Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Elevated plasminogen activator inhibitor-1 (PAI-1) plasma levels, responsible for reduced fibrinolysis, are associated with animal and human obesity and with increased cardiovascular disease. The expression of PAI-1 has been found recently in animal and human adipose tissue. Factors and mechanisms regulating such an expression remain to be elucidated. In omental and/or subcutaneous biopsies from obese non-diabetic patients, incubated in Medium 199, we have confirmed that human adipose tissue expresses PAI-1 protein and mRNA; furthermore we have demonstrated that such an expression is clearly evident also in collagenase isolated human adipocytes and that it is stimulated by incubation itself and enhanced by exogenous human tumor necrosis factor-alpha (h-TNF-alpha). Since human adipose tissue produces TNF-alpha, to further characterize the relationship of PAI-1 to TNF-alpha, human fat biopsies were also incubated with Pentoxifylline (PTX) or Genistein, both known to inhibit endogenous TNF-alpha through different mechanisms. PTX caused a dose-dependent decrease of basal PAI-1 protein release, reaching 80% maximal inhibitory effect at 10(-3)M, the same inhibitory effect caused by Genistein at 100 microg/ml. This was associated to a marked inhibition of PAI-1 mRNA and of endogenous TNF-alpha production. Furthermore, when human fat biopsies were incubated in the presence of polyclonal rabbit neutralizing anti-human TNF-alpha antibody (at a concentration able to inhibit 100 UI/ml human TNF-alpha activity), a modest but significant decrease of the incubation induced expression of PAI-1 mRNA was observed (19.8+/-19.0% decrease, P = 0.04, n = 7). In conclusion, the results of this study demonstrate that PAI-I expression is present in human isolated adipocytes and that it is enhanced in human adipose tissue in vitro by exogenous TNF-alpha. Furthermore our data support the possibility of a main role of endogenous TNF-alpha on human adipose tissue PAI-1 expression. This cytokine, produced by human adipose tissue and causing insulin resistance, may be a link in the clinical relationship between insulin-resistance syndrome and increased PAI-1 plasma levels.
 ...
PMID:Expression of plasminogen activator inhibitor-1 in human adipose tissue: a role for TNF-alpha? 1020 82

Obesity is frequently associated with insulin resistance. Recently an important role of the cytokine tumor necrosis factor-alpha in mediating insulin resistance of obesity through its overexpression in fat tissue has been reported. In order to examine the relation of insulin resistance to obesity and to serum neopterin, as a parameter of immune activation, we studied 1234 otherwise healthy outpatients, who visited the physician's office for a medical health check-up. 7% showed elevated glucose concentrations, 34% elevated body mass indices. There were significant correlations between glucose concentrations and body mass indices and of the latter with serum neopterin concentrations. Neopterin concentrations were significantly higher in patients with elevated body mass indices (Mann-Whitney test, U = 131 358, p = 0.0003) and elevated glucose concentrations (Mann-Whitney test, U = 35 350 p =0.02). The data may indicate that moderate immune stimulation plays a role in the development of insulin resistance, and an influence of tumor necrosis factor-alpha seems to be probable.
 ...
PMID:Association between insulin resistance, body mass and neopterin concentrations. 1034 Apr 39

Tumour necrosis factor-alpha (TNF) is a pleiotropic cytokine involved in many metabolic responses in both normal and pathophysiological states. In spite of the fact that this cytokine (also known as "cachectin") has been related to many of the metabolic abnormalities associated with cachexia, recent studies suggest that TNF may also have a central role in obesity modulating energy expenditure, fat deposition and insulin resistance. This review deals with the role of TNF in the control of fat mass and obesity.
 ...
PMID:Tumour necrosis factor, a key role in obesity? 1037 Nov 92

Excessive alcohol ingestion disturbs the metabolism of most nutrients. Although alcohol can lead to severe hypoglycemia, alcoholics are usually glucose intolerant, probably due to a inhibition of glucose-stimulated insulin secretion. Ethanol intake also leads to negative nitrogen balance and an increased protein turnover. Alcohol also alters lipid metabolism, causing a profound inhibition of lipolysis. Looking for an association between alcohol intake, nutrition, and alcoholic liver disease, we have observed a higher prevalence of subclinical histologic liver damage among obese alcoholics. Multivariate analysis in a large group of alcoholics has shown that obesity is an independent predictor of alcoholic liver disease. Other authors have reported that alcoholics with a history of obesity have a two to three times higher risk of having alcoholic liver disease than non-obese alcoholics. The possible explanation for this association is that the microsomal system, which plays an important pathogenic role in alcoholic liver disease, is induced in non-alcoholic obese subjects and alcoholics. Also, peripheral blood monocyte cells of obese alcoholics produce higher levels of interleukin-1, a cytokine that can contribute to liver damage. The ingestion of polyunsaturated fatty acids can also increase the damaging effects of alcohol on the liver, as has been demonstrated in rats subjected to continuous intragastric infusion of alcohol. Observations in human alcoholics have shown that liver damage is associated with a higher ratio of C:18:1/C:18:0 and a lower ratio of C:22:4/C:18:2 in liver lipids, consistent with an induction of delta 9 desaturase and an increased peroxidation of C:22:4.
 ...
PMID:Nutritional and metabolic effects of alcoholism: their relationship with alcoholic liver disease. 1042 91

Hypofibrinolysis caused by increased PAI-1 levels in patients with insulin resistance (IR) is one of the most common acquired prothrombotic states with higher risk of arterial thrombosis associated with atherosclerosis. Increased PAI-1 levels are caused by PAI-1 hyperproduction in various compartments owing to various factors (multicompartmental and multifactorial model). Metabolic compartment, including visceral adipocytes and hepatocytes, is sensitive on stimulative action of insulin, proinsulin and some cytokines. This pool is responsible for elevated PAI-1 levels in obesity. Vascular compartment, including mainly endothelium, is sensitive on thrombin, angiotensin IV, cytokines, biological active lipids and oxidative stress effect, while insulin inhibits cytokine induced PAI-1 production on contrary. This compartment is responsible for elevated PAI-1 levels in patients with type 2 diabetes mellitus and hypertension with endothelial dysfunction. PAI-1 levels in patients with IR represent cumulative production in described compartments.
 ...
PMID:[A multicomparmental and multifactorial model of production of plasminogen activator inhibitor (PAI-1). I. Experimental studies]. 1042 16

TNF-alpha (so-called cachectin), IL-1 and 6 are important regulating agents in the homeostasis of energy in the organism, as among others they control processes of apoptosis and thus also the volume of adipose and muscular tissues. They are produced not only in immunocompetent cells but also in adipocytes and muscle cells. The cytokine system is then activated not only in tumours and infections but elevated values were found also in obesity, NIDDM, in myocardial infarction and in advanced decompensated cardiac patients. By acting on phosphorylation of IRS-1 and PI-3 kinase TNF-alpha promotes significantly insulin resistance, causes deterioration of diabetes, as well as elevated body temperature, sleepiness and anorexia. In a group of 65 patients, mostly with android obesity, in hyperleptinaemic and insulin resistant probands with coronarographically confirmed microvascular angina pectoris (n = 22) or IHD, mostly after a myocardial infarction (n = 43) with one or more significant stenoses on the epicardial coronary arteries in half the patients positive or elevated TNF-alpha was found and in 28% also IL-6. This increase did not correlate however with BMI, the percentage of body fat, IRI and C peptide levels nor with cortisol and leptin levels. Insulin resistant subjects had more frequently elevated homocysteine and Lp(a) values which are further two independent risk factors of atherothrombogenesis. Hyperhomocysteinaemia can be favourably influenced by vitamin fortification of the diet or by administration of folate and pyridoxine (1 tablet per day) involving negligible financial costs.
 ...
PMID:[Relation between cytokines (TNF-alpha, IL-1 and 6) and homocysteine in android obesity and the phenomenon of insulin resistance syndromes]. 1042 20

Leptin concentrations are elevated in the majority of obese individuals raising the possibility that leptin resistance contributes to their obesity. Peripheral leptin administration for 48 h caused a several-fold increase in mRNA encoding the suppressors of cytokine signaling SOCS-3 and CIS in hypothalamus and peripheral tissues. Paradoxically, CIS and SOCS-3 mRNAs are also elevated in the leptin-deficient ob/ob mouse. Forced expression of CIS in insulinoma cells prevented transactivation mediated by leptin. Thus tissues continuously exposed to leptin and/or other factors associated with obesity accumulate excessive amounts of SOCS-3 and CIS which could provide a potential mechanism for leptin resistance.
 ...
PMID:Leptin treatment increases suppressors of cytokine signaling in central and peripheral tissues. 1042 95

The recent discovery of leptin as a major controller of appetite has led to a detailed analysis of its specific actions in this process as well as any potential role in the etiology of obesity. It has also emerged that leptin has a wider spectrum of biological activities and has been strongly implicated in fertility and reproduction. The structural similarity between leptin and its receptor and cytokine-receptor systems that control hemopoiesis has also prompted investigation of the potential for this hormone to influence blood cell formation. Recent studies have shown that the leptin receptor is expressed on a diverse range of hemopoietic cells. Leptin itself appears to enhance proliferation of hemopoietic cells in vitro, particularly in combination with other cytokines and may augment some mature hemopoietic cell functions. Although only relatively minor hemopoietic deficiencies have been reported in mice lacking leptin or its receptor, these emerging studies suggest that further analysis of leptin actions in hemopoiesis may be warranted.
 ...
PMID:A role for leptin in hemopoieses? 1046 69

Thanks to progress in zinc research, it is now possible to describe in more detail how zinc ions (Zn++) and nitrogen monoxide (NO), together with glutathione (GSH) and its oxidized form, GSSG, help to regulate immune responses to antigens. NO appears to be able to liberate Zn++ from metallothionein (MT), an intracellular storage molecule for metal ions such as zinc (Zn++) and copper (Cu++). Both Zn++ and Cu++ show a concentration-dependent inactivation of a protease essential for the proliferation of the AIDS virus HIV-1, while zinc can help prevent diabetes complications through its intracellular activation of the enzyme sorbitol dehydrogenase (SDH). A Zn++ deficiency can lead to a premature transition from efficient Th1-dependent cellular antiviral immune functions to Th2-dependent humoral immune functions. Deficiencies of Zn++, NO and/or GSH shift the Th1/Th2 balance towards Th2, as do deficiencies of any of the essential nutrients (ENs) - a group that includes methionine, cysteine, arginine, vitamins A, B, C and E, zinc and selenium (Se) - because these are necessary for the synthesis and maintenance of sufficient amounts of GSH, MT and NO. Via the Th1/Th2 balance, Zn++, NO, MT and GSH collectively determine the progress and outcome of many diseases. Disregulation of the Th1/Th2 balance is responsible for autoimmune disorders such as diabetes mellitus. Under Th2, levels of interleukin-4 (II-4), II-6, II-10, leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) are raised, while levels of II-2, Zn++, NO and other substances are lowered. This makes things easier for viruses like HIV-1 which multiply in Th2 cells but rarely, if ever, in Th1 cells. AIDS viruses (HIVs) enter immune cells with the aid of the CD4 cell surface receptor in combination with a number of co-receptors which include CCR3, CCR5 and CXCR4. Remarkably, the cell surface receptor for LTB4 (BLTR) also seems to act as a co-receptor for CD4, which helps HIVs to infect immune cells. The Th2 cytokine II-4 increases the number of CXCR4 and BLTR co-receptors, as a result of which, under Th2, the HIV strains that infect immune cells are precisely those that are best able to accelerate the AIDS disease process. The II-4 released under Th2 therefore not only promotes the production of more HIVs and the rate at which they infect immune cells, it also stimulates selection for the more virulent strains. Zn++ inhibit LTB4 production and numbers of LTB4 receptors (BLTRs) in a concentration-dependent way. Zn++ help cells to keep their LTB4 'doors' shut against the more virulent strains of HIV. Moreover, a sufficiency of Zn++ and NO prevents a shift of the Th1/Th2 balance towards Th2 and thereby slows the proliferation of HIV, which it also does by inactivating the HIV protease. Research makes it look likely that deficiencies of ENs such as zinc promote the proliferation of Th2 cells at the expense of Th1 cells. Zinc deficiency also promotes cancer. Under the influence of Th1 cells, zinc inhibits the growth of tumours by activating the endogenous tumour-suppressor endostatin, which inhibits angiogenesis. The modern Western diet, with its excess of refined products such as sugar, alcohol and fats, often contains, per calorie, a deficiency of ENs such as zinc, selenium and vitamins A, B, C and E, which results in disturbed immune functions, a shifted Th1/Th2 balance, chronic (viral) infections, obesity, atherosclerosis, autoimmunity, allergies and cancer. In view of this, an optimization of dietary composition would seem to give the best chance of beating (viral) epidemics and common (chronic) diseases at a realistic price.
 ...
PMID:Modern diets and diseases: NO-zinc balance. Under Th1, zinc and nitrogen monoxide (NO) collectively protect against viruses, AIDS, autoimmunity, diabetes, allergies, asthma, infectious diseases, atherosclerosis and cancer. 1049 17

The heterogeneous nature of juvenile rheumatoid arthritis is further defined in publications from the past year. Decreased IL-10 production, an anti-inflammatory cytokine, and soluble IL-6 receptor are associated with systemic juvenile rheumatoid arthritis (JRA). IL-4 may have an anti-inflammatory role in the pathogenesis of pauciarticular JRA and may protect, along with IL-10, against the development of joint erosions. Active JRA is associated with lower levels of platelet activating factor acetylhydrolase, which may contribute to the loss of anti-inflammatory activity and increased risk of atherogenesis. The phase 3 clinical trial of etanercept confirmed its efficacy and safety in JRA. Intra-articular steroids are safe and effective in the treatment of JRA. Methotrexate does have disease-modifying effects. The risk of hepatotoxicity with methotrexate use increases with serial transaminase abnormalities and with obesity. Osteoclasts are responsible for joint erosions. Cyclosporine A, mycophenolate mofetil, and methotrexate are effective in the treatment of refractory uveitis. During the past year a number of scientific publications have contributed significantly to our understanding and treatment of juvenile rheumatoid arthritis.
 ...
PMID:Juvenile rheumatoid arthritis. 1050 57


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>