintegration and release of myofilaments from the myofibrils may be an important initial step of muscle breakdown during sepsis and other catabolic conditions. Continued studies to define mechanisms of the catabolic response to stress and injury are important for improving the metabolic care of patients with muscle catabolism.
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PMID:Catabolic response to stress and injury: implications for regulation. 1119 8

Sepsis is associated with increased muscle proteolysis and upregulated transcription of several genes in the ubiquitin-proteasome proteolytic pathway. Glucocorticoids are the most important mediator of sepsis-induced muscle cachexia. Here, we examined the influence of sepsis in rats on the transcription factors NF-kappaB and AP-1 in skeletal muscle and the potential role of glucocorticoids in the regulation of these transcription factors. Sepsis was induced by cecal ligation and puncture (CLP). Control rats were sham-operated. NF-kappaB and AP-1 DNA binding activity was determined by electrophoretic mobility shift assay (EMSA) in extensor digitorum longus muscles at different time points up to 16 h after sham-operation or CLP. Sepsis resulted in an early (4 h) upregulation of NF-kappaB activity followed by inhibited NF-kappaB activity at 16 h. AP-1 binding activity was increased at all time points studied during the septic course. When rats were treated with the glucocorticoid receptor antagonist RU38486, NF-kappaB activity increased, whereas AP-1 activity was not influenced by RU38486. The results suggest that NF-kappaB and AP-1 are differentially regulated in skeletal muscle during sepsis and that glucocorticoids may regulate some but not all transcription factors in septic muscle.
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PMID:The transcription factors NF-kappab and AP-1 are differentially regulated in skeletal muscle during sepsis. 1124 82

Studies of many different rodent models of muscle wasting have indicated that accelerated proteolysis via the ubiquitin-proteasome pathway is the principal cause of muscle atrophy induced by fasting, cancer cachexia, metabolic acidosis, denervation, disuse, diabetes, sepsis, burns, hyperthyroidism and excess glucocorticoids. However, our understanding about how muscle proteins are degraded, and how the ubiquitin-proteasome pathway is activated in muscle under these conditions, is still very limited. The identities of the important ubiquitin-protein ligases in skeletal muscle, and the ways in which they recognize substrates are still largely unknown. Recent in-vitro studies have suggested that one set of ubquitination enzymes, E2(14K) and E3(alpha), which are responsible for the 'N-end rule' system of ubiquitination, plays an important role in muscle, especially in catabolic states. However, their functional significance in degrading different muscle proteins is still unclear. This review focuses on the many gaps in our understanding of the functioning of the ubiquitin-proteasome pathway in muscle atrophy, and highlights the strengths and limitations of the different experimental approaches used in such studies.
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PMID:What do we really know about the ubiquitin-proteasome pathway in muscle atrophy? 1151 50

The ubiquitin-proteasome pathway is regarded as playing a crucial role in protein breakdown in inflammation and sepsis as well as in the regulation of inflammatory cell responses. In this pathway, ubiquitylation of target proteins is believed to act as a recognition signal for degradation by the 26S proteasome. As yet neither the ubiquitylation rate of cytosolic proteins, as a result of the total ubiquitin-protein ligase (tUbPL) activity, nor the specific ubiquitylation of calmodulin (ubiquitin-calmodulin ligase, uCaM-synthetase) has been determined in human mononuclear cells. Therefore, we studied cytosolic protein ubiquitylation in normal and in endotoxin (LPS)-stimulated human peripheral blood mononuclear cells (PBMNCs).PBMNCs from healthy volunteers were incubated with 0 or 100 ng/ml LPS for 18 h. Cytosolic extracts were obtained by hypotonic lysis and ultracentrifugation. TUbPL was measured as [(125)I]-[CT]-ubiquitin incorporation into the sum of cytosolic proteins. UCaM-synthetase activity was quantified with the fluphenazine (FP)-Sepharose affinity adsorption test. Endotoxin stimulation appears to inhibit tUbPL 3.7 +/- 2.7-fold to 48 +/- 43 fkat/mg (n = 6). UCaM-synthetase in cultures (n = 5) without endotoxin was determined to be 91 +/- 32 fkat/mg +Ca(2+) and 29 +/- 23 fkat/mg -Ca(2+). With endotoxin uCaM-synthetase was 138 +/- 73 fkat/mg +Ca(2+) and 14 +/- 22 fkat/mg -Ca(2+). Ca(2+)-specificity (ratio +/- Ca(2+)) of uCaM-synthetase increases from 3.1 without LPS to 10 after LPS stimulation, which was caused by a 2-fold decrease in minus Ca(2+) activity and a 1.5-fold increase in plus Ca(2+) activity. The data indicate specific regulatory effects of endotoxin on the cytosolic ubiquitylation systems in human PBMNCs.
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PMID:Cytosolic protein ubiquitylation in normal and endotoxin stimulated human peripheral blood mononuclear cells. 1152 Oct 75


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