Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006625 (cachexia)
 5,650 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In an attempt to define the relationship between tumor burden (cachexia) and host hepatocyte gluconeogenesis, the following experiments were performed with the use of an F344 male rat bearing a transplantable sarcoma. Food intake of tumor-bearing (TB) rats was constant until day 24 following implant and a tumor burden of 18 +/- 5.2% (mean +/- SD), at which time food intake progressively declined daily. Tumor burden was arbitrarily divided at 12.8% to determine if any measured changes occurred prior to or following the approximate time when a significant decline in food intake occurred. Plasma glucose levels decreased with tumor burden. Whole-blood lactate levels increased with tumor burden. Fasting plasma alanine levels decreased with tumor burden. Plasma 3-methylhistidine levels increased with tumor burden. Plasma glucagon levels increased with tumor burden, whereas plasma insulin levels decreased. Hormone changes were noted at small tumor burdens prior to a decline in food intake. Viable hepatocytes were isolated from 4 groups: non-tumor-bearing (NTB), small tumor burden [(STB) 3.5% total body weight (TBW)], moderate tumor burden [(MTB) 14% TBW], and large tumor burden [(LTB) 23% TBW]. As expected in NTB rats, hepatocytes produced significantly more glucose with 20 mM lactate than 20 mM alanine or than Hanks' balanced salt solution (HBSS) alone. Hepatocytes from STB rats demonstrated the same basic relationship for lactate, alanine, and HBSS, but they produced significantly more glucose from lactate and HBSS alone than NTB hepatocytes. With alanine as substrate, the rates of glucose production by hepatocytes were not affected by the presence or size of tumor. However, with lactate as substrate, hepatocytes from MTB and LTB rats produced progressively less glucose as tumor burden increased (r = -0.85, p less than .001), which may partly explain the reduction in blood glucose and elevation in blood lactate levels observed. Elevated gluconeogenesis in TB rats occurred early prior to a decline in food intake. The key precursor appeared to be lactate. The balance between glucagon and insulin appeared to promote the abnormal host carbohydrate metabolism observed.
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PMID:Gluconeogenesis in the tumor-influenced rat hepatocyte: importance of tumor burden, lactate, insulin, and glucagon. 331 83

It has been suggested that the monokine tumor necrosis factor (TNF) (cachectin) is responsible for metabolic abnormalities frequently accompanying malignant neoplasms. The acute metabolic effects of TNF in patients with cancer were studied. Subcutaneous administration of recombinant human TNF led to a rise in the C-reactive protein level (4.4 +/- 1.2 mg/dL vs 11.6 +/- 1.8 mg/dL) and a reduction in the serum zinc level (12.9 +/- 0.8 mumol/L vs 7.3 +/- 0.8 mumol/L [79 +/- 5 mg/dL vs 48 +/- 5 mg/dL]) (values are the mean +/- SEM). Forearm efflux of total amino acids more than doubled after intravenous TNF injection, principally because of increases in release of the gluconeogenic amino acids alanine and glutamine. Concomitantly, the arterial levels of alanine, glutamine, and total amino acids fell, indicating that TNF also stimulated the uptake of amino acids by other tissues. The observed amino acid pattern cannot be explained solely on the basis of measured changes in cortisol, glucagon, or insulin levels. These findings are discussed in relation to known alterations of amino acid metabolism in cancer-associated cachexia.
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PMID:The acute metabolic effects of tumor necrosis factor administration in humans. 368 16

The increased energy expended by the host to synthesize substrate, which is utilized by the tumor, is a potential cause of cancer cachexia. In vivo glucose and alanine kinetics were examined by tracer methodology in a sarcoma-bearing rat model. The effects of 3-mercaptopicolinic acid, a potent inhibitor of gluconeogenesis, was also examined on this model. Both tumor-bearing (TB) and nontumor bearing (NTB) animals were gaining weight prior to study and the tumors were relatively small. The TB animals had significantly lower plasma glucose and higher blood lactic acid levels compared with NTB animals. After inhibition of gluconeogenesis, the plasma glucose decreased and the blood lactate increased significantly more in TB than NTB animals. The glucose turnover rate was significantly greater in TB compared with NTB animals, as was the rate of glucose recycling and the rate of gluconeogenesis (alanine leads to glucose), both energy demanding processes. These results suggest that the tumor-bearing animal, even prior to significant cachexia, has an excess demand for energy, the provision of which may be a significant factor in malignant cachexia.
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PMID:Metabolic alterations in a noncachectic animal tumor system. 722 7

An increase in gluconeogenesis contributes to the cachexia seen in severe injury, sepsis, and malignancy by converting amino acids from skeletal muscle to glucose. Since tumor necrosis factor alpha (TNF alpha) may mediate this cachexia, we examined the effect of this cytokine on gluconeogenesis. Twenty-eight male Fischer rats were injected intraperitoneally with TNF alpha (250 micrograms/kg) or saline, and after 4 hours, isolated hepatocytes were obtained by in situ collagenase liver perfusion. Hepatocytes were incubated with alanine (10 mM), and rates of gluconeogenesis were determined. Plasma lactate, glucose, insulin, glucagon, cortisol, and amino acids were measured. TNF alpha administration resulted in a 50% increase in gluconeogenesis from alanine (P < 0.05) and a three-fold increase in plasma glucagon (P = 0.01). Total and glucogenic plasma amino acids decreased with TNF alpha injection (P < 0.05). In vivo TNF alpha causes an increase in hepatic gluconeogenesis associated with increased plasma glucagon.
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PMID:Tumor necrosis factor alpha stimulates gluconeogenesis from alanine in vivo. 763 Jan 67

The tumor-bearing state is associated with an increase in gluconeogenesis which may contribute to the development of cancer cachexia. The purpose of this study was to determine if tolbutamide, a drug known to decrease gluconeogenesis in diabetes, could decrease gluconeogenesis in hepatocytes isolated from tumor-bearing rats. Hepatocytes from 24-hr fasted normal and methylcholanthrene-induced sarcoma-bearing rats (5-10% tumor burden) were isolated by in situ collagenase liver perfusion. Hepatocytes (n = 12 samples) from non-tumor-bearing (NTB) controls and tumor-bearing (TB) rats were incubated with lactate (10 mM) and alanine (10 mM) with and without 1 mM tolbutamide. Supernatant glucose concentration was measured at 30-min intervals for 2 hr. Rates of gluconeogenesis (+/- standard error) were calculated by linear regression and are expressed as nmole glucose/10(6) cells/min. Comparisons were made by two-way analysis of variance and significance defined as P < 0.05. TB hepatocytes had an increased rate of gluconeogenesis (P < 0.0001) from alanine and lactate (3.8 +/- 0.30 and 2.2 +/- 0.10, respectively) compared with NTB hepatocytes (0.66 +/- 0.10 and 1.2 +/- 0.04, respectively). TB hepatocytes treated with tolbutamide had a decreased (P < 0.0001) rate of gluconeogenesis from alanine and lactate (3.1 +/- 0.10 and 1.1 +/- 0.10, respectively) compared with untreated TB hepatocytes (5.3 +/- 0.10 and 2.1 +/- 0.10, respectively). Tolbutamide inhibits gluconeogenesis from lactate and alanine in tumor-influenced hepatocytes.
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PMID:Tolbutamide inhibits gluconeogenesis in the tumor-influenced hepatocyte. 823 Nov 77

Patients who develop squamous cell carcinoma of the head and neck (SCCHN) are often malnourished because of poor dietary habits, excessive alcohol consumption, local tumor effects, tumor-induced cachexia, and the effects of various therapies. The composition of the diet may be a risk factor for the development of head and neck cancer as well as tumor progression. This study compares the amino acid profiles in the banked serum of patients with and without SCCHN. In comparison to the control group, patients with SCCHN had significantly decreased preoperative serum levels of alanine (p = 0.006), asparagine (p = 0.002), aspartic acid (p = 0.0001), glycine (p = 0.0002), histidine (p = 0.002), 3-methylhistidine (p = 0.001), ornithine (p = 0.001), phenylalanine (p = 0.002), serine (p = 0.002), taurine (p < 0.0001), and threonine (p = 0.001). Levels of cystine were significantly elevated in the group of cancer patients (p < 0.0001). No significant differences were noted on the basis of T stage, N stage, or nutritional status. Serum levels increased postoperatively for the majority of the amino acids tested. Postoperative histidine levels were associated with tumor recurrence (p = 0.04). Serum amino acid levels may prove to be useful markers of disease status and provide prognostic information.
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PMID:Altered serum amino acid profiles in head and neck cancer. 958 33

Cachexia, a depressed immune function, and an increased infection rate are recurring problems for cancer patients; the response of the host to an infection may also be increased. We have reported that the transplantable Ward colon tumor (WCT) enhanced the lethality of endotoxin (lipopolysaccharide [LPS]) to the host. The mechanism of this increased LPS lethality and the effect of the presence of the WCT on the host inflammatory response, however, have not been reported. The effect of a transplantable WCT on the innate and endotoxin-induced inflammatory response of rats was, therefore, investigated. The innate inflammatory response was investigated in two ways. First, the formation of a granuloma around a sterile string implanted subcutaneously for 6 days was determined. Second, the effect of tumor presence on the trafficking of leukocytes to a sponge implanted subcutaneously for 2 or 6 days was determined. The tumor decreased the foreign body granuloma formation around a sterile string. The presence of the WCT also significantly blunted the increase of lymphocytes that migrated to the sponge area at 6 days. There was no significant effect of the WCT, however, on the migration of neutrophils, monocytes, or eosinophils to the implanted sponge. The leukocyte distribution of the peripheral blood was not affected by the presence of the WCT or implantation of a sterile string or sponge. To determine the effect of the presence of the WCT on the response of the host to an infection, rats were given LPS (5 mg/kg, i.p.) and the alanine amino transferase (ALT) of plasma and inducible isoforms of nitric oxide synthase (NOS2) protein content of liver, spleen, and terminal ileum was determined. The LPS challenge resulted in an increase in plasma ALT concentrations and NOS2 protein content of liver and spleen, but not the terminal ileum of WCT rats. This elevation in WCT rats confirms that the enhanced LPS-related toxicity in WCT rats was related to an increased liver toxicity. The increased toxicity may be related to an increase in the nitric oxide synthesis of the liver. These results suggest that the WCT, and possibly other tumors, will reduce the ability of the host to respond to a foreign body. If this were an infection, the host would be more likely to succumb to the resulting inflammatory mediators. Further evaluations of the lymphocyte subsets and cytokines in the sponge exudate will be required to completely understand this response.
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PMID:Influence of the ward colon tumor on the innate and endotoxin-induced inflammatory response of the rat. 1157 11

Decreased albumin expression is a frequent feature of cachexia patients afflicted with chronic diseases, including cancer, and a major contributor to their morbidity. Here we show that tumor necrosis-alpha (TNF-alpha) treatment of primary mouse hepatocytes or TNF-alpha overexpression in a mouse model of cachexia induces oxidative stress, nitric oxide synthase (NOS) expression and phosphorylation of C/EBPbeta on Ser239, within the nuclear localization signal, thus inducing its nuclear export, which inhibits transcription from the albumin gene. SIN-1, a NO donor, duplicated the TNF-alpha effects on hepatocytes. We found similar molecular abnormalities in the liver of patients with cancer-cachexia. The cytoplasmic localization and association of C/EBPbeta-PSer239 with CRM1 (exportin-1) in TNF-alpha-treated hepatocytes was inhibited by leptomycin B, a blocker of CRM1 activity. Hepatic cells expressing the non-phosphorylatable C/EBPbeta alanine mutant were refractory to the inhibitory effects of TNF-alpha on albumin transcription since the mutant remained localized to the nucleus. Treatment of TNF-alpha mice with antioxidants or NOS inhibitors prevented phosphorylation of C/EBPbeta on Ser239 and its nuclear export, and rescued the abnormal albumin gene expression.
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PMID:Nuclear export of phosphorylated C/EBPbeta mediates the inhibition of albumin expression by TNF-alpha. 1172 7

The ubiquitin-proteasome proteolytic pathway plays a major role in degradation of myofibrillar proteins in skeletal muscle during cancer cachexia. The end-product of this pathway is oligopeptides and these are degraded by the extralysomal peptidase tripeptidyl-peptidase II (TPPII) together with various aminopeptidases to form tripeptides and amino acids. To investigate if a relationship exists between the activity of the proteasome and TPPII, functional activities have been measured in gastrocnemius muscle of mice bearing the MAC16 tumour, and with varying extents of weight loss. TPPII activity was quantitated using the specific substrate Ala-Ala-Phe-7-amido-4-methylcoumarin, while proteasome activity was determined as the 'chymotrypsin-like' enzyme activity. Both proteasome proteolytic activity and TPPII activity increased in parallel with increasing weight loss, reaching a maximum at 16% weight loss, after which there was a progressive decrease in activity for both proteases with increasing weight loss. In murine myotubes, proteolysis-inducing factor, which is a sulphated glycoprotein produced by cachexia-inducing tumours, induced an increase in activity of both proteasome and TPPII, with an identical dose-response curve, and both activities were inhibited by eicosapentaenoic acid. These results suggest that the activities of both the proteasome and TPPII are regulated in a parallel manner in cancer cachexia, and that both are induced by the same factor and probably have the same intracellular signalling pathways and transcription factors.
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PMID:Effect of cancer cachexia on the activity of tripeptidyl-peptidase II in skeletal muscle. 1567 Aug 99

Zn-alpha(2)-glycoprotein (ZAG) is a soluble lipid-mobilizing factor associated with cancer cachexia and is a novel adipokine. Its X-ray crystal structure reveals a poly(ethylene glycol) molecule, presumably substituting for a higher affinity natural ligand, occupying an apolar groove between its alpha(1) and alpha(2) domain helices that corresponds to the peptide binding groove in class I MHC proteins. We previously provided evidence that the groove is a binding site for hydrophobic ligands that may relate to the protein's signaling function and that the natural ligands are probably (polyunsaturated) fatty acid-like. Using fluorescence-based binding assays and site-directed mutagenesis, we now demonstrate formally that the groove is indeed the binding site for hydrophobic ligands. We also identify amino acid positions that are involved in ligand binding and those that control the shape and exposure to solvent of the binding site itself. Some of the mutants showed minimal effects on their binding potential, one showed enhanced binding, and several were completely nonbinding. Particularly notable is Arg-73, which projects into one end of the binding groove and is the sole charged amino acid adjacent to the ligand. Replacing this amino acid with alanine abolished ligand binding and closed the groove to solvent. Arg-73 may therefore have an unexpected dual role in binding site access and anchor for an amphiphilic ligand. These data add weight to the distinctiveness of ZAG among MHC class I-like proteins in addition to providing defined binding-altered mutants for cellular signaling studies and potential medical applications.
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PMID:Zn-alpha2-glycoprotein, an MHC class I-related glycoprotein regulator of adipose tissues: modification or abrogation of ligand binding by site-directed mutagenesis. 1647 92


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