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)

Alteration of skeletal muscle protein breakdown is a hallmark of a set of pathologies, including sepsis, with negative consequences for recovery. The aim of the present study was to search for muscle markers associated with protein loss, which could help in predicting and understanding pathological wasting. With the use of differential display reverse transcription-PCR, we screened differentially expressed genes in muscle from septic rats in a long-lasting catabolic state. One clone was isolated, confirmed as being overexpressed in septic skeletal muscle and identified as encoding the lysosomal cysteine endopeptidase cathepsin L. Northern- and Western-blot analysis of cathepsin L in gastrocnemius or tibialis anterior muscles of septic rats confirmed an elevation (up to 3-fold) of both mRNA and protein levels as early as 2 days post-infection, and a further increase 6 days post-infection (up to 13-fold). At the same time, the increase in mRNAs encoding other lysosomal endopeptidases or components of the ubiquitin-proteasome pathway did not exceed 4-fold. Cathepsin L mRNA was also increased in tibialis anterior muscle of rats treated with the glucocorticoid analogue, dexamethasone, or rats bearing the Yoshida Sarcoma. The increase in cathepsin L mRNA was reduced by 40% when the tumour-bearing animals were treated with pentoxifylline, an inhibitor of tumour necrosis factor-alpha production. In conclusion, these results demonstrate a positive and direct correlation between cathepsin L mRNA and protein level and the intensity of proteolysis, and identify cathepsin L as an appropriate early marker of muscle wasting. Cathepsin L presumably participates in the pathological response leading to muscle loss, with glucocorticoids and tumour necrosis factor-alpha potentially being involved in the up-regulation of cathepsin L.
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PMID:Identification of cathepsin L as a differentially expressed message associated with skeletal muscle wasting. 1169 1

The development of new pharmacological approaches for preventing muscle wasting in cancer is an important goal because cachectic patients display a reduced response to chemotherapy and radiotherapy. Xanthine derivatives such as pentoxifylline inhibit tumour necrosis factor-alpha (TNF) production, which has been implicated in the signalling of muscle wasting. However, the effect of pentoxifylline has been inconclusive in clinical trials. We report here the first direct evidence that daily injections of torbafylline (also known as HWA 448), another xanthine derivative, had no effect by itself on muscle proteolysis in control healthy rats. In cancer rats, the drug blocked the lipopolysaccharide-induced hyperproduction of TNF and prevented muscle wasting. In these animals HWA 448 suppressed the enhanced proteasome-dependent proteolysis, which is sensitive to the proteasome inhibitor MG132, and the accumulation of high-molecular-mass ubiquitin (Ub) conjugates in the myofibrillar fraction. The drug also normalized the enhanced muscle expression of Ub, which prevails in the atrophying muscles from cancer rats. In contrast, HWA 448 did not reduce the increased expression of either the 14 kDa Ub conjugating enzyme E2 or the ATPase and non-ATPase subunits of the 19 S regulatory complex of the 26 S proteasome, including the non-ATPase subunit S5a, which recognizes polyUb degradation signals. Finally, the drug also prevented muscle wasting in septic rats (which exhibit increased TNF production), and was much more potent than pentoxifylline or other xanthine derivatives. Taken together, the data indicate that HWA 448 is a powerful inhibitor of muscle wasting that blocks enhanced Ub-proteasome-dependent proteolysis in situations where TNF production rises, including cancer and sepsis.
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PMID:Torbafylline (HWA 448) inhibits enhanced skeletal muscle ubiquitin-proteasome-dependent proteolysis in cancer and septic rats. 1177 90

Sepsis-induced muscle cachexia is associated with increased expression of several genes in the ubiquitin-proteasome proteolytic pathway, but little is known about the activation of transcription factors in skeletal muscle during sepsis. We tested the hypothesis that sepsis upregulates the expression and activity of the transcription factors CCAAT/enhancer binding protein (C/EBP)-beta and -delta in skeletal muscle. Sepsis was induced in rats by cecal ligation and puncture, and control rats were sham operated. C/EBP-beta and -delta DNA-binding activity was determined by electrophoretic mobility shift assay and supershift analysis. In addition, C/EBP-beta and -delta nuclear protein levels were determined by Western blot analysis. Sepsis resulted in increased DNA-binding activity of C/EBP, and supershift analysis suggested that this reflected activation of the beta- and delta-isoforms of C/EBP. Concomitantly, C/EBP-beta and -delta protein levels were increased in the nuclear fraction of skeletal muscle. In additional experiments, we tested the role of glucocorticoids in sepsis-induced activation of C/EBP-beta and -delta by treating rats with the glucocorticoid receptor antagonist RU-38486. This treatment inhibited the sepsis-induced activation of C/EBP-beta and -delta, suggesting that glucocorticoids participate in the upregulation of C/EBP in skeletal muscle during sepsis. The present results suggest that C/EBP-beta and -delta are activated in skeletal muscle during sepsis and that this response is, at least in part, regulated by glucocorticoids.
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PMID:C/EBP DNA-binding activity is upregulated by a glucocorticoid-dependent mechanism in septic muscle. 1179 53

Ubiquitin is suggested to play a key role in essential intracellular functions, such as heat shock response, protein breakdown, and regulation of immune responses. Ubiquitin has also been detected in the extracellular space, but the function and biologic significance is unclear. We describe a new function of extracellular ubiquitin and show that extracellular ubiquitin specifically inhibits ex vivo secretion of tumor necrosis factor-alpha (TNF-alpha) and TNF-alpha mRNA expression from peripheral blood mononuclear cells (PBMNCs) in response to endotoxin in a dose-dependent manner. In contrast, the TNF-alpha response to zymosan or Staphylococcus aureus as well as the interleukin-6 (IL-6) and IL-8 responses to endotoxin were unaffected by ubiquitin. Measurement of serum ubiquitin levels showed a significant 5- to 7-fold increase in sepsis and trauma patients, to the level required for inhibition of the PBMNC TNF-alpha response to endotoxin by ubiquitin. Elevated ubiquitin levels in serum were significantly correlated with a reduced TNF-alpha production. Antibodies to ubiquitin were able to (1) significantly increase (2- to 5-fold) the TNF-alpha response to endotoxin in whole blood from trauma and sepsis patients, (2) completely neutralize the inhibitory effect of trauma patients' serum on healthy donors' TNF-alpha production, and (3) partially neutralize the inhibitory effect of sepsis patients' serum on healthy donors' TNF-alpha production. Ubiquitin-depleted serum from trauma patients lost the inhibitory activity for TNF-alpha production, whereas extracted endogenous ubiquitin exerts the inhibitory activity. The results demonstrate that extracellular ubiquitin acts as a cytokinelike protein with anti-inflammatory properties and indicate that extracellular ubiquitin is involved in the regulation of immunodepression in critical illness.
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PMID:Extracellular ubiquitin inhibits the TNF-alpha response to endotoxin in peripheral blood mononuclear cells and regulates endotoxin hyporesponsiveness in critical illness. 1240

The catabolic response to sepsis, severe injury, and burn is characterized by whole-body protein loss, mainly reflecting increased breakdown of muscle proteins, in particular myofibrillar proteins. Glucocorticoids and various proinflammatory cytokines are important regulators of muscle proteolysis in stressed patients. There is evidence that breakdown of proteins by the ubiquitin-proteasome pathway plays an important role in muscle cachexia, although other mechanisms may participate, such as calcium- and calpain-dependent release of myofilaments from the sarcomere. Three types of treatments have been used to reduce or prevent the catabolic response to injury and sepsis: 1). nutritional, 2). hormonal, and 3). pharmacologic. With regard to nutrition support, it is generally believed that enteral feeding is superior to parenteral feeding and that early feeding is better than late feeding. Although "immune-enhancing" enteral nutrition has been shown in several recent studies to improve outcome in critically ill patients, the specific effects of these treatments on the catabolic response in muscle are not known. In addition to nutrition support, various hormones, including insulin, growth hormone, and insulin-like growth factor-1, may blunt the catabolic response in patients with stress. Experimental studies have indicated that other treatments may become available in the future, including cytokine antibodies, calcium antagonists, and induction of heat shock response. Methods to prevent or reduce the catabolic response to stress are important considering the significant clinical consequences of muscle cachexia.
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PMID:Catabolic response to stress and potential benefits of nutrition support. 1243 20

The daily turnover of cellular proteins is the same as the amount of protein contained in 1 to 1.5 kg of muscle. Consequently, even a small but persistent increase in protein degradation or decrease in protein synthesis results in substantial loss of muscle mass, as shown in patients with trauma, sepsis, or kidney failure. Activation of the ubiquitin-proteasome proteolytic system in muscle is the major pathway contributing to loss of muscle mass in catabolic illnesses. At least 3 signals have been identified as causing loss of muscle mass: acidosis, defective insulin action, and glucocorticoids. The influence of inflammatory cytokines on this system in muscle is more complicated because cytokines can suppress the system unless glucocorticoids are present. An initial reaction that breaks down muscle appears to involve caspases. Such information could lead to therapies that successfully prevent the loss of muscle mass in catabolic illnesses.
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PMID:Mechanisms activating proteolysis to cause muscle atrophy in catabolic conditions. 1267 40

Muscle atrophy is a common consequence of catabolic conditions like kidney failure, cancer, sepsis, and acute diabetes. Loss of muscle protein is due primarily to activation of the ubiquitin-proteasome proteolytic system. The proteolytic responses to catabolic signals include increased levels of mRNA that encode various components of the system. In the case of two genes, the proteasome C3 subunit and ubiquitin UbC, the higher levels of mRNA result from increased transcription but the mechanisms of transactivation differ between them. This review summaries the evidence that cachectic signals activate a program of selective transcriptional responses in muscle that frequently occurs coordinately with increased protein destruction.
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PMID:Increased transcription of ubiquitin-proteasome system components: molecular responses associated with muscle atrophy. 1267 54

Muscle wasting during sepsis reflects increased expression and activity of the ubiquitin-proteasome proteolytic pathway and is at least in part mediated by glucocorticoids. The ubiquitination of proteins destined to be degraded by the proteasome is regulated by multiple enzymes, including ubiquitin ligases. We tested the hypothesis that sepsis upregulates the gene expression of the newly described ubiquitin ligases, MuRF1 and atrogin-1/MAFbx. Sepsis was induced in rats by cecal ligation and puncture. Control rats were sham-operated. In some experiments, rats were treated with the glucocorticoid receptor antagonist RU 38486 before induction of sepsis. At various time points after induction of sepsis, mRNA levels for MuRF1 and atrogin-1/MAFbx were determined in extensor digitorum longus muscles by real-time PCR. Sepsis resulted in a 10-16-fold increase in gene expression of the ubiquitin ligases studied here. These changes were much greater than those observed previously for another ubiquitin ligase, E3alpha, in muscle during sepsis. Treatment of rats with RU 38486 prevented the sepsis-induced increase in mRNA levels for MuRF1 and atrogin-1/MAFbx, suggesting that glucocorticoids participate in the upregulation of these genes in muscle during sepsis. The present results lend further support to the concept that the ubiquitin-proteasome pathway plays an important role in sepsis-induced muscle proteolysis and suggest that multiple ubiquitin ligases may participate in the development of muscle wasting during sepsis.
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PMID:Sepsis upregulates the gene expression of multiple ubiquitin ligases in skeletal muscle. 1267 61

Skeletal muscle atrophy occurs in multiple clinical settings, including cancer, AIDS and sepsis, and is caused in part by an increase in the rate of ATP-dependent ubiquitin-mediated proteolysis. The expression of two recently identified genes encoding ubiquitin-protein ligases, MAFbx/Atrogin-1 and MuRF1, has been shown to increase during muscle atrophy. Mouse knockout studies have demonstrated that MAFbx and MuRF1 are required for muscle atrophy, and thus might be targets for clinical intervention. A second strategy for blocking atrophy involves the stimulation of pathways leading to skeletal muscle hypertrophy. Insulin-like growth factor 1 (IGF-1) is a protein growth factor that can induce skeletal muscle hypertrophy by activating the phosphatidylinositol 3-kinase (PI3K)-Akt pathway. The pathways modulating hypertrophy and atrophy will be further discussed, to highlight potential targets for clinical intervention.
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PMID:Molecular mechanisms modulating muscle mass. 1292 36

With trauma, sepsis, cancer, or uremia, animals or patients experience accelerated degradation of muscle protein in the ATP-ubiquitin-proteasome (Ub-P'some) system. The initial step in myofibrillar proteolysis is unknown because this proteolytic system does not break down actomyosin complexes or myofibrils, even though it degrades monomeric actin or myosin. Since cytokines or insulin resistance are common in catabolic states and will activate caspases, we examined whether caspase-3 would break down actomyosin. We found that recombinant caspase-3 cleaves actomyosin, producing a characteristic, approximately 14-kDa actin fragment and other proteins that are degraded by the Ub-P'some. In fact, limited actomyosin cleavage by caspase-3 yields a 125% increase in protein degradation by the Ub-P'some system. Serum deprivation of L6 muscle cells stimulates actin cleavage and proteolysis; insulin blocks these responses by a mechanism requiring PI3K. Cleaved actin fragments are present in muscles of rats with muscle atrophy from diabetes or chronic uremia. Accumulation of actin fragments and the rate of proteolysis in muscle stimulated by diabetes are suppressed by a caspase-3 inhibitor. Thus, in catabolic conditions, an initial step resulting in loss of muscle protein is activation of caspase-3, yielding proteins that are degraded by the Ub-P'some system. Therapeutic strategies could be designed to prevent these events.
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PMID:Activation of caspase-3 is an initial step triggering accelerated muscle proteolysis in catabolic conditions. 1470 15


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