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)

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

During the last 30 years, investigation of the transcriptional and translational mechanisms of gene regulation has been a major focus of molecular cancer biology. More recently, it has become evident that cancer-related mutations and cancer-related therapies also can affect post-translational processing of cellular proteins and that control exerted at this level can be critical in defining both the cancer phenotype and the response to therapeutic intervention. One post-translational mechanism that is receiving considerable attention is degradation of intracellular proteins through the multicatalytic 26S proteasome. This follows growing recognition of the fact that protein degradation is a well-regulated and selective process that can differentially control intracellular protein expression levels. The proteasome is responsible for the degradation of all short-lived proteins and 70-90% of all long-lived proteins, thereby regulating signal transduction through pathways involving factors such as AP1 and NFKB, and processes such as cell cycle progression and arrest, DNA transcription, DNA repair/misrepair, angiogenesis, apoptosis/survival, growth and development, and inflammation and immunity, as well as muscle wasting (e.g. in cachexia and sepsis). In this review, we discuss the potential involvement of the proteasome in both cancer biology and cancer treatment.
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PMID:The proteasome in cancer biology and treatment. 1160 57

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

Muscle cachexia induced by sepsis, severe injury, cancer, and a number of other catabolic conditions is mainly caused by increased protein degradation, in particular breakdown of myofibrillar proteins. Ubiquitin-proteasome-dependent proteolysis is the predominant mechanism of muscle protein loss in these conditions, but there is evidence that several other regulatory mechanisms may be important as well. Some of those mechanisms are reviewed in this article and they include pre-, para-, and postproteasomal mechanisms. Among preproteasomal mechanisms, mediators, receptor binding, signaling pathways, activation of transcription factors, and modification of proteins are important. Several paraproteasomal mechanisms may influence the trafficking of ubiquitinated proteins and their interaction with the proteasome, including the expression and activity of the COP9 signalosome, the carboxy terminus of heat shock protein 70-interacting protein (CHIP) and valosin-containing protein (VCP). Finally, because the proteasome does not degrade proteins completely into free amino acids but into peptides, postproteasomal degradation of peptides by the giant protease tripeptidyl peptidase II (TPP II) and various aminopeptidases is important in muscle catabolism. Thus, multiple mechanisms and regulatory steps may influence the breakdown of ubiquitinated muscle proteins by the 26S proteasome.
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PMID:Molecular regulation of muscle cachexia: it may be more than the proteasome. 1177 24

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-proteasome-dependent protein degradation plays a central role in sepsis-induced muscle wasting. Because the proteasome degrades proteins into small peptides rather than free amino acids, it is likely that additional mechanisms downstream of the proteasome are involved in sepsis-induced muscle proteolysis. Recent studies suggest that the extralysosomal peptidase tripeptidyl-peptidase II (TPP II) degrades peptides generated by the proteasome. We hypothesized that TPP II expression and activity are increased in skeletal muscle during sepsis. Sepsis was induced in rats by cecal ligation and puncture. Control rats were sham-operated. TPP II activity was determined by using the specific substrate Ala-Ala-Phe-7-amido-4-methylcoumarin (AAF-AMC). TPP II protein and gene expression were determined by Western blot and real-time PCR, respectively. Sepsis resulted in increased activity and protein and gene expression of TPP II in extensor digitorum longus muscles. This result was blunted by the glucocorticoid receptor antagonist RU 38486, indicating that glucocorticoids participate in the upregulation of TPP II in skeletal muscle during sepsis. The results suggest that proteolytic mechanisms downstream of the proteasome may be important for the complete degradation of muscle proteins during sepsis.
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PMID:Tripeptidyl-peptidase II expression and activity are increased in skeletal muscle during sepsis. 1214 24

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


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