Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Cachexia”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,279 records · Page 71Linked to original sources
PubMed1993

The role of interleukin-6 in lipopolysaccharide-induced weight loss, hypoglycemia and fibrinogen production, in vivo.

It was recently shown that interleukin (IL)-6 is an important mediator involved in the Colon (C)-26 model of experimental cancer cachexia. In this study, we wished to determine whether IL-6 is also involved in several metabolic changes associated with lipopolysaccharide (LPS) challenge. Administration of a relatively high amount of LPS to mice induced a transient weight loss, hypoglycemia, hypertriglyceridemia and an increase in the hepatic acute phase reactant, fibrinogen. Pretreatment of mice with the rat anti-murine IL-6 antibody (20F3), but not with a control antibody, resulted in a significant improvement of LPS-induced hypoglycemia and weight loss as well as a significant decrease of plasma fibrinogen. Anti-IL-6 antibody had no effect on LPS-induced hypertriglyceridemia. On the other hand, the pretreatment of mice with anti-murine TNF (TN3.19) antibody was able to completely inhibit elevation of triglycerides and modestly improve LPS-induced weight loss although it had no effect on hypoglycemia and fibrinogen production. Taken together, these results suggest that IL-6 plays a role in some of the metabolic changes associated with both an acute (i.e. LPS challenge) and chronic (C-26 cachexia) inflammatory conditions.

Analysis of Variance↗
PubMed1994

Characterization of differentiation factor/leukaemia inhibitory factor effect on lipoprotein lipase activity and mRNA in 3T3-L1 adipocytes.

Alterations in lipid metabolism characterized in major part by a decrease in lipoprotein lipase (LPL) activity in adipose tissue are a central feature of cachexia from chronic infection or malignancy. These metabolic derangements may be mediated in large part through endogenous host proteins produced in response to various pathological stimuli. Differentiation factor/leukaemia inhibitory factor (D-factor) is a cytokine whose functions overlap those of tumour necrosis factor-alpha (TNF), IL-6 and IL-1. Recombinant murine D-factor produced a dose- and time-dependent inhibition of heparin-releasable LPL activity in differentiated 3T3-L1 adipocytes. Although 2-10 fold less potent than recombinant murine TNF, D-factor inhibited LPL activity at concentrations of 1-10 ng/ml. When added together, D-factor and TNF produced a synergistic inhibition of LPL activity. Interleukin 6 (IL-6) was 100-fold less potent than D-factor; 0.1 ng/ml of D-factor or 10 ng/ml of IL-6 caused a 50% inhibition of LPL activity. D-factor and TNF increased IL-6 production in 3T3-L1 cells. Ten ng/ml of D-factor or 1.0 ng/ml of TNF stimulated the release of < 1 ng/ml of IL-6 and inhibited LPL activity to 11 +/- 3% and 3 +/- 2% of control, respectively, whereas 50 ng/ml of recombinant IL-6 was required to decrease LPL activity to 24 +/- 19% of control. TNF produced a marked decrease in LPL mRNA, whereas D-factor had minimal or no effect at doses which inhibited LPL activity almost completely. Western blot analysis of cell extracts showed that TNF caused a greater decrease in LPL protein production than D-factor.2+ with TNF, may contribute to the manifestations of cachexia.

3T3 Cells↗
PubMed1993

Pathology induced by leukemia inhibitory factor.

Leukemia inhibitory factor is a glycoprotein growth and differentiation factor with pleiotropic activity. LIF has potent effects on the hematopoietic system, including megakaryocyte progenitor cells. In addition, LIF has bone regeneration activity, induces cachexia and acute-phase response in hepatocytes, and inhibits adipogenesis, to mention the more important activities. In vivo LIF treatment in monkeys and rodents was followed by signs of general toxicity, cachexia, acute-phase reaction, and stimulation of hematopoiesis. The safety margin for possible therapeutic effects on hematopoiesis seems to be very narrow.

Acute-Phase Reaction↗
PubMed2006

The obesity paradox: fact or fiction?

Although the adverse health consequences of obesity in the general population have been well documented, recent evidence suggests that obesity is associated with better outcomes in patients with heart failure (HF). Studies of patients with HF that specifically examined the impact of body mass index (BMI) on outcomes have suggested the existence of an "obesity paradox." However, closer examination of these studies raises important questions on the validity of the paradox. First, the diagnosis of HF in obese patients, particularly when made using clinical variables, may not be accurate; the obese patients in these studies may actually be "healthier" than their nonobese comparators. Second, the deleterious effects of cachexia, rather than the salutary ones of obesity, are likely the main reason for the inverse correlation between BMI and HF outcome, especially once the underlying biologic mechanisms behind cachexia and obesity in patients with HF are considered. Furthermore, few studies have specifically examined the more severely obese population (BMI >35 kg/m(2)) when assessing outcomes, and those that have suggest that severely obese patients may have worse outcomes than patients with normal weights or those who are mildly obese. Therefore, a "U-shaped" outcome curve according to BMI for patients with HF may actually exist, in which mortality is greatest in cachectic patients; lower in normal, overweight, and mildly obese patients; but higher again in more severely obese patients. Further prospective studies assessing the impact of more marked degrees of obesity on outcomes in patients with HF are needed to more conclusively determine whether the obesity paradox truly exists.

Body Mass Index↗
PubMed2003

Ghrelin promotes pancreatic adenocarcinoma cellular proliferation and invasiveness.

Ghrelin, a newly described potent orexigenic peptide, may have therapeutic potential in patients with cachexia. We assessed whether pancreatic adenocarcinoma, commonly associated with marked cachexia, is a ghrelin-responsive malignancy. Pancreatic adenocarcinoma cells were exposed to ghrelin (0-100 nM). Proliferation was determined by MTT assay. Ghrelin, ghrelin 1a and 1b receptor expression and Akt phosphorylation were assessed. The effects of ghrelin (+/- its antagonist D-Lys-GHRP6, or the PI3-K inhibitor Wortmannin) on cellular motility and invasiveness were quantified by Matrigel Boyden chamber assay. All cell lines expressed ghrelin 1a and 1b receptor transcript and protein, but only PANC1 weakly expressed ghrelin transcript. Ten nanomolar ghrelin increased proliferation, motility, invasiveness, and Akt phosphorylation in all cell lines. Proliferation was affected dose-dependently, being suppressed at higher ghrelin concentrations. D-Lys-GHRP6 suppressed ghrelin-induced proliferation, invasion, and Akt phosphorylation. Wortmannin abolished the effects of ghrelin on motility and invasiveness. Pancreatic adenocarcinoma is a ghrelin-responsive malignancy.

Adenocarcinoma↗
PubMed2004

Effect of zinc-alpha2-glycoprotein (ZAG) on expression of uncoupling proteins in skeletal muscle and adipose tissue.

The plasma protein zinc-alpha2-glycoprotein (ZAG) has been shown to be identical with a lipid mobilizing factor capable of inducing loss of adipose tissue in cancer cachexia through an increased lipid mobilization and utilization. The ability of ZAG to induce uncoupling protein (UCP) expression has been determined using in vitro models of adipose tissue and skeletal muscle. ZAG induced a concentration-dependent increase in the expression of UCP-1 in primary cultures of brown, but not white, adipose tissue, and this effect was attenuated by the beta3-adrenergic receptor (beta3-AR) antagonist SR59230A. A 6.5-fold increase in UCP-1 expression was found in brown adipose tissue after incubation with 0.58 microM ZAG. ZAG also increased UCP-2 expression 3.5-fold in C2C12 murine myotubes, and this effect was also attenuated by SR59230A and potentiated by isobutylmethylxanthine, suggesting a cyclic AMP-mediated process through interaction with a beta3-AR. ZAG also produced a dose-dependent increase in UCP-3 in murine myotubes with a 2.5-fold increase at 0.58 microM ZAG. This effect was not mediated through the beta3-AR, but instead appeared to require mitogen activated protein kinase. These results confirm the ability of ZAG to directly influence UCP expression, which may play an important role in lipid utilization during cancer cachexia.

Adipocytes↗
PubMed2006

Omega-3 fatty acid effects on biochemical indices following cancer surgery.

Epidemiological studies have indicated that a high intake of saturated fat and/or animal fat increases the risk of colon and breast cancer. Laboratory and clinical investigations have shown a reduced risk of colon carcinogenesis after alimentation with omega-3 fatty acids, as found in fish oil. Mechanisms accounting for these anti-tumor effects are reduced levels of PGE(2) and inducible NO synthase as well as an increased lipid peroxidation, or translation inhibition with subsequent cell cycle arrest. Further, omega-3 eicosapentaenoic acid is capable of down-regulating the production and effect of a number of mediators of cachexia, such as IL-1, IL-6, TNF-alpha and proteolysis-inducing factor. In patients with advanced cancer, it is possible to increase energy and protein intake via an enteral or parenteral route, but this seems to have little impact on progressive weight loss. Fish oil administration improved patients' conditions in cancer cachexia and during radio- and chemotherapy. In patients undergoing tumor resection surgery we observed improvement of liver and pancreas biochemical indices when omega-3 fatty acids were administered. This paper is a review of recent developments in the field of nutrition in cancer patients with emphasis on the acute phase response following cancer surgery and the beneficial aspects of fish oil administration.

Acute-Phase Reaction↗
PubMed2004

IKKbeta/NF-kappaB activation causes severe muscle wasting in mice.

Muscle wasting accompanies aging and pathological conditions ranging from cancer, cachexia, and diabetes to denervation and immobilization. We show that activation of NF-kappaB, through muscle-specific transgenic expression of activated IkappaB kinase beta (MIKK), causes profound muscle wasting that resembles clinical cachexia. In contrast, no overt phenotype was seen upon muscle-specific inhibition of NF-kappaB through expression of IkappaBalpha superrepressor (MISR). Muscle loss was due to accelerated protein breakdown through ubiquitin-dependent proteolysis. Expression of the E3 ligase MuRF1, a mediator of muscle atrophy, was increased in MIKK mice. Pharmacological or genetic inhibition of the IKKbeta/NF-kappaB/MuRF1 pathway reversed muscle atrophy. Denervation- and tumor-induced muscle loss were substantially reduced and survival rates improved by NF-kappaB inhibition in MISR mice, consistent with a critical role for NF-kappaB in the pathology of muscle wasting and establishing it as an important clinical target for the treatment of muscle atrophy.

Animals↗
PubMed2004

The systemic inflammatory response is involved in the regulation of K(+) channel expression in brain via TNF-alpha-dependent and -independent pathways.

TNF-alpha, generated during the systemic inflammatory response, triggers a wide range of biological activities that mediate the neurologic manifestations associated with cancer and infection. Since this cytokine regulates ion channels in vitro (especially Kv1.3 and Kir2.1), we aimed to study Kv1.3 and Kir2.1 expression in brain in response to in vivo systemic inflammation. Cancer-induced cachexia and LPS administration increased plasma TNF-alpha. Kv1.3 and Kir2.1 expression was impaired in brain during cancer cachexia. However, LPS treatment induced Kv1.3 and downregulated Kir2.1 expression, and TNF-alpha administration mimicked these results. Experiments using TNF-alpha double receptor knockout mice demonstrated that the systemic inflammatory response mediates K(+) channel regulation in brain via TNF-alpha-dependent and -independent redundant pathways. In summary, distinct neurological alterations associated with systemic inflammation may result from the interaction of various cytokine pathways tuning ion channel expression in response to neurophysiological and neuroimmunological processes.

Animals↗
PubMed2005

Both oxidative and nitrosative stress are associated with muscle wasting in tumour-bearing rats.

Reactive oxygen and nitrogen species (ROS and RNS) have been proposed as mechanisms of cancer-induced cachexia. In this study, we assessed using Western blot analysis the levels of total protein carbonylation (2,4-dinitrophenylhydrazine assay), both malondialdehyde- (MDA-) and 2-hydroxy-4-nonenal- (HNE-) protein adducts, Mn-superoxide dismutase (Mn-SOD), catalase, heme oxygenase-1 (HO-1) and 3-nitrotyrosine formation in gastrocnemius muscles of rats bearing the Yoshida AH-130 hepatoma. In the muscles of the tumour-bearing animals, protein carbonylation as measured by total levels of carbonyl group formation and both HNE and MDA-protein adducts, and protein tyrosine nitration were significantly greater than in control muscles. Protein levels of the antioxidant enzymes Mn-SOD, catalase, and HO-1 were not significantly modified in the rat cachectic muscles compared to controls. The inefficiency of the antioxidant enzymes in neutralizing excessive ROS production may account for elevated markers of protein oxidation and be responsible for the development of both oxidative and nitrosative stress in cancer-induced cachexia.

Animals↗
PubMed2006

UCP3 in muscle wasting, a role in modulating lipotoxicity?

UCP3 has been postulated to function in the defense against lipid-induced oxidative muscle damage (lipotoxicity). We explored this hypothesis during cachexia in rats (zymosan-induced sepsis), a condition characterized by increased oxidative stress and supply of fatty acids to the muscle. Muscle UCP3 protein content was increased 2, 6 and 11 days after zymosan injection. Plasma FFA levels were increased at day 2, but dropped below control levels on days 6 and 11. Muscular levels of the lipid peroxidation byproduct 4-hydroxy-2-nonenal (4-HNE) were increased at days 6 and 11 in zymosan-treated rats, supporting a role for UCP3 in modulating lipotoxicity during cachexia.

Aldehydes↗
PubMed2005

Common symptoms in advanced cancer.

The key points of this article are anorexia and cachexia are: A major cause of cancer deaths. Several drugs are available to treat anorexia and cachexia. Dyspnea in cancer usually is caused by several factors. Treatment consists of reversing underlying causes, empiric bronchodilators, cortico-steroids--and in the terminally ill patients-opioids, benzodiazepines,and chlorpromazine. Delirium is associated with advanced cancer. Empiric treatment with neuroleptics while evaluating for reversible causes is a reasonable approach to management. Nausea and vomiting are caused by extra-abdominal factors (drugs,electrolyte abnormalities, central nervous system metastases) or intra-abdominal factors (gastroparesis, ileus, gastric outlet obstruction, bowel obstruction). The pattern of nausea and vomiting differs depending upon whether the cause is extra- or intra-abdominal. Reversible causes should be sought and empiric metoclopramide or haloperidol should be initiated. Fatigue may be caused by anemia, depression, endocrine abnormalities,or electrolyte disturbances that should be treated before using empiric methylphenidate. Constipation should be treated with laxatives and stool softeners. Both should start with the first opioid dose.

Anorexia↗
PubMed2002

Reversal of cancer-related wasting using oral supplementation with a combination of beta-hydroxy-beta-methylbutyrate, arginine, and glutamine.

BACKGROUND: Cancer-related cachexia is caused by a diverse combination of accelerated protein breakdown and slowed protein synthesis. The hypothesis proposed in this study is that supplementation of specific nutrients known to positively support protein synthesis and reduce protein breakdown will reverse the cachexia process in advanced cancer patients. METHODS: Patients with solid tumors who had demonstrated a weight loss of at least 5% were considered for the study. Patients were randomly assigned in a double-blind fashion to either an isonitrogenous control mixture of nonessential amino acids or an experimental treatment containing beta-hydroxy-beta-methylbutyrate (3 g/d), L-arginine (14 g/d), and L-glutamine (14 g/d [HMB/Arg/Gln]). The primary outcomes measured were the change in body mass and fat-free mass (FFM), which were assessed at 0, 4, 8, 12, 16, 20, and 24 weeks. RESULTS: Thirty-two patients (14 control, 18 HMB/Arg/Gln) were evaluated at the 4-week visit. The patients supplemented with HMB/Arg/Gln gained 0.95 +/- 0.66 kg of body mass in 4 weeks, whereas control subjects lost 0.26 +/- 0.78 kg during the same time period. This gain was the result of a significant increase in FFM in the HMB/Arg/Gln-supplemented group (1.12 +/- 0.68 kg), whereas the subjects supplemented with the control lost 1.34 +/- 0.78 kg of FFM (P = 0.02). The response to 24-weeks of supplementation was evaluated by an intent-to-treat statistical analysis. The effect of HMB/Arg/Gln on FFM increase was maintained over the 24 weeks (1.60 +/- 0.98 kg; quadratic contrast over time, P <0.05). There was no negative effect of treatment on the incidence of adverse effects or quality of life measures. CONCLUSIONS: The mixture of HMB/Arg/Gln was effective in increasing FFM of advanced (stage IV) cancer. The exact reasons for this improvement will require further investigation, but could be attributed to the observed effects of HMB on slowing rates of protein breakdown, with improvements in protein synthesis observed with arginine and glutamine.

Aged↗
PubMed1997

Wasting as independent risk factor for mortality in chronic heart failure.

BACKGROUND: Wasting in chronic heart failure (CHF) has long been known but is little investigated. We sought to find out whether the cachectic state in CHF provides additional prognostic information about all-cause mortality. METHODS: Between June, 1993, and May, 1995, we studied 171 consecutive patients with CHF (mean age 60 years [SD 11; range 27-86]; 17 female). We assessed exercise capacity (peak oxygen consumption; mean 17.5 mL kg-1 min-1 [6.7]), functional status (New York Heart Association [NYHA] class: 21 class I, 63 class II, 68 class III, 19 class IV), and left-ventricular ejection fraction (mean 30% [SD 15]; n = 115). The cachectic status was defined prospectively as a non-intentional documented weight loss of at least 7.5% of previous normal weight (28 patients; range 9-36% or 6-30 kg) during at least 6 months. The Cox proportional-hazards model was used to assess the association of variables with survival, and Kaplan-Meier cumulative survival plots were constructed to estimate the influence of risk factors. FINDINGS: At the end of follow-up in November, 1996, 49 patients had died (after a mean 324 days [SD 283]). The mean follow-up of the survivors was 834 days (SD 186; range 549-1269). The cachectic state was predictive of 18-month mortality independent of age, NYHA class, left-ventricular ejection fraction, and peak oxygen consumption. Mortality in the cachectic patients (n = 28) was 18% at 3 months, 29% at 6 months, 39% at 12 months, and 50% at 18 months. Patients who had a peak oxygen consumption below 14 mL kg-1 min-1 (n = 53) had mortality at 3, 6, 12, and 18 months of 19%, 30%, 40%, and 51%. 18-month survival was 23% (95% CI 0-46) for the 13 patients with both of these risk factors (cachexia and low peak oxygen consumption) compared with 93% (88-98) in those (n = 103) with neither risk factor (p < 0.0001). INTERPRETATION: The cachectic state is a strong independent risk factor for mortality in patients with CHF. Combined with a low peak oxygen consumption, it identifies a subset of patients at extremely high risk of death. Assessment of cachexia should be included in transplant programmes and studies that investigate the effect of interventions by survival analyses.

Adult↗
PubMed2000

Effect of cytokines on hypothalamic neuropeptide Y release in vitro.

Studies involving altered energy balance states in rodents have demonstrated that hypothalamic neuropeptide Y (NPY) activity is strongly activated in states of negative energy balance, such as periods of dietary restriction or starvation. However, in cancer cachexia, when there is a significant reduction in body weight as a result of appetite loss, leading to loss in fat and lean tissue mass, there is no augmentation in the activity of the hypothalamic NPY system. Therefore, we have examined whether cytokines, interleukin (IL)-1, IL-1beta, IL-6, and tumor-necrosis factor-alpha (TNF-alpha; cachectin), which are elevated in cancer patients, can attenuate NPY release from hypothalamic slices in vitro. None of the cytokines altered either the basal or stimulated NPY release from the hypothalamic slices. However, we were able to measure a significant reduction in potassium-stimulated NPY release (-60%) by using the nonselective voltage-dependent calcium channel blocker NiCl (30 microM) without any effect on basal release, as a positive control. Therefore, we suggest that the failure to activate the hypothalamic NPY system in states of cancer cachexia cannot be attributed to a cytokine-induced reduction in neurotransmitter release.

Animals↗
PubMed2002

Induction of protein catabolism and the ubiquitin-proteasome pathway by mild oxidative stress.

Muscle wasting in cancer cachexia is associated with increased levels of malondialdehyde (MDA) in gastrocnemius muscles, suggesting an increased oxidative stress. To determine whether oxidative stress contributes to muscle protein catabolism, an in vitro model system, consisting of C2C12 myotubes, was treated with either 0.2 mM FeSO4, 0.1 mM H2O2, or both, to replicate the rise in MDA content in cachexia. All treatments caused an increased protein catabolism and a decreased myosin expression. There was an increase in the proteasome chymotrypsin-like enzyme activity, while immunoblotting showed an increased expression of the 20S proteasome alpha-subunits, p42, and the ubiquitin-conjugating enzyme, E214k. 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.

Animals↗
PubMed1998

Host metabolism: a target in clinical oncology?

The presence of the tumour induces important metabolic changes in the cancer patient which are not merely due to the fact that the tumour acts as a parasite, thus depleting the host of nutrients, but that are mainly the result of both tumoral and humoral mediators. The new metabolic status of the cancer patient may lead to cancer cachexia (a pathological state characterized by weight loss together with anorexia, weakness, anaemia and asthenia) which represents one of the worst effects of malignancy, accounting for nearly a third of cancer deaths. The complications associated with the appearance of the cachectic syndrome affect both the physiological and biochemical balance of the patient and have effects on the efficiency of the anticancer treatment, resulting in a considerably decreased survival time. At the metabolic level, cachexia is associated with loss of skeletal muscle protein together with a depletion of body lipid stores. The present study emphasizes the fact that neutralizing some of the metabolic changes in the patient may be an essential therapeutic strategy in controlling tumour growth and improving survival.

Anorexia↗
PubMed1998

Nutritional support of the pediatric oncology patient.

The child with a malignancy frequently will have associated cachexia with significant weight loss and malnutrition. The reasons for this are multifactorial and may be related directly to the tumor, such as increased metabolic rate, circulating peptides leading to anorexia, and decreased intake due to poor appetite or gut involvement. There appears to be other reasons involved, including increased whole body protein breakdown, increased lipolysis, and increased gluconeogenesis. Release of certain cytokines, such as tumor necrosis factor, interleukin-1, interleukin-6, and others may increase the cancer cachexia. Malnutrition in these children leads to intolerance of chemotherapy and radiotherapy as well as increased local and systemic infections. For many years, oncologists were hesitant to provide nutrition support to cancer patients for fear that tumor growth would be enhanced. Pediatric oncologists learned early that starvation plays no positive role in cancer therapy. Adjunctive nutritional support, either enterally or parenterally, supports the patient during therapy with surgery, chemotherapy, or radiation. Many studies have now shown that the nutritionally replete patient tolerates therapy better and in some pediatric malignancies may enhance survival.

Cachexia↗