M J Tisdale

..These results suggest that some tumours are dependent on lipoxygenase metabolites of LA and AA for their continual growth, and interference with this pathway produces a specific growth inhibition...

..This review compares the catabolic actions of tumour necrosis factor-alpha (TNF-alpha) and proteolysis-inducing factor (PIF) and their involvement in human cancer cachexia...

..These results suggest that HMB may be effective in attenuating muscle atrophy in a range of catabolic conditions...

..25 g/kg). These results suggest that HMB attenuates the depression of protein synthesis by PIF in myotubes through multiple mechanisms...

..These results provide a link between the depression of protein synthesis in skeletal muscle and the increase in protein degradation...

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..Eicosapentaenoic acid, found in oily fish, effectively attenuates protein degradation in cachectic muscle by inhibiting the increased proteasome expression and can stabilize body weight in cachectic cancer patients...

..There have been a number of important developments in this area over the past 12 months, particularly with respect to protein catabolism...

..Further knowledge on the biochemical mechanisms of muscle protein catabolism will aid the development of effective therapy for cachexia...

..These results show that proteolysis-inducing factor co-ordinately upregulates both ubiquitin conjugation and proteasome activity in both myoblasts and myotubes and may play an important role in the muscle wasting seen in cancer cachexia...

..Recent studies have suggested that both tumor and host factors play a major role in tissue catabolism in cachexia, leading to upregulation of degradative pathways in both skeletal muscle and adipose tissue...

..In order to develop new agents, more fundamental research is required on the cellular mechanisms governing protein synthesis and degradation in skeletal muscle in cachexia...

..Further trials are required to confirm the efficacy of eicosapentaenoic acid and to determine the anticachectic activity in other types of cancer...

..EPA is able to down-regulate the increased expression of this pathway and prevents muscle wasting in cancer patients...

..Thus, by producing circulating factors certain malignant tumors are able to interfere with host metabolism even without metastasis to that particular site...

..Knowledge of the mechanisms of tissue destruction in cachexia should improve methods of treatment...

..This review focuses on a novel adipokine, zinc-alpha2-glycoprotein (ZAG), which plays an important role in the mobilization and utilization of stored lipids...

..Although cachexia has a major effect on both the morbidity and mortality of cancer patients, information on the mechanisms responsible for this condition is limited. This review summarizes recent data in this area...

..These results suggest that the ubiquitin-proteasome pathway is an appropriate therapeutic target to prevent muscle wasting...

..Furthermore, only antagonists to proteolysis inducing factor prevent muscle loss in cancer patients, suggesting that tumor factors are the most important...

..These results suggest that mechanistic studies into the causes of cancer cachexia will allow appropriate therapeutic intervention...

..The results further suggest that EPA may attenuate protein degradation induced by PIF, at least partly, by preventing NF-kappaB accumulation in the nucleus...

..The inactivity of curcumin was probably due to a low bioavailability. These results suggest that agents which inhibit nuclear translocation of NF-kappaB may prove useful for the treatment of muscle wasting in cancer cachexia...

..These results suggest that EPA may preserve adipose tissue in cachectic mice by downregulation of ZAG expression through interference with glucocorticoid signalling...

..A monoclonal antibody to PIF attenuated the enhanced protein degradation in soleus muscle from mice bearing the MAC16 tumour, confirming that PIF is responsible for the loss of skeletal muscle in cachectic mice...

..This result suggests that depletion of lean body mass in mice bearing G361 melanoma arises from the production of PIF...

..Thus in these experimental models cachexia appears to be correlated with the presence of PIF...

..This suggests that PKC may be involved in the phosphorylation and degradation of I-kappaBalpha, induced by PIF, necessary for the release of NF-kappaB from its inactive cytosolic complex...

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..These results show that the material of M(r) 24,000 present in the urine of cachectic cancer patients is capable of producing a syndrome of cachexia in mice...

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..To determine the effectiveness of the polyanionic, metal binding agent D-myo-inositol-1,2,6-triphosphate (alpha trinositol, AT), and its hexanoyl ester (HAT), in tissue wasting in cancer cachexia...

..This suggests a direct effect of PIF on glucose uptake by skeletal muscle. These results suggest that in addition to a direct catabolic effect on skeletal muscle PIF has a profound effect on glucose utilization during cachexia...

..It is concluded that weight loss produced by TNF-alpha arises from an anorexic effect and that this differs from the complex metabolic changes associated with cancer cachexia...

..These results suggest an alternative mechanism involving PKR to explain the effect of insulin and IGF-I on protein synthesis and degradation in skeletal muscle in the presence of catabolic factors...

..These results suggest that Ca(2+) is involved in the increase in protein degradation and decrease in protein synthesis by PIF and Ang II through activation of PKR by caspases-3 and -8...

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..The lipid mobilising species may be responsible for catabolism of host adipose tissue in the cachectic state...

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..These results suggest that in cachectic tumour-bearing animals mobilisation of body lipids is accompanied by an increased utilisation...

..These results suggest that PUFAs may play an important role in tumour growth and may offer a potential target for the development of chemotherapeutic agents...

..The relationship between the induction of cachexia and alteration in blood glucose levels remains unknown...

..These results suggest that PIF enhances protein degradation as a result of an increased production of 15-HETE...

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..The inhibitory effect of these agents on cell growth may result from an imbalance of metabolism of arachidonic acid between the 5-, 12- and 15-lipoxygenase pathways...

..Tumour sensitivity may be correlated with increased DT-diaphorase that are required to metabolise CV-6504 to the active hydroquinone, which inhibits 5-lipoxygenase activity...

..These results suggest that protein catabolism in starvation and cancer cachexia is mediated through a common pathway, which is inhibited by EPA and is likely to involve a lipoxygenase metabolite as a signal transducer...

..The ability of mutant I-kappaBalpha to inhibit PIF-induced protein degradation, as well as expression of the ubiquitin-proteasome pathway, confirms that both of these responses depend on initiation of transcription by NF-kappaB...

..77, P=0.004). These results suggest that phosphorylation of PKR may be an important initiator of muscle wasting in cancer patients...

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..Both of these processes would contribute to the loss of skeletal muscle in cancer cachexia...

..The results suggest that combination therapy of cancer cachexia involving both inhibition of the enhanced protein degradation and stimulation of the reduced protein synthesis may be more effective than either treatment alone...

..To investigate the anti-obesity effect of the adipokine zinc-α(2)-glycoprotein (ZAG) in rats and the mechanism of this effect...

..Thus EPA antagonizes loss of skeletal muscle proteins in cancer cachexia by down-regulation of proteasome expression, and this may also be the mechanism for inhibition of tumor growth...

..This suggests that this tumour-derived lipolytic factor acts to sensitize adipose tissue to lipolytic stimuli, and that this effect is attenuated by EPA, which is known to preserve adipose tissue in cancer cachexia...

..These results show that in addition to its lipid-mobilizing activity LMF also increases protein accumulation in skeletal muscle both by an increase in protein synthesis and a decrease in protein catabolism...

..Antagonists of tumor catabolic factors will provide important new agents in the treatment of cancer cachexia...

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..These results suggest that muscle protein degradation in cancer cachexia is associated with a rise in PGE2 content...

..D-myo-inositol-1,2,6-triphosphate (alpha-trinositol, AT) is a polyanionic molecule capable of chelating divalent metal ions with anti-tumour and anti-cachectic activity in a murine model...

..This suggests that glucocorticoids stimulate lipolysis through an increase in ZAG expression, and that they are responsible for the increase in ZAG expression seen in adipose tissue of cachectic mice...

..These results suggest that the increased degradation of skeletal muscle seen in this model of cachexia may be due to a circulating proteolysis-inducing factor...

..79 and 0.70 respectively) when the total body weight loss did not exceed 20%. This suggests that weight loss in cancer patients may be attributed, at least in part, to an, as yet, unidentified lipolytic factor...

..These results indicate that LMF antagonises the antiproliferative effect of agents working through a free radical mechanism, and may partly explain the unresponsiveness to the chemotherapy of cachexia-inducing tumours...

..These results suggest that muscle protein catabolism in sepsis is mediated by the same intracellular signalling pathways as found in other catabolic conditions...

..These results suggest that HMB attenuates PIF-induced activation and increased gene expression of the ubiquitin-proteasome proteolytic pathway, reducing protein degradation...

..These results show that mild oxidative stress increases protein degradation in skeletal muscle by causing an increased expression of the major components of the ubiquitin-proteasome pathway...

..These results suggest that ZAG may be effective in the treatment of obesity...

..These results confirm the ability of ZAG to directly influence UCP expression, which may play an important role in lipid utilization during cancer cachexia...

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..The anticachectic effect of EPA was only seen in combination with 5-fluorouracil. CONCLUSION: These results suggest that n-3 fatty acids do not interfere with the action of chemotherapy and may potentiate the effect of certain agents...

..The ability of AT to attenuate muscle atrophy by a range of stimuli suggests that it may be effective in several catabolic conditions...

..These changes would be expected to increase protein synthesis, whereas a reduction in the activation of PKR would be expected to attenuate the increased protein degradation...

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..These results confirm that the PIF binding protein has a functional role in muscle protein atrophy in cachexia and that it represents a potential new therapeutic target...

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..The ester 5g, the acetate 4b and the carbamate 2b displayed a cytotoxicity in the low micromolar range. Further, an IC50 (50% inhibitory concentration) of 50 nM and 30 nM was determined for the epoxide 7 and the aziridine 8...

..On the resistant MAC 16 cell line the pyridazone 9b displayed 52% tumour inhibition in mice at a dose of 50 mg kg(-1) compared with 27% for the 5-FU standard...

..Increased ROS formation is known to induce protein degradation through the ubiquitin-proteasome pathway...

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..These results suggest that induction of proteasome expression by angiotensin I/II involves a signalling pathway involving PKC and NF-kappaB...

..There was an increase in skeletal muscle mass due to an increase in protein synthesis and a decrease in protein degradation. These results suggest that ZAG may potentially be effective in the treatment of type 2 diabetes...

..These results suggest that protein catabolism in hyperthermia and cancer cachexia is mediated through a common pathway...

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..This suggests that the presence of the tumor alone is sufficient to cause an increase in cycling rate, and in the absence of an elevated energy intake (MAC16) this may contribute to the depletion of adipose tissue...

..These results confirm that PIF acts directly to stimulate the proteasome pathway in muscle cells and may play a pivotal role in protein catabolism in cancer cachexia...

..These results suggest that the induction of proteasome expression by TPA may involve the transcription factor NF-kappaB...

..These results suggest that inhibition of the autophosphorylation of PKR may represent an appropriate target for the attenuation of muscle atrophy in cancer cachexia...

..Neither chain was cleaved into disaccharides with chondroitinase ABC, suggesting that the material is a sulfated glycoprotein...

..CONCLUSION: This suggests that PIF may be responsible for changes in protein and RNA content of tissues with the development of cachexia...

..These results suggest that protein accretion in skeletal muscle in response to ZAG may be due to changes in intracellular cAMP and also that ZAG may have a therapeutic application in the treatment of muscle wasting conditions...

..These results suggest potential control points in proteasome activation that could be useful for therapeutic intervention...

..The catechols were also potent inhibitors of rabbit reticulocyte 15-lipoxygenase (IC(50) approximately 1 microM)...

..These results suggest that transient activation of Akt results in an increased protein degradation through activation of NF-kappaB and that this also allows for a specific synthesis of proteasome subunits...

..The effect was attenuated by insulin-like growth factor-1 (IGF-1) (25-100 ng/ml). Thus, Ang I/II have the ability to induce muscle atrophy through inhibition of protein synthesis...

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..These results suggest that prostaglandins are not involved in the anorectic effect of TNF-alpha...

..It is concluded that the weight loss produced by TNF arises from a combination of semi-starvation and a reduced water intake, and that the effect only occurred with the first administration of TNF...

..These results suggest that a ketogenic diet is more effective than insulin administration in reversing the cachectic process and has the advantage of a concomitant reduction in tumour weight...