Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: HUMANGGP:017444 (TNF)
 61,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Under normal conditions, food intake is controlled in the hypothalamus by: (i) transducing metabolic/sensorial inputs arising from the periphery into neuronal response; (ii) integrating the information originating from different tissues; and (iii) triggering the appropriate feeding responses. Thus, the anorexia associated with a number of chronic diseases, including cancer, may result from an abnormal input of information to the hypothalamus, or in its defective transduction and integration, or in the induction of exaggerated and inappropriate feeding responses. Currently available data suggest that the pathogenesis of secondary anorexia is multifactorial, and involves most of the neuronal signalling pathways modulating energy intake, including hormones (e.g. leptin), neuropeptides (e.g. NPY), cytokines (e.g. IL-1, IL-6, TNF) and neurotransmitters (e.g. serotonin and dopamine). However, it is unlikely that they represent separate and distinct pathogenic mechanisms, rather it appears that close interrelationships may exist among them. In line with this reasoning, consistent experimental and human data suggest that the hypothalamic serotonergic neurotransmission may represent a major target on which different anorexia-related factors converge. Thus, interfering pharmacologically with hypothalamic serotonin synthesis and activity may represent an effective therapeutic strategy in anorectic patients, as suggested by recent preliminary clinical data.
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PMID:Cancer anorexia: a model for the understanding and treatment of secondary anorexia. 1216 10

Our previous studies suggested that the cytokine tumor necrosis factor-alpha (TNF-alpha) may act within the neural circuitry of the medullary dorsal vagal complex (DVC) to affect changes in gastric function, such as gastric stasis, loss of appetite, nausea, and vomiting. The definitive demonstration that endogenously generated TNF-alpha is capable of affecting gastric function via the DVC circuitry has been impeded by the lack of an antagonist for TNF-alpha. The present studies used localized central nervous system applications of the TNF-adsorbant construct (TNFR:Fc; TNF-receptor linked to the Fc portion of the human immunoglobulin IgG1) to attempt to neutralize the suppressive effects of endogenously produced TNF-alpha. Gastric motility of thiobutabarbital-anesthetized rats was monitored after systemic administration of lipopolysaccharide (LPS) to induce TNF-alpha production. Continuous perfusion of the floor of the fourth ventricle with TNFR:Fc reversed the potent gastroinhibition induced by LPS, i.e., central thyrotropin-releasing hormone-induced increases in motility were not inhibited. This disinhibition of gastric stasis was not seen after intravenous administration of similar doses of TNFR:Fc nor ventricular application of the Fc fragment of human immunoglobulin. These results validate our previous studies that suggest that circulating TNF-alpha may act directly within the DVC to affect gastric function in a variety of pathophysiological states.
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PMID:LPS-induced suppression of gastric motility relieved by TNFR:Fc construct in dorsal vagal complex. 1218 Nov 77

The relationship between malnutrition and inflammation is by now well established. IL-6 and, probably, other proinflammatory cytokines (mainly IL-1 and TNF) may represent the link between these two entities since these interleukins may promote loss of appetite, muscle protein breakdown and reduced hepatic synthesis of "negative" acute phase proteins like albumin, prealbumin and transferrin. IL-6 also stimulates up to 1000 fold the hepatic synthesis of "positive" acute phase proteins, mainly C-reactive Protein (CRP) and Serum Amyloid A. The association between CRP and cardiovascular mortality in the general population, as well as in haemodialysed uraemic patients, is well established. These crucial interrelationships have modified the interpretation of serum albumin concentration in the diagnosis of malnutrition; a reduced serum albumin concentration, in fact, in the presence of high CRP values should point towards a diagnosis of inflammation, though the inflammation may often induce weight loss or a condition of malnutrition. After switching most patients to a more biocompatible dialysis membrane and improvement of the quality of the dialysis fluid (by adopting hydrophobic filters at the water entry of dialysis devices and bicarbonate powder cartridges) nephrologists have focused their attention on other sources of inflammation (e.g. artificial vascular protheses, presence of infected thrombi, Clamidiae, Helicobacter Pilori, dental granulomas etc.). Starting from these assumptions the diagnosis of malnutrition, once focused mainly on serum albumin reduction, must be based on other parameters (clinical history of body mass wasting, dietary and anthropometric assessment, subjective global assessment, bioimpedance analysis etc.). All these investigations, however, must be examined together to obtain suitable information on the risk of malnutrition in dialysis patients. A comprehensive approach to malnutrition-inflammation in dialysis patients is the object of the present nephrology conference.
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PMID:[Predictive and diagnostic factors of malnutrition in hemodialysis patients]. 1236 50

Growth failure (GF) is one of the major complications affecting children with inflammatory bowel disease. The faltering is temporary in 40-50% of cases and prolonged in 10-20% in Crohn's disease (CD). Such failure is rare in children with ulcerative colitis (5%). This complication is often associated with retarded bone development and delayed onset of sexual maturation. The delayed linear growth has a variety of causes including insufficient intake due to anorexia and the inflammatory process with increased energy and protein expenditure. Other factors are increased intestinal loss, secondary hypopituitarism and treatment with steroids. Therapeutic strategies of CD in children have changed this last decade by introducing new therapeutic agents such as topic steroids, immunosuppressors, anti-TNF (antibody and notably in children enteral nutrition which has shown its efficacy in inducing remissions of active CD, restoring nutritional status and stimulation of linear growth. The results of a recent prospective multicentric study over 2 years in 82 CD show that severe GF (-2 SD) is initially present in 15% (n = 12), among them 11 remain < -2SD after 2 years of follow-up. Six patients who were on the normal range initially increased their GF during the follow-up (< -2SD) (total 21% < -2SD (n = 17) at 2 years). At inclusion in this group there was no difference in growth velocity, used of steroids, enteral nutrition or severity of CD as compared to the group with no GF. It suggests that new treatment strategy should be developed in the future for this specific complication of paediatric CD.
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PMID:Growth in paediatric Crohn's disease. 1237 7

The cytokine tumor necrosis factor alpha (TNF(alpha)) may act within the neural circuitry of the medullary dorsal vagal complex (DVC) to affect changes in gastric function such as gastric stasis, loss of appetite, nausea, and vomiting. The definitive demonstration that endogenously generated TNF(alpha) is acting within the DVC circuitry to affect these changes has been impeded by the lack of an antagonist for TNF(alpha). The present studies used localized central nervous system microinjections of the TNF-adsorbant construct (TNFR:Fc) to specifically neutralize the ability of endogenously produced TNF(alpha) to activate NST neurons. Our studies reveal that TNFR:Fc suppresses induction of cFos normally evoked by TNF(alpha). These results validate our hypothesis that circulating TNF(alpha) may act directly within the DVC to affect gastric function in a variety of pathophysiological states.
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PMID:TNFalpha-stimulation of cFos-activation of neurons in the solitary nucleus is suppressed by TNFR:Fc adsorbant construct in the dorsal vagal complex. 1276 23

Cancer anorexia-cachexia syndrome (CACS) is a combination of anorexia, tissue wasting, weight loss and poor performance status. Some CACS symptoms are due to a macrophage production of TNF and IL-1, while the metabolic effects are mainly explained by the release of IL-6 from tumor cells. Clinical treatment of CACS involves progestational agents (medroxyprogesterone acetate, MPA, megestrol acetate, MA) for long term treatment. The use of prokinetic agents (like metoclopramide) is recommended, especially if patients need concomitant opioid treatment for pain; if otherwise indicated, corticosteroids are useful for short periods. The administration of artificial nutrition should be individualized following the clinical condition of the patient and possibly taking into account the wishes of the patient. The practical evaluation criteria of the drugs employed for CACS are based on weight increase and appetite stimulation. Hence, a new approach to the mechanism of action of MPA, MA and of other agents is urgently needed.
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PMID:Treatment of the cancer anorexia-cachexia syndrome: a critical reappraisal. 1286 46

Chronic inflammation is very common in patients on maintenance dialysis. It is associated with an increase of many cytokines (especially: IL-1, IL-6 and TNF alpha). This inflammation leads to hormonal dysregulation (leptin, adiponectin, insulin). Increase in cytokines is associated with a high cardio-vascular morbi-mortality for general population as well as for uremic patients. Many metabolic abnormalities are due to chronic inflammation: protein catabolism, anorexia and many others. Among them, the "metabolic" syndrome includes adiposis, dyslipemia, insulinoresistance and high blood pressure very often present in chronic uremic patients. It is still unknown whether anti-inflammatory treatments would improve inflammation consequences in dialysis.
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PMID:[Metabolic consequences of inflammation in kidney failure]. 1465 Jul 51

Cancer cachexia is a syndrome of weight loss, muscle wasting, fatigue, and anorexia that occurs in patients with advanced or recurrent solid tumor disease. Tumor necrosis factor-alpha (TNFalpha) and prostaglandin E2 (PGE2) have been implicated in the biology of cachexia and serve as possible targets for treatment of this condition. Conjugated linoleic acid (CLA) is a polyunsaturated fatty acid that alters the synthesis of PGE2 and reduces the negative effects of TNF on body weight of healthy mice. We hypothesized that a diet supplemented with .5% CLA might reduce muscle wasting in mice bearing the colon-26 adenocarcinoma, an animal model of cancer cachexia. CLA preserved gastrocnemius muscle mass and reduced TNF receptors in muscle of tumor-bearing mice. These data suggest that CLA may preserve muscle mass by reducing the catabolic effects of TNF on skeletal muscle.
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PMID:Conjugated linoleic acid preserves gastrocnemius muscle mass in mice bearing the colon-26 adenocarcinoma. 1562 11

The cytokine tumor necrosis factor(alpha) (TNF(alpha)) is associated with a constellation of physiological and behavioral characteristics that follow in response to infection such as fever, fatigue, listlessness, loss of appetite, malaise, and tactile hypersensitivity. These responses are examples of central nervous system (CNS) functions modified by the activated immune system. Our studies have focused on the involvement of TNF(alpha) in CNS control of gastrointestinal function and "visceral malaise". We have demonstrated that TNF(alpha) can elicit gastric stasis in a dose-dependent fashion via its interaction with vago-vagal neurocircuitry in the brainstem. Sensory elements of the vago-vagal reflex circuit (i.e., neurons of the solitary tract [NST] and area postrema [AP]) are activated by exposure to TNF(alpha), while the efferent elements (i.e., dorsal motor neurons of the vagus [DMN]) cause gastroinhibition. Transient exposure to low doses of TNF(alpha) cause potentiated (exaggerated) NST responses to stimulation. Subsequent studies suggest that TNF(alpha) presynaptically modulates the release of glutamate from primary afferents to the NST. Using immunohistochemical studies, we have observed the constitutive expression of the TNFR1 receptor on central vagal afferents and spinal trigeminal afferents in the medulla, as well as on cells and afferent fibers within the dorsal root ganglia and within laminae I and II of the dorsal horn throughout the spinal cord. The constitutive presence of these receptors on these afferents may explain why inflammatory or infectious processes that generate TNF(alpha) can disrupt gastrointestinal functions and cause tactile hypersensitivity. These receptors may also play a critical role in the chronic allodynia and hyper-reflexia observed after spinal cord injury or peripheral nerve damage.
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PMID:TNF(alpha) modulation of visceral and spinal sensory processing. 1585 70

Macrophage-activating lipopeptide-2 (MALP-2) from Mycoplasma fermentans has been identified as a pathogen-associated molecular pattern of Mycoplasmas that causes activation of the innate immune system through the activation of the heterodimeric Toll-like receptors (TLRs)-2 and -6. The aim of this study was to characterize the ability of MALP-2 and a synthetic analog fibroblast-stimulating lipopeptide-1 (FSL-1; represents the NH2-terminal sequence of a lipoprotein from M. salivarium) to act as exogenous pyrogens, to induce formation of cytokines (endogenous pyrogens), and to cause sickness behavior, such as depressed motor activity, anorexia, and adipsia. For this purpose, body temperature, activity, food intake, and water intake were recorded for 3 days by use of telemetry devices in several groups of rats treated with MALP-2/FSL-1 or the respective control solutions. Intraperitoneal injections of FSL-1 caused fever at doses of 10 or 100 microg/kg, which was preceded by a pronounced phase of hypothermia in response to a dose of 1,000 microg/kg. The maximal fever (a peak of 1.5 degrees C above baseline) was caused by the 100 microg/kg dose with almost identical responses to both MALP-2 and FSL-1. Fever was accompanied by pronounced rises of the proinflammatory cytokines TNF and IL-6 in plasma. Treatment with the TLR-2 and -6 agonists further induced a dose-dependent manifestation of anorexia and adipsia, as well as a reduction of motor activity. We could thus demonstrate that activation of TLR-2 and -6 can induce systemic inflammation in rats accompanied by the classical signs of brain-controlled illness responses.
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PMID:Pyrexia, anorexia, adipsia, and depressed motor activity in rats during systemic inflammation induced by the Toll-like receptors-2 and -6 agonists MALP-2 and FSL-1. 1615 16


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