Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0235394 (wasting)
 8,040 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cancer cachexia, characterized by anorexia, weight loss and progressive tissue wasting, has been postulated to be mediated by various cytokines. However, the precise mechanism of cachexia induction is not fully explained. We have developed synthetic double-stranded oligodeoxynucleotides (ODN) as 'decoy' cis-elements that block the binding of nuclear factors to promoter regions of targeted genes, resulting in the inhibition of gene transactivation in vivo as well as in vitro. This novel molecular strategy could be useful for treating a broad range of human diseases including cancer. In this study, we injected decoy ODN targeting the transcriptional factor, NF-kappa B (NF kappa B) binding cis-elements, which are essential for transactivation of gene expression of cytokines, directly into tumors of adenocarcinoma colon26 in mice, in order to examine whether or not cachexia is alleviated by inhibiting the action of cytokines. Tumor growth was not affected by transfection of NF kappa B decoy ODN as compared with scrambled decoy ODN. Nevertheless, transfection of NF kappa B decoy, but not scrambled decoy, ODN resulted in attenuation of the reductions in body weight, epididymal fat, gastrocnemius muscle mass and food intake, which were induced by the tumor presence. Interleukin 6 mRNA in the tumor was also markedly decreased by the transfection of NF kappa B decoy ODN. It is known that the transcriptional factor E2F plays a pivotal role in the coordinated transactivation of cell cycle regulatory genes. Therefore, we hypothesized that the introduction of synthetic double-stranded DNA with high affinity for E2F in vivo as 'decoy' cis-elements might inhibit the tumor growth of colon26, resulting in turn in inhibition of cachexia induction. However, injection of E2F decoy ODN failed to inhibit tumor growth and cachexia induction, as compared with mismatched decoy ODN. Overall, the present study demonstrated that cachexia induced by adenocarcinoma colon26 was inhibited by blocking of NF kappa B, using a novel molecular decoy strategy, without an effect on tumor growth, and also that tumor growth and cachexia induction in the colon26 model were not affected by E2F decoy ODN. These results suggest that cytokines regulated by NF kappa B may play a pivotal role in the induction of cachexia by colon26, providing a new therapeutic strategy for cancer cachexia.
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PMID:Intratumoral injection of oligonucleotides to the NF kappa B binding site inhibits cachexia in a mouse tumor model. 1034 80

The mechanism of wasting, as it occurs in malignant diseases and various etiologically unrelated conditions, is still poorly understood. We have, therefore, studied putative cause/effect relationships in a murine model of cancer cachexia, C57BL/6 mice bearing the fibrosarcoma MCA-105. The plasma of these mice showed decreased albumin and increased glutamate levels, which are typically found in practically all catabolic conditions. Skeletal muscles from tumor-bearing mice were found to have an abnormally low mitochondrial respiratory chain activity (mito.RCA) and significantly decreased glutathione (GSH) levels. The decrease in mito.RCA was correlated with an increase in the i.m. GSH disulfide/GSH ratio, the plasma cystine/thiol ratio, and the GSH disulfide/GSH ratio in the bile. This is indicative of a generalized shift in the redox state extending through different body fluids. Treatment of tumor-bearing mice with ornithine, a precursor of the radical scavenger spermine, reversed both the decrease in mito.RCA and the change in the redox state, whereas treatment with cysteine, a GSH precursor, normalized only the redox state. Treatment of normal mice with difluoromethyl-ornithine, a specific inhibitor of ornithine decarboxylase and spermine biosynthesis, inhibited the mito.RCA in the skeletal muscle tissue, thus illustrating the importance of the putrescine/spermine pathway in the maintenance of mito.RCA. Ornithine, cysteine, and N-acetyl-cysteine (NAC) also reconstituted the abnormally low concentrations of the GSH precursor glutamate in the skeletal muscle tissue of tumor-bearing mice. Higher doses, however, enhanced tumor growth and increased the plasma glucose level in normal mice. In the latter, cysteine and NAC also decreased i.m. catalase and GSH peroxidase activities. Taken together, our studies on the effects of ornithine, cysteine, and NAC illuminate some of the mechanistic pathways involved in cachexia and suggest targets for therapeutic intervention.
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PMID:Differential reconstitution of mitochondrial respiratory chain activity and plasma redox state by cysteine and ornithine in a model of cancer cachexia. 1041 20

Cancer patients present high mobilization of host protein, with a decrease in lean body mass and body fat depletion occurring in parallel to neoplastic growth. Since leucine is one of the principal amino acids used by skeletal muscle for energy, we investigated the changes in body composition of pregnant tumor-bearing rats after a leucine-supplemented diet. Sixty pregnant Wistar rats divided into six groups were fed a normal protein diet (18%, N) or a leucine-supplemented diet (3% L-leucine, L). The pregnant groups were: control (CN), Walker 256 carcinoma-bearing rats (WN), control rats pair-fed with tumor-bearing rats (pfN), leucine-supplemented (CL), leucine-supplemented tumor-bearing (WL), and leucine-supplemented rats pair-fed with tumor-bearing rats (pfL). At the end of pregnancy, all animals were sacrificed and body weight and tumor and fetal weight were determined. The carcasses were then analyzed for water, fat and total, collagen and non-collagen nitrogen content. Carcass weight was reduced in the WN, WL, pfN and pfL groups compared to control. The lean body mass and total carcass nitrogen were reduced in both tumor-bearing groups. Despite tumor growth and a decrease in fetal weight, there was a slight decrease in collagen (7%) and non-collagen nitrogen (8%) in the WL group compared with the WN group which showed a decrease of 8 and 12%, respectively. Although the WL group presented severe tumor growth effects, total carcass nitrogen and non-collagen nitrogen were particularly higher in this leucine-supplemented group compared to the WN group. These data suggest that the leucine-supplemented diet had a beneficial effect, probably attenuating body wasting.
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PMID:Effect of a leucine-supplemented diet on body composition changes in pregnant rats bearing Walker 256 tumor. 1126 83

We previously showed that the natural herb Coptidis rhizoma has an anticachectic effect in nude mice bearing human esophageal cancer cells. We further investigated this phenomenon by examining the anticachectic effect of C. rhizoma in syngeneic mice bearing colon 26/clone 20 carcinoma cells, which cause IL-6-related cachexia after cell injection. We evaluated nutritional parameters such as serum glucose level and wasting of adipose tissue and muscle in tumor-bearing and non-tumor-bearing mice treated with C. rhizoma (CR) supplement or a normal diet. IL-6 levels in those mice were quantified by ELISA and real-time RT-PCR. CR supplementation significantly attenuated weight loss in tumor-bearing mice without changing food intake or tumor growth. Furthermore, these mice maintained good nutritional status. IL-6 mRNA levels in tumors and spleens and IL-6 protein levels in tumors and sera were significantly lower in tumor-bearing mice treated with CR supplement than in those treated with a normal diet. CR supplementation did not affect food intake, body weight, nutritional parameters and IL-6 levels in non-tumor-bearing mice. An in vitro study showed that C. rhizoma and its major component, berberine, inhibited IL-1-induced IL-6 mRNA expression in a dose-dependent manner in colon 26/clone 20 cells. Our results showed that C. rhizoma exerts an anticachectic effect on colon 26/clone 20-transplanted mice and that its effect is associated with tumor IL-6 production. We also suggest that its effect might be due to berberine.
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PMID:Anticachectic effects of the natural herb Coptidis rhizoma and berberine on mice bearing colon 26/clone 20 adenocarcinoma. 1197 46

Cachexia--a wasting condition--seriously impairs the quality of life of patients with advanced cancer. Previous studies have shown that several inflammatory cytokines mediate the development of cancer-associated cachexia. Experimentally, cachexia-like symptoms can be induced in tumor-bearing mice and treatment of such mice with chemotherapeutic agents reverses cachexia as a result of its therapeutic action. Nonetheless, cancer chemotherapy occasionally induces anorexia as an adverse reaction. For example, treatment with antitubulin taxanes reduces body weight in tumor-bearing mice more than healthy mice, even when the agents significantly reduce tumor growth. However, the complex relationship between cancer cachexia and the effects of anticancer drugs remains to be elucidated. This review outlines what is known about the development of cachectic reactions, especially in tumor-bearing mice, that occur during treatment with anticancer agents and highlights the clinical relevance of the information.
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PMID:Anticancer drugs that induce cancer-associated cachectic syndromes. 1211 61

Animals and humans respond to starvation with a complex neuroendocrine response that ultimately leads to an increase in appetite, a sparing of lean body mass (LBM) and burning of fat, and an overall decrease in basal metabolic rate. In contrast, cachexia is a pathological state of malnutrition associated with many infections and chronic diseases, wherein appetite is diminished concomitant with an increase in metabolic rate, and a relative wasting of LBM. In previous studies, we demonstrated that anorexia and weight loss in mouse cachexia models induced by lipopolysaccharide (LPS) administration and by tumor growth are ameliorated by central melanocortin-4 (MC4) receptor (MC4-R) blockade. In contrast to the results seen with MC4 blockade, melanocortin-3 (MC3) receptor knockout (MC3-RKO) mice show illness-induced anorexia and weight loss with LPS administration and with cytokine administration, and they have similar decreases in mobility. Both MC3-RKOs and MC4-RKOs have an intact corticosterone response and fever with LPS injection. In tumor models, we show that MC4-RKO mice resist the loss of LBM brought about by tumor growth, whereas MC3-RKO animals show enhanced tissue wasting. These data underscore the importance of central melanocortin signaling in weight homeostasis and demonstrate differential effects of MC3-R and MC4-R blockade on the development of cachexia.
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PMID:Differential role of melanocortin receptor subtypes in cachexia. 1263 36

Cancer cachexia induces host protein wastage but the mechanisms are poorly understood. Branched-chain amino acids play a regulatory role in the modulation of both protein synthesis and degradation in host tissues. Leucine, an important amino acid in skeletal muscle, is higher oxidized in tumor-bearing animals. A leucine-supplemented diet was used to analyze the effects of Walker 256 tumor growth on body composition in young weanling Wistar rats divided into two main dietary groups: normal diet (N, 18% protein) and leucine-rich diet (L, 15% protein plus 3% leucine), which were further subdivided into control (N or L) or tumor-bearing (W or LW) subgroups. After 12 days, the animals were sacrificed and their carcass analyzed. The tumor-bearing groups showed a decrease in body weight and fat content. Lean carcass mass was lower in the W and LW groups (W = 19.9 0.6, LW = 23.1 1.0 g vs N = 29.4 1.3, L = 28.1 1.9 g, P < 0.05). Tumor weight was similar in both tumor-bearing groups fed either diet. Western blot analysis showed that myosin protein content in gastrocnemius muscle was reduced in tumor-bearing animals (W = 0.234 0.033 vs LW = 0.598 0.036, N = 0.623 0.062, L = 0.697 0.065 arbitrary intensity, P < 0.05). Despite accelerated tumor growth, LW animals exhibited a smaller reduction in lean carcass mass and muscle myosin maintenance, suggesting that excess leucine in the diet could counteract, at least in part, the high host protein wasting in weanling tumor-bearing rats.
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PMID:A leucine-supplemented diet improved protein content of skeletal muscle in young tumor-bearing rats. 1457 14

There have been a number of reports suggesting inhibition of prostaglandin production may impact tumor-mediated wasting and levels of associated humoral factors such as hypercalcemia. These reductions were achieved using traditional nonsteroidal anti-inflammatory drugs (NSAIDs), which are often contraindicated in cancer patients. This is especially true during chemotherapeutic regimens due to concerns of bleeding from gastrointestinal and hematopoietic toxicities associated with inhibition of the housekeeping cyclooxygenase enzyme COX-1. Here, we report that celecoxib, one of the new class of selective COX-2 inhibitors, has the potential to reverse tumor-mediated wasting and associated humoral factors such as interleukin (IL)-6 and hypercalcemia in preclinical models of cachexia. Tumor bearing mice in late stage cachexia regained weight within days of the start of celecoxib treatment. Two models were tested. The first was the Colon 26 (Col26) syngeneic murine model that induces high levels of circulating IL-6 and hypercalcemia. The second was the human head and neck 1483 HNSCC xenograft model, which is less inflammatory and produces less prostaglandin than Col26. Despite the observation that no significant impact on tumor growth was observed between vehicle and celecoxib-treated animals over the course of the studies, celecoxib rapidly reversed weight loss in both cachectic models. With the added safety of celecoxib over traditional NSAIDs, these results suggest a possible therapeutic use for celecoxib for treating tumor-mediated wasting.
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PMID:Inhibition of cyclooxygenase-2 by celecoxib reverses tumor-induced wasting. 1471 36

Overexpression of the proto-oncogene c-ski in mice results in the development of a hypertrophic phenotype, characterized by increases in body and muscle weights. It has been previously shown in our laboratories that down-regulation of muscle protein breakdown associated with reduced expression of genes pertaining to different proteolytic systems likely account for this hypertrophic pattern. The aim of the present study was to evaluate the resistance of c-ski transgenic mice to catabolic stimuli such as those induced by the growth of the Lewis lung carcinoma. The tumor elicited a loss of body weight either in transgenic or in non-transgenic animals, although it was less pronounced in the former. The mass of gastrocnemius, tibialis and extensor digitorum longus (EDL) muscles were significantly reduced in non-transgenic tumor-bearing mice. Despite the anabolic setting displayed by the transgenic animals, the EDL only is completely protected against wasting. Indeed, gastrocnemius, tibialis and soleus show a reduction in weight, the latter two being significantly more depleted when compared to the non-transgenic tumor bearers. Similarly, the perigenital white adipose tissue presented a reduced mass which was more marked in the transgenic group. The quantitation of gene expression for ubiquitin, E2, C8 and calpain in the EDL showed marked differences between the transgenic and the non-transgenic groups of tumor hosts. As expected from previous results, in the latter group most of the transcripts examined increased with respect to controls as a consequence of tumor growth; by contrast, in the transgenic tumor hosts there was a significant reduction of ubiquitin, E2, C8 subunit, and calpain mRNA levels in comparison with the transgenic tumor-free animals. These results show that c-ski hyperexpression prevents tumor-induced muscle wasting in the EDL muscle, likely by impairing the state of activation of different proteolytic systems. However, the lack of effectiveness in the other muscles examined suggests that the achievement of a significant interference with the development of cachexia at the molecular level is not an easy task and probably should be designed taking into consideration more than one target.
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PMID:Effect of c-ski overexpression on the development of cachexia in mice bearing the Lewis lung carcinoma. 1537 7

The present study aims to access the effects of sophora alkaloids on the production of pro-inflammatory cytokines and evaluate their therapeutic efficiency on cachexia. The comparative study showed that all sophora alkaloids tested here, including matrine, oxymatrine, sophocarpine, sophoramine, and sophoridine, inhibited TNF-alpha and IL-6 production in both RAW264.7 cells and murine primary macrophages, and sophocarpine showed the most potent inhibitory effect among them. Quantification of TNF-alpha and IL-6 mRNA in RAW264.7 cells by real-time RT-PCR revealed that both sophocarpine and matrine suppressed TNF-alpha and IL-6 expression and sophocarpine has stronger suppressing potency than matrine. Inoculation (s.c.) of colon26 adenocarcinoma cells into BALB/c mice induced cachexia, as evidenced by progressive weight loss, reduction in food intake, wasting of gastrocnemius muscle and epididymal fat, and increase in serum levels of TNF-alpha and IL-6. Administration of 50 mg/kg/d sophocarpine or matrine for 5 days from the onset of cachexia did not inhibit the tumor growth but resulted in attenuation of cachexia symptoms. Furthermore, sophocarpine and matrine decreased the serum levels of TNF-alpha and IL-6, and sophocarpine showed a better therapeutic effect than matrine. These results suggest that sophocarpine and matrine exert anti-cachectic effects probably through inhibition of TNF-alpha and IL-6.
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PMID:Sophocarpine and matrine inhibit the production of TNF-alpha and IL-6 in murine macrophages and prevent cachexia-related symptoms induced by colon26 adenocarcinoma in mice. 1877 99


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