Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim was to explore efficacy of tumor necrosis factor (TNF) inhibitors in attenuating increases in anorexia and ubiquitin proteasome pathway transcripts in cardiac cachexia, a potentially lethal condition that responds poorly to current treatments. Cardiac cachexia was rapidly induced with monocrotaline in Sprague-Dawley rats. Either soluble TNF receptor-1 or the general inhibitor of TNF production, pentoxifylline, was given to diminish TNF action on the first indication of cachexia. Animals were anesthetized with a ketamine-xylazine-acepromazine cocktail, and then skeletal muscles were removed for subsequent measurements including ubiquitin proteasome pathway transcripts and Western blots. Both soluble TNF receptor-1 and pentoxifylline attenuated losses in both body and skeletal muscle masses and also reduced increases in selected ubiquitin proteasome pathway transcripts. The action of soluble TNF receptor-1 was partly through reversal of reduced food consumption, while the effects of pentoxifylline were independent of food intake. Here we demonstrate, for the first time, that attenuation of anorexia by soluble TNF receptor-1 treatment in monocrotaline-induced cardiac cachexia is responsible for attenuating increases in some ubiquitin proteasome pathway transcripts as well as preserving body mass and attenuating loss of skeletal muscle mass.
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PMID:Anti-TNF treatment reduces rat skeletal muscle wasting in monocrotaline-induced cardiac cachexia. 1880 59

Cachexia is a term used to describe the poor status of a patient suffering from a benign disease (Crohn's disease, chronic heart and kidney failure) as well as from a malignant disease. Cachexia has an important impact on the survival and morbidity in patients with cancer. The aim of this study is to elucidate the pathophysiology in cancer cachexia with a special emphasis on pancreatic cancer. The dramatic weight loss in malignant diseases is due to anorexia resulting in malnutrition and is characterised by a progressive loss of muscle and fat tissue. Different cytokines like TNF-alpha, IFN-gamma, IL-1, IL-6 are involved in this process. Via the ubiquitin-proteasome pathway, in which also the proteolysis inducing factor (PIF) is involved, the majority of protein is degraded. In patients with cancer cachexia we find an elevated level of lipases, which indicates that rather fat catabolism and not reduced fat synthesis is the main factor in fat metabolism. The development of an effective (pharmacological) treatment is still the main challenge. As yet, none of the used therapies show a long-lasting effect on weight stabilisation and survial. Cachexia is an important issue, especially in pancreatic cancer; it influences the qualitiy of life and has an important impact on survival. Today, there are only a few different pharmacological therapies used in the treatment of cancer cachexia, but each and every single treatment has failed to show a persistent effect on survival. The aim of research and treatment is to interrupt the natural clinical course of cachexia.
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PMID:[Molecular mechanisms and its clinical impact in cancer cachexia]. 1905 8

Cardiac cachexia as a terminal stage of chronic heart failure carries a poor prognosis. The definition of this clinical syndrome has been a matter of debate in recent years. This review describes the ongoing discussion about this issue and the complex pathophysiology of cardiac cachexia and chronic heart failure with particular focus on immunological, metabolic, and hormonal aspects at the intracellular and extracellular level. These include regulators such as neuropeptide Y, leptin, melanocortins, ghrelin, growth hormone, and insulin. The regulation of feeding is discussed as are nutritional aspects in the treatment of the disease. The mechanisms of wasting in different body compartments are described. Moreover, we discuss several therapeutic approaches. These include appetite stimulants like megestrol acetate, medroxyprogesterone acetate, and cannabinoids. Other drug classes of interest comprise angiotensin-converting enzyme inhibitors, beta-blockers, anabolic steroids, beta-adrenergic agonists, anti-inflammatory substances, statins, thalidomide, proteasome inhibitors, and pentoxifylline.
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PMID:Cardiac cachexia: a systematic overview. 1906 14

Impaired functioning of the gastrointestinal system may also contribute to malnutrition and cardiac cachexia (CC) in patients with chronic heart failure (CHF). Targets for future interventions include the deranged hormonal systems involved in energy balance as well as malabsorption from the gut and dietary supplementation. Other targets are the inhibition of proteasome-dependent protein degradation and the direct inhibition of pro-inflammatory pathways. The beneficial effects of ACE inhibitors, aldesterone inhibitors and beta-blockers in preventing or delaying the collagen deposition in the small intestine wall need to be elucidated. We strongly believe that by improving our understanding of the role of the gut in CC will lead to the development of novel therapeutic strategies in the near future.
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PMID:The small intestine: a critical linkage in pathophysiology of cardiac cachexia. 2111 52

Up to 50% of cancer patients suffer from a progressive atrophy of adipose tissue and skeletal muscle, called cachexia, resulting in weight loss, a reduced quality of life, and a shortened survival time. Anorexia often accompanies cachexia, but appears not to be responsible for the tissue loss, particularly lean body mass. An increased resting energy expenditure is seen, possibly arising from an increased thermogenesis in skeletal muscle due to an increased expression of uncoupling protein, and increased operation of the Cori cycle. Loss of adipose tissue is due to an increased lipolysis by tumor or host products. Loss of skeletal muscle in cachexia results from a depression in protein synthesis combined with an increase in protein degradation. The increase in protein degradation may include both increased activity of the ubiquitin-proteasome pathway and lysosomes. The decrease in protein synthesis is due to a reduced level of the initiation factor 4F, decreased elongation, and decreased binding of methionyl-tRNA to the 40S ribosomal subunit through increased phosphorylation of eIF2 on the alpha-subunit by activation of the dsRNA-dependent protein kinase, which also increases expression of the ubiquitin-proteasome pathway through activation of NFkappaB. Tumor factors such as proteolysis-inducing factor and host factors such as tumor necrosis factor-alpha, angiotensin II, and glucocorticoids can all induce muscle atrophy. Knowledge of the mechanisms of tissue destruction in cachexia should improve methods of treatment.
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PMID:Mechanisms of cancer cachexia. 1934 10

Muscle wasting or cachexia is caused by accelerated muscle protein breakdown via the ubiquitin-proteasome complex. We investigated the effect of curcumin c3 complex (curcumin c3) on attenuation of muscle proteolysis using in vitro and in vivo models. Our in vitro data indicate that curcumin c3 as low as 0.50 microg/ml was very effective in significantly inhibiting (30 %; P < 0.05) tyrosine release from human skeletal muscle cells, which reached a maximum level of inhibition of 60 % (P < 0.05) at 2.5 microg/ml. Curcumin c3 at 2.5 microg/ml also inhibited chymotrypsin-like 20S proteasome activity in these cells by 25 % (P < 0.05). For in vivo studies, we induced progressive muscle wasting in mice by implanting the MAC16 colon tumour. The in vivo data indicate that low doses of curcumin c3 (100 mg/kg body weight) was able to prevent weight loss in mice bearing MAC16 tumours whereas higher doses of curcumin c3 (250 mg/kg body weight) resulted in approximately 25 % (P < 0.05) weight gain as compared with the placebo-treated animals. Additionally, the effect of curcumin c3 on preventing and/or reversing cachexia was also evident by gains in the weight of the gastrocnemius muscle (30-58 %; P < 0.05) and with the increased size of the muscle fibres (30-65 %; P < 0.05). Furthermore, curcumin inhibited proteasome complex activity and variably reduced expression of muscle-specific ubiquitin ligases: atrogin-1/muscle atrophy F-box (MAFbx) and muscle RING finger 1 (MURF-1). In conclusion, oral curcumin c3 results in the prevention and reversal of weight loss. The data imply that curcumin c3 may be an effective adjuvant therapy against cachexia.
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PMID:Attenuation of proteolysis and muscle wasting by curcumin c3 complex in MAC16 colon tumour-bearing mice. 1939 14

D-myo-inositol 1,2,6-triphosphate (alpha trinositol, AT) has been shown to attenuate muscle atrophy in a murine cachexia model through an increase in protein synthesis and a decrease in degradation. The mechanism of this effect has been investigated in murine myotubes using a range of catabolic stimuli, including proteolysis-inducing factor (PIF), angiotensin II (Ang II), lipopolysaccharide, and tumor necrosis factor-alpha/interferon-gamma. At a concentration of 100 muM AT was found to attenuate both the induction of protein degradation and depression of protein synthesis in response to all stimuli. The effect on protein degradation was accompanied by attenuation of the increased expression and activity of the ubiquitin-proteasome pathway. This suggests that AT inhibits a signalling step common to all four agents. This target has been shown to be activation (autophosphorylation) of the dsRNA-dependent protein kinase (PKR) and the subsequent phosphorylation of eukaryotic initiation factor 2 on the alpha-subunit, together with downstream signalling pathways leading to protein degradation. AT also inhibited activation of caspase-3/-8, which is thought to lead to activation of PKR. The mechanism of this effect may be related to the ability of AT to chelate divalent metal ions, since the attenuation of the increased activity of the ubiquitin-proteasome pathway by PIF and Ang II, as well as the depression of protein synthesis by PIF, were reversed by increasing concentrations of Zn(2+). The ability of AT to attenuate muscle atrophy by a range of stimuli suggests that it may be effective in several catabolic conditions.
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PMID:Mechanism of attenuation of protein loss in murine C2C12 myotubes by D-myo-inositol 1,2,6-triphosphate. 1971 18

Macrophages from mice bearing advanced mammary tumors are critically impaired in their immune functions, exhibiting reduced expression at the mRNA and protein levels of the crucial transcription factors, nuclear factor kappaB (NFkappaB) and CCAAT enhancer binding protein (C/EBP). We have previously shown that tumor-derived factors such as transforming growth factor beta (TGFbeta) and prostaglandin E2 (PGE2) modulate NFkappaB and C/EBP expression in macrophages. Transcriptional, post-transcriptional, translational and/or post-translational mechanisms may also play a role in altered levels of NFkappaB and C/EBP in macrophages from tumor hosts, contributing to impaired inflammatory response. One of the post-translational mechanisms that may tune down or recycle proteins in cells is the proteasomal pathway. Since upregulation of ubiquitin/proteasomal pathways has been described under cancer-induced cachexia, we examined the possible role of this proteolytic machinery in the decrease of NFkappaB and C/EBP proteins in macrophages from tumor hosts. Using MG-132 proteasome inhibitor to block the proteasome machinery in macrophages from normal and tumor-bearing animals we found that macrophages from tumor hosts display higher ubiquitination and proteolysis compared to those from normal mice and also that NFkappaB and C/EBP downregulation is reversed in these treated cells. Thus, proteasome degradation may contribute, at least in part, to NFkappaB and C/EBP impairment in macrophages from tumor-bearers.
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PMID:Role of the proteasome in the downregulation of transcription factors NFkappaB and C/EBP in macrophages from tumor hosts. 2012 32

Both cytokines and tumor factors have been implicated in tissue loss in cancer cachexia. Loss of adipose tissue is most likely due to the tumor (and host) factor zinc-alpha2-glycoprotein because of its direct lipolytic effect, ability to sensitize adipocytes to lipolytic stimuli and increased expression in cachexia. TNF-alpha and the tumor factor proteolysis-inducing factor are the major contenders for skeletal muscle atrophy; both increase protein degradation through the ubiquitin-proteasome pathway and depress protein synthesis through phosphorylation of eukaryotic initiation factor 2 alpha. However, while most studies report proteolysis-inducing factor levels to correlate with the appearance of cachexia, there is some disagreement regarding a correlation between serum levels of TNF-alpha and weight loss. Furthermore, only antagonists to proteolysis inducing factor prevent muscle loss in cancer patients, suggesting that tumor factors are the most important.
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PMID:Are tumoral factors responsible for host tissue wasting in cancer cachexia? 2037 65

Muscle wasting and cachexia have long been postulated to be key determinants of cancer-related death, but there has been no direct experimental evidence to substantiate this hypothesis. Here, we show that in several cancer cachexia models, pharmacological blockade of ActRIIB pathway not only prevents further muscle wasting but also completely reverses prior loss of skeletal muscle and cancer-induced cardiac atrophy. This treatment dramatically prolongs survival, even of animals in which tumor growth is not inhibited and fat loss and production of proinflammatory cytokines are not reduced. ActRIIB pathway blockade abolished the activation of the ubiquitin-proteasome system and the induction of atrophy-specific ubiquitin ligases in muscles and also markedly stimulated muscle stem cell growth. These findings establish a crucial link between activation of the ActRIIB pathway and the development of cancer cachexia. Thus ActRIIB antagonism is a promising new approach for treating cancer cachexia, whose inhibition per se prolongs survival.
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PMID:Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival. 2088 4


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