Gene/Protein Disease Symptom Drug Enzyme Compound
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This article reviews work we have carried out to investigate (1) the transport mechanisms responsible for the high distribution ratio of free glutamine commonly observed in skeletal muscle; (2) the fall in the distribution ratio that accompanies starvation, injury and chronic disease, whether directly involving muscle or not; and (3) the effect of modulation of intracellular free-glutamine concentration on protein synthesis and breakdown in skeletal muscle. We suggest that the results are consistent with the controlling role of the muscle membrane glutamine-sodium cotransporter in the regulation of the intracellular glutamine pool, the existence of pathophysiological mechanisms for the modulation of intramuscular glutamine and anabolic effects of glutamine in promoting protein synthesis, with a smaller effect in reducing protein breakdown. The mechanisms by which glutamine affects skeletal muscle protein turnover, and thus muscle protein balance, and the extent of the net flow of amino acids between the periphery and the viscera are unknown as yet, but the results suggest that modulation of transporter activity may offer the possibility of therapeutic intervention to reduce muscle wasting associated with injury and disease.
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PMID:Skeletal muscle glutamine transport, intramuscular glutamine concentration, and muscle-protein turnover. 266 3

Anorexia, net proteolysis of skeletal muscle and consumption of body fat are hallmarks of the cachexia syndrome associated with chronic disease states. While inanition contributes to cachexia, this wasting diathesis has little in common with simple starvation. The cachexia syndrome is characterized by progressive weight loss and depletion of lean body mass in excess to that resulting from comparable caloric restriction. Accelerated mobilization and consumption of host protein stores from peripheral tissues occurs to support gluconeogenesis and acute phase protein synthesis [1, 2]. In contrast, simple starvation is associated with a relative sparing of lean tissue with the preferential consumption of fat. While the clinical manifestations of cachexia are readily apparent, identification of the specific mechanisms responsible for the development of cachexia remains an enigma. In recent years, interest has focused on the role that the immune system plays in the development of cachexia. Investigators initially hypothesized that the chronic production of two inflammatory cytokines, tumour necrosis factor alpha (TNF alpha) and/or interleukin-1 (IL-1), could explain the host non-specific responses resulting in cachexia [3-5]. Other pro-inflammatory cytokines, including interleukin-6 (IL-6) [6, 7] and interferon-gamma [8, 9], have been more recently proposed to be involved in this complex process. Although no consensus exists for the exclusive role of any one cytokine in the pathogenesis of cachexia, there is growing acceptance that the progression of cachexia results in part from the inappropriate release of one or more pro-inflammatory cytokines [10, 11]. In the present review, the current role of TNF alpha as a mediator of cachexia is examined.
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PMID:Tumor necrosis factor and cachexia: a current perspective. 788 18

Proper bodily response to environmental toxicants presumably requires proper function of the xenobiotic (foreign chemical) detoxification pathways. Links between phenotypic variations in xenobiotic metabolism and adverse environmental response have long been sought. Metabolism of the drug S-carboxymethyl-L-cysteine (SCMC) is polymorphous in the population, having a bimodal distribution of metabolites, 2.5% of the general population are thought to be nonmetabolizers. The researchers developing this data feel this implies a polymorphism in sulfoxidation of the amino acid cysteine to sulfate. While this interpretation is somewhat controversial, these metabolic differences reflected may have significant effects. Additionally, a significant number of individuals with environmental intolerance or chronic disease have impaired sulfation of phenolic xenobiotics. This impairment is demonstrated with the probe drug acetaminophen and is presumably due to starvation of the sulfotransferases for sulfate substrate. Reduced metabolism of SCMC has been found with increased frequency in individuals with several degenerative neurological and immunological conditions and drug intolerances, including Alzheimer's disease, Parkinson's disease, motor neuron disease, rheumatoid arthritis, and delayed food sensitivity. Impaired sulfation has been found in many of these conditions, and preliminary data suggests that it may be important in multiple chemical sensitivities and diet responsive autism. In addition, impaired sulfation may be relevant to intolerance of phenol, tyramine, and phenylic food constituents, and it may be a factor in the success of the Feingold diet. These studies indicate the need for the development of genetic and functional tests of xenobiotic metabolism as tools for further research in epidemiology and risk assessment.
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PMID:Phenotypic variation in xenobiotic metabolism and adverse environmental response: focus on sulfur-dependent detoxification pathways. 871 48

Nutrition is a final common pathway in chronic disease, and weight loss is a major manifestation of acquired immunodeficiency syndrome (AIDS). In sub-Saharan Africa, studies have shown that 25% of children with malnutrition have human immunodeficiency virus (HIV) infection, although patterns of malnutrition are indistinguishable from those who are HIV negative. Breast-feeding increases the risk of vertical transmission, and the overall risk versus benefit needs continuing careful consideration in relation to local mortality from gastroenteritis and malnutrition. Chronic diarrhea is much more common in HIV-infected children in Africa and may have a multiplicity of causes, including infection with adherent forms of Escherichia coli, protozoa, and even direct HIV infection of intestinal mucosal cells. The HIV wasting syndrome produces reduction in bioelectrical impedence, fat, lean body mass, and body cell mass, but the changes can be predicted from equations used in starvation states. Micronutrients may be important, but observed changes may be due to immune mediator activation, rather than malnutrition. Calorie supplementation is beneficial when delivered by any route, but is likely to produce the greatest positive change when CD4 counts are highest in relation to calorie intake. Paradoxically, HIV-infected children may be obese early in the disease until AIDS develops. There is an inextricable link between disease and nutritional status. In children with AIDS wasting syndrome, a low CD4 count and high viral load are likely so that effective antiviral treatment may ultimately produce the greatest improvement in health, including nutritional status.
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PMID:Global issues in pediatric nutrition: AIDS. 978 58

Multiple and complex mechanisms are likely to be involved in producing the growth retardation that occurs in children with chronic disease. The principal mechanisms in the pathway leading to growth arrest include too little substrate available to the child, excessive need for and over-consumption of substrate, and inefficient management of body components needed for growth. It is proposed that alterations in the growth hormone (GH)-insulin-like growth factor (IGF) system play a major role at each of the steps between insult from chronic disease and growth retardation. When substrate is insufficient, the production and action of IGF-I are attenuated at multiple points in the GH-IGF cascade. When over-consumption of substrate occurs, a situation of 'internal starvation' probably develops--leading to events similar to those that take place when substrate supply is inadequate. Finally, conditions that cause inefficient management of body components needed for growth, as characterized by increased proteolysis, appear to be attenuated by GH and IGF-I.
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PMID:Growth retardation in chronic diseases: possible mechanisms. 1010 62

Severe or chronic disease can lead to cachexia which involves weight loss and muscle wasting. Cancer cachexia contributes significantly to disease morbidity and mortality. Multiple studies have shown that the metabolic changes that occur with cancer cachexia are unique compared to that of starvation. Specifically, cancer patients seem to lose a larger proportion of skeletal muscle mass. There are three pathways that contribute to muscle protein degradation: the lysosomal system, cytosolic proteases and the ubiquitin (Ub)-proteasome pathway. The Ub-proteasome pathway seems to account for the majority of skeletal muscle degradation in cancer cachexia and is stimulated by several cytokines including tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, interferon-gamma and proteolysis-inducing factor. Cachexia is particularly severe in pancreatic cancer and contributes significantly to the quality of life and mortality of these patients. Several factors contribute to weight loss in these patients, including alimentary obstruction, pain, depression, side effects of therapy and a high catabolic state. Although no single agent has proven to halt cachexia in these patients there has been some progress in the areas of nutrition with supplementation and pharmacological agents such as megesterol acetate, steroids and experimental trials targeting cytokines that stimulate the Ub-proteasome pathway.
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PMID:Mechanisms of skeletal muscle degradation and its therapy in cancer cachexia. 1745 54

Adiponectin and adiponectin receptors (AdipoRs) have been found to play significant roles in the etiology of obesity-related chronic disease. Their discovery has been a long and complicated path, with many challenges. Developing methods to unravel the molecular secrets has been an informative process in itself. However, with both functional and genetic studies confirming adiponectin as a therapeutic target adipokine, many roles and interactions with certain other biomolecules have been clearly defined. We have found that decreased high molecular weight (HMW) adiponectin plays a crucial and causal role in obesity-linked insulin resistance and metabolic syndrome; that AdipoR1 and AdipoR2 serve as the major AdipoRs in vivo; and that AdipoR1 activates the AMP kinase (AMPK) pathway and AdipoR2, the peroxisome proliferator-activated receptor alpha (PPARalpha) pathway in the liver, to increase insulin sensitivity and decrease inflammation. Further conclusions are that decreased adiponectin action and increased monocyte chemoattractant protein-1 (MCP-1) form a vicious adipokine network causing obesity-linked insulin resistance and metabolic syndrome; PPARgamma upregulates HMW adiponectin and PPARalpha upregulates AdipoRs; that dietary osmotin can serve as a naturally occurring adiponectin receptor agonist; and finally, that under starvation conditions, MMW adiponectin activates AMPK in hypothalamus, and promotes food intake, and at the same time HMW adiponectin activates AMPK in peripheral tissues, such as skeletal muscle, and stimulates fatty-acids combustion. Importantly, under pathophysiological conditions, such as obesity and diabetes, only HMW adiponectin was decreased; therefore, strategies to increase only HMW adiponectin may be a logical approach to provide a novel treatment modality for obesity-linked diseases, such as insulin resistance and type 2 diabetes. It is hoped that these data will be helpful in developing treatments to counteract the destructive, expensive and painful effects of obesity.
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PMID:Physiological and pathophysiological roles of adiponectin and adiponectin receptors in the integrated regulation of metabolic and cardiovascular diseases. 1913 82

High-yielding cereals and other staples have produced adequate calories to ward off starvation for much of the world over several decades. However, deficiencies in certain amino acids, minerals, vitamins and fatty acids in staple crops, and animal diets derived from them, have aggravated the problem of malnutrition and the increasing incidence of certain chronic diseases in nominally well-nourished people (the so-called diseases of civilization). Enhanced global nutrition has great potential to reduce acute and chronic disease, the need for health care, the cost of health care, and to increase educational attainment, economic productivity and the quality of life. However, nutrition is currently not an important driver of most plant breeding efforts, and there are only a few well-known efforts to breed crops that are adapted to the needs of optimal human nutrition. Technological tools are available to greatly enhance the nutritional value of our staple crops. However, enhanced nutrition in major crops might only be achieved if nutritional traits are introduced in tandem with important agronomic yield drivers, such as resistance to emerging pests or diseases, to drought and salinity, to herbicides, parasitic plants, frost or heat. In this way we might circumvent a natural tendency for high yield and low production cost to effectively select against the best human nutrition. Here we discuss the need and means for agriculture, food processing, food transport, sociology, nutrition and medicine to be integrated into new approaches to food production with optimal human nutrition as a principle goal.
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PMID:Elevating optimal human nutrition to a central goal of plant breeding and production of plant-based foods. 2046 63

Established guidelines and standardized protocols exist to assist clinicians in effectively addressing disease-related malnutrition in hospitalized adults. The goals of this treatment vary according to the disease state and the severity of the malnutrition. In starvation-related malnutrition, the goal of nutrition therapy is to restore healthy levels of lean body mass and body fat. For chronic disease-related malnutrition, the goals of treatment are to maintain and improve lean body mass and body fat. In acute-disease-related malnutrition, the goals of nutrition therapy are to support vital organ function and preserve the host response through the acute episode. The success of addressing malnutrition in hospitalized patients depends not just on the nutrition therapy selected, but also on the timely and appropriate application of guidelines and protocols by the clinicians dedicated to caring for malnourished patients. Coordination of nutrition care among providers is highly desirable, and usually includes a multidisciplinary team of clinicians typically comprising a physician, nurse, dietitian, and pharmacist. For greatest success, this attention to recognizing and addressing malnutrition begins at admission and continues beyond discharge to the community. When addressing malnutrition in hospitalized patients, oral feeding through diet enrichment or oral nutrition supplementation (ONS) is the first line of defense. ONS has consistently been demonstrated to provide nutrition, clinical, functional, and economic benefits to malnourished patients in both individual trials and meta-analyses. In an era when the cost of healthcare is rising as the population ages, addressing malnutrition in hospitalized patients is an important priority.
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PMID:Addressing malnutrition in hospitalized adults. 2396 10

The prevalence of nutritional alterations in rheumatologic diseases ranges from 4 to 95%, depending on the detection method used. Formerly described as the single term rheumatoid cachexia, nutritional alterations can currently be grouped and subdivided based on the physiopathological mechanisms involved: chronic disease-related inflammatory conditions (cachexia), malnutrition associated to acute malnutrition inflammatory conditions (protein-caloric malnutrition) and starvation-related malnutrition. Clinical manifestations of malnutrition associated to rheumatic diseases vary from the patient with low weight or overweight and obesity; with lean body mass depletion as well as functional repercussions, and impact of quality of life as a common denominator. Additionally, the associated increase in body fat mass increases the risk for cardiovascular morbidity. A multidisciplinary approach towards rheumatic diseases should include aspects oriented towards prevention, early identification, diagnosis and correction of nutritional alterations.
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PMID:Rheumatoid cachexia and other nutritional alterations in rheumatologic diseases. 2609 23


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