Cause Of Cachexia Research Articles

Muscle wasting in cancer

The aim of the present review is to examine the impact of mitochondrial dysfunction in cancer cachexia. Oxidative pathways are altered in this tissue during muscle wasting and this seems to be a consequence of mitochondrial abnormalities that include altered morphology and function, decreased ATP synthesis and uncoupling. An alteration of energy balance is the immediate cause of cachexia. Both alterations in energy intake and expenditure are responsible for the wasting syndrome associated with different types of pathological conditions, such as cancer. Different types of molecular mechanisms contribute to energy expenditure and, therefore, involuntary body weight loss, one of which is mitochondrial dysfunction.

Evaluation of ghrelin level and appetite regulation in patients with acute exacerbations of chronic obstructive pulmonary disease.

BackgroundAppetite reduction is a major cause of cachexia in acute exacerbations of chronic obstructive pulmonary disease (AECOPD). This study tested the correlation of appetite and circulating levels of acylated ghrelin in patients with AECOPD.MethodsThirty-six patients with AECOPD and 23 healthy adults were enrolled in this study. Circulating total ghrelin, acylated ghrelin, and obestatin levels, Simplified Nutritional Appetite Questionnaire (SNAQ) score, and caloric intake were compared in patients and healthy controls. Additionally, the above parameters were compared between admission and discharge in the patients with AECOPD.ResultsCompared with healthy controls, SNAQ scores and caloric intake were significantly lower in patients with AECOPD, but there were no significant differences in total ghrelin, acyl ghrelin, or obestatin levels. In patients with AECOPD, the total ghrelin level was significantly higher at admission than on discharge, the SNAQ score and caloric intake were significantly increased at discharge when compared with admission, and there was no significant difference in acylated ghrelin level between admission and discharge.ConclusionWe demonstrated lower appetite scores and caloric intake in patients with AECOPD, but could not confirm that these effects were caused by insufficient levels of the orexigenic peptide, acyl ghrelin. Further studies are needed to confirm our findings and to determine the mechanism regulating appetite in patients with AECOPD.

Chronic metabolic acidosis may be the cause of cachexia: Body fluid pH correction may be an effective therapy

Cachexia is a pathological state characterized by weight loss and protein mobilization during various diseases. Nutritional supplementation or appetite stimulants are unable to restore the loss of lean body mass. Agents interfering with TNF-alpha have not been very successful to date. Only eicosapentaenoic acid was able to interfere with the action of proteolysis-inducing factors. An acceleration of proteolysis and branched-chain amino acid oxidation was correlated with chronic metabolic acidosis. Therefore, we suggest here that the main cause of cachexia is the increased acidity of the body fluids, which results in a higher and non-specific proteolysis of muscle proteins. Moderate hypoxia might be close related to lactic acid production within the whole body, not only in the cancer cells. Anorexia seems to be a consequence, but a cause of cachexia: the cachectic patients are in fact well fed, unfortunately they use fatty acids from their fat and glucose via muscle proteins, amino acids, alanine, and lactic acid. Our hypothesis is consistent with the most findings reported in literature and opens new ways for cachexia prevention and therapy, such as pH correction or higher oxygenation.

Adipokines and Gut Hormones in End-Stage Renal Disease

Cachexia is common in end-stage renal disease (ESRD) patients, and it is an important risk factor for poor quality of life and increased mortality and morbidity. Chronic inflammation is an important cause of cachexia in ESRD patients. In the present review, we examine recent evidence suggesting that adipokines or adipocytokines such as leptin, adiponectin, resistin, tumor necrosis factor alpha, interleukin-6, and interleukin-1beta may play important roles in uremic cachexia. We also review the physiology and the potential roles of gut hormones, including ghrelin, peptide YY, and cholecystokinin in ESRD. Understanding the molecular pathophysiology of these novel hormones in ESRD may lead to novel therapeutic strategies.

Endotoxin attenuates growth hormone-induced hepatic insulin-like growth factor I expression by inhibiting JAK2/STAT5 signal transduction and STAT5b DNA binding

Gram-negative sepsis with release of endotoxin is a frequent cause of cachexia that develops partly because of resistance to growth hormone (GH) with reduced insulin-like growth factor-I (IGF-I) expression. We set out to more fully characterize the mechanisms for the resistance and to determine whether in addition to a defect in the janus kinase 2 (JAK2)-signal transducer and activator of transcription (STAT) 5b pathway, required for GH-induced IGF-I expression, there might also be a more distal defect. Conscious rats were given endotoxin and studied 4 h later. In liver of these animals, GH-induced JAK2 and STAT5 phosphorylation was impaired and appeared to be caused, at least in part, by a marked increase in hepatic tumor necrosis factor-alpha and interleukin-6 mRNA expression accompanied by elevated levels of inhibitors of GH signaling, namely cytokine-inducible suppressors of cytokine signaling-1 and -3 and cytokine-inducible SH2 protein (CIS). Nuclear phosphorylated STAT5b levels were significantly depressed to 61% of the control values and represent a potential cause of the reduced GH-induced IGF-I expression. In addition, binding of phosphorylated STAT5b to DNA was reduced to an even greater extent and averaged 17% of the normal control value. This provides a further explanation for the impaired IGF-I gene transcription. Interestingly, when endotoxin-treated rats were treated with GH, there was a marked increase in proinflammatory cytokine gene expression in the liver. If such a response were to occur in humans, this might provide a partial explanation for the adverse effect of GH treatment reported in critically ill patients.

Cachexia in chronic kidney disease: role of inflammation and neuropeptide signaling

This review will update clinicians and basic scientists who are interested in the clinical relevance and molecular mechanism of uremic cachexia. Recent studies that examine the role of cytokines and hypothalamic neuropeptides are emphasized. A current hypothesis of the cause of cachexia in chronic illness is that proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-6, and leptin, act on the central nervous system to alter the release and function of several key neurotransmitters, thereby altering both appetite and metabolic rate. Proinflammatory cytokines also activate the transcription factor nuclear factor-kappaB, resulting in decreased protein synthesis, and activate the ubiquitin-mediated proteolytic system, which is the major system involved in increased protein degradation. This review highlights the importance of melanocortin signaling in the pathogenesis of uremia-associated cachexia and the potential of peripheral administration of melanocortin-4 receptor antagonists as a novel therapeutic approach.

Serum levels of Interleukin-6 (IL-6) and failing to thrive (FTT) in children infected with human immunodeficiency virus (HIV). ♦ 719

Previous studies have suggested that certain proinflammatory cytokines mediate the cachexia that accompanies acute inflammation in addition to mediating the initiation of immune defenses against an invading pathogen. Tumor necrosis factor (TNF) alpha has been consistently implicated as a cause of cachexia and IL-6 is more recently being proposed as a mediator of the wasting associated with chronic disease, such as in HIV infection. Elevated levels of IL-6 in serum and CSF have been found in patients with AIDS. We evaluated IL-6 and TNF-alpha levels by ELISA from serum obtained at times of routine examination in HIV+ children who were growing normally (Group 1), and in those with abnormal growth (Group 2, 3), to examine the association between cytokine derangement of HIV infection and poor growth. Age, mean CD4 count, and CDC stages were also compared. Table

Cytokines and Their Role in the Pathophysiology of Cancer Cachexia

Cancer cachexia describes a syndrome that consists of weight loss, and abnormalities in carbohydrate, protein, and lipid metabolism, which result in a state of persistent net negative energy balance. Patients suffering from cancer cachexia have a significantly shortened survival after cancer treatment. Recent experimental studies have focused on the belief that the mechanisms of cancer cachexia involve the host's production of inflammatory cytokines, which through broad physiologic actions ultimately lead to a chronic state of wasting, malnourishment, and death. Cytokines that have been thought to play a role in the pathophysiology of cachexia include tumor necrosis factor, interleukin-1, interleukin-6, interferon-gamma and differentiation factor. It has become clear that these cytokines have overlapping physiologic activities, which makes it likely that no single substance is the sole cause of cachexia in most cancer patients. Only further investigation may make it possible to more clearly define the role of cytokines in the pathophysiology of cancer cachexia. Specific strategies to reverse the cachectic effects of these substances may then be developed to ultimately improve cancer treatment.

Malignancy, weight loss, and the small intestinal mucosa

The mucosal architecture and mucosal dynamics of the small bowel have been studied in patients with malignant disease not of the gastrointestinal tract but associated with severe weight loss. Mucosal changes in malignant disease are demonstrated by stereomicroscopy, mucosal architectural measurement, and decreased lactose utilization. Measurement of the epithelial DNA loss rate indicates, in association with mucosal measurement, that the architectural changes are caused by a hypoplasia of the epithelium. Similar findings are demonstrated in patients with profound weight loss due to other non-malignant wasting diseases. Although mucosal changes undoubtedly occur in malignant disease, the changes are not specific for malignancy and the concept of ;cancer enteropathy' is not tenable. It is suggested that mucosal changes are the effect of and not the cause of cachexia.

THE PITUITARY AND HYPOTHALAMIC REGION IN CHRONIC EPIDEMIC ENCEPHALITIS

1. In chronic epidemic encephalitis there is frequently some change in the pituitary. 2. The hypothalamic region of the brain in chronic epidemic encephalitis is more severely affected than any other area except the substantia nigra of the mid-brain. The changes in the two regions are usually, but not invariably, parallel. 3. In all the cases of epidemic encephalitis the changes in the hypothalamic region were greater than in the same area in brains from cases of Huntington's chorea and general paralysis of the insane, where elsewhere there were severe degenerative changes. 4. Severe lesions in the hypothalamic region do not give rise to diabetes insipidus nor to obesity, but less intense lesions may cause these conditions. The part played by the pituitary in the production of obesity remains uncertain. 5. Cachexia is probably independent of any changes in the pituitary. There is no absolute proof, although there is a possibility, that pathological alterations in the hypothalamic region are the cause of cachexia. On the other hand, it seems certain there is no causal relationship between destruction of the substantia nigra and cachexia. 6. There is not any definite relationship between disturbances of sleep in epidemic encephalitis and alterations in the anterior lobe of the hypophysis. As the hypothalamus was affected in all the brains, and is not commonly the chief site of attack in other degenerative diseases, disturbance of its function—perhaps due to increase of calcium salts—probably plays some share in the causation of disorders of sleep. An increase of calcium salts does not usually occur in conditions such as Huntington's chorea and general paralysis of the insane. 7. Haemorrhages were more common in the hypothalamic region and mid-brain than elsewhere, and may have been the cause of sudden death in one young patient.