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

Benzazepines 1 and 2 (SCH 23390 and SCH 39166, respectively) are two classical benzazepine D1/D5 antagonists, with Ki values 1.4 and 1.2 nM, respectively. Compound 2 has been in human clinical trials for a variety of diseases, including schizophrenia, cocaine addition, and obesity. Both 1 and 2 displayed low plasma levels and poor oral bioavailability, due to rapid first-pass metabolism of the phenol moieties. Several heterocyclic systems containing an N-H hydrogen bond donor were synthesized and evaluated as phenol isosteres. The preference orientation of the hydrogen bond was established by comparison of analogues containing different NH vectors. Replacement of the phenol group of 2 with an indole ring generated the first potent D1/D5 antagonist 11b. Further optimization led to the synthesis of very potent benzimidazolones 19, 20 and benzothiazolone analogues 28, 29. These compounds have excellent selectivity over D2-D4 receptors, alpha2a receptor, and the 5-HT transporter. Compared to 2, these heterocyclic phenol isosteres showed much better pharmacokinetic profiles as demonstrated by rat plasma levels. In sharp contrast, similar phenolic replacements in 1 decreased the binding affinity dramatically, presumably due to a conformational change of the pendant phenyl group. However, one indazole compound 33 was identified as a potent D1/D5 ligand in this series.
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PMID:Dopamine D1/D5 receptor antagonists with improved pharmacokinetics: design, synthesis, and biological evaluation of phenol bioisosteric analogues of benzazepine D1/D5 antagonists. 1568 53

An imbalance between triacylglycerol synthesis and breakdown is necessary for the development of obesity. The direct precursor for triacylglycerol biosynthesis is alpha-glycerol phosphate, which can have glycolytic and glyceroneogenic origins. We present a technique for determining the relative glyceroneogenic contribution to triacylglyceride glycerol by labeling the glycerol moiety with 2H2O. The number of hydrogen atoms (n) incorporated from H2O into C-H bonds reflects the metabolic source of alpha-glycerol phosphate and can be calculated by combinatorial analysis of the distribution of mass isotopomers in triacylglyceride glycerol. Three physiological settings with potential effects on glyceroneogenesis and glycolysis were studied in rodents. Adipose tissue acylglyceride glycerol in mice fed a low carbohydrate diet had significantly higher values of n than in mice fed a high carbohydrate diet, suggesting an increased contribution from glyceroneogenesis of from 17 to 50% on the low carbohydrate diet. Similarly, mice administered rosiglitazone had a significant relative increase in glyceroneogenesis (from 17 to 53%), indicated by an increase in adipose acylglyceride glycerol n. Fructose infusion in overnight fasted rats rapidly lowered plasma triacylglyceride glycerol n, reflecting a decreased contribution from glyceroneogenesis (from 66 to 34%) presumably because of increased glycolytic input. In conclusion, we demonstrate that the number of C-H atoms derived from cellular H2O in triacylglyceride glycerol is an informative indicator of alpha-glycerol phosphate origin and, ultimately, triacylglycerol metabolism. Under certain physiological conditions, glyceroneogenesis can be up-regulated in adipose (e.g. low carbohydrate diet) or down-regulated in liver (e.g. fructose infusion). Additionally, stimulation of glyceroneogenesis by rosiglitazone in adipose tissue may be an important factor in the antilipolytic actions of thiazolidinediones.
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PMID:Physiologic and pharmacologic factors influencing glyceroneogenic contribution to triacylglyceride glycerol measured by mass isotopomer distribution analysis. 1588 53

Leptin, secreted by adipose tissue, is involved in the pathogenesis of arterial hypertension, however, the mechanisms through which leptin increases blood pressure are incompletely elucidated. We investigated the effect of leptin, administered for different time periods, on renal Na(+),K(+)-ATPase activity in the rat. Leptin was infused under anesthesia into the abdominal aorta proximally to the renal arteries for 0.5-3 h. Leptin administered at doses of 1 and 10 microg/min per kg for 30 min decreased the Na(+),K(+)-ATPase activity in the renal medulla. This effect disappeared when the hormone was infused for > or =1 h. Leptin infused for 3 h increased the Na(+),K(+)-ATPase activity in the renal cortex and medulla. The stimulatory effect was abolished by a specific inhibitor of Janus kinases (JAKs), tyrphostin AG490, as well as by an NAD(P)H oxidase inhibitor, apocynin. Leptin increased urinary excretion of hydrogen peroxide (H(2)O(2)) between 2 and 3 h of infusion. The effect of leptin on renal Na(+),K(+)-ATPase and urinary H(2)O(2) was augmented by a superoxide dismutase mimetic, tempol, and was abolished by catalase. In addition, infusion of H(2)O(2) for 30 min increased the Na(+),K(+)-ATPase activity. Inhibitors of extracellular signal regulated kinases (ERKs), PD98059 or U0126, prevented Na(+),K(+)-ATPase stimulation by leptin and H(2)O(2). These data indicate that leptin, by acting directly within the kidney, has a delayed stimulatory effect on Na(+),K(+)-ATPase, mediated by JAKs, H(2)O(2) and ERKs. This mechanism may contribute to the abnormal renal Na(+) handling in diseases associated with chronic hyperleptinemia such as diabetes and obesity.
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PMID:Time-dependent effect of leptin on renal Na+,K+-ATPase activity. 1608 15

Obese people are at high risk for developing diabetes, dyslipidemia, hypertension, and cardiovascular diseases, which lead to an increased risk of mortality. Activated polymorphonuclear neutrophils (PMN) generate extremely high amounts of reactive oxygen species (ROS), but these are normally targeted at pathogens inside intracellular phagosomes. These same beneficial antimicrobial functions can cause significant local tissue injury and lead to the development of pathologic systemic inflammatory conditions. PMN apoptosis is a major mechanism associated with the resolution of inflammatory reactions. The goals of the present study were: 1) to evaluate the level of reactive oxygen species production in PMN from obese people before and during body mass reduction, 2) to investigate the in vitro effect of flavonoids: quercetin and rutin on oxidative metabolism and apoptosis of stimulated neutrophils in obese patient. We tested 30 obese patients (women) before body mass reduction and 20 patients during low calories diet. The inclusion criteria were based on physical examination, BMI, WHR, the body composition examination based on bioimpedance method and biochemical assessment. PMN were isolated and oxidant production, in response to 1 microg/ml PMA, was characterised by the production of hydrogen peroxide, nitric oxide and chemiluminescence intensity. Caspase-3 activation was assayed by the method of DEVD-AMC cleavage in PMN cultured up to 24 hours. The results of our study showed: 1) the decrease in PMN oxidant production in patient during the mass reduction, 2) the strong antioxidant activity of quercetin and rutin in obese patients before and during the body mass reduction, these effects were dose dependent and rutin was less potent than quercetin, 3) acceleration of PMN apoptosis by rutin is associated with an increase in caspase 3 activity.
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PMID:[Oxidative metabolism of neutrophils in obese patients before and during body mass reduction: the in vitro effect of quercetin and rutin]. 1612 80

Babassu is the popular name of Orbignya phalerata Mart. [Arecaceae (Palmae)], which fruits mesocarp has been used in Brazil as medicine for the treatment of pains, constipation, obesity, leukemia, rheumatism, ulcerations, tumors and inflammations. In this study, we investigated the effect of babassu mesocarp flour aqueous extract (BM) on C3H/HePas mice peritoneal cellular migration and macrophage activation by measuring the nitric oxide (NO), hydrogen peroxide (H(2)O(2)) and tumor necrosis factor (TNF) release, spreading activity and major histocompatibility complex (MHC) class II expression. Our results demonstrate that BM injected once ip in mice at 10 and 20 mg/kg increased the cellular influx to the peritoneal cavity, the MHC class II expression and the spreading ability, and also induced the production of NO, TNF and H(2)O(2). The increase in NO-production and MHC expression was also observed after the addition of BM to resident macrophage cultures (100 microg/ml). Thus, BM-treatment was able to activate peritoneal macrophages in vitro and in vivo inducing the production of inflammatory and cytotoxic metabolites, which could justify the popular use of babassu mesocarp in the treatment of tumor diseases, but not in inflammatory pathologies.
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PMID:Macrophage activation induced by Orbignya phalerata Mart. 1615 4

Pulsating electrostatic field (PESF) therapy was investigated to assess the possibility of increasing the resting metabolic rate (RMR) in 14 adult females. The pumping effect of positive calcium and hydrogen ions was obtained by 30 min daily exposure to negative PESF, adjusted individually between 2 and 9 kV. This treatment could result in a buffering effect on blood pH and reduction of the rouleaux formation of erythrocytes, thus ameliorating the oxygen exchange potential and the red cell circulation in the capillary system. After PESF therapy, the average RMR (measured by indirect calorimetry) of 1255 kcal was increased on average by 323 kilocalories, indicating a possible role of PESF in the obesity treatment.
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PMID:Resting metabolic rate incremented by pulsating electrostatic field (PESF) therapy. 1629 54

The present study was designed to examine the effects of lifestyle modification on key contributing factors to atherogenesis, including oxidative stress, inflammation, chemotaxis, and cell adhesion. Obese men (n = 31), 15 of whom had metabolic syndrome, were placed on a high-fiber, low-fat diet in a 3-wk residential program where food was provided ad libitum and daily aerobic exercise was performed. In each subject, pre- and postintervention fasting blood was drawn for circulating levels of serum lipids, glucose and insulin (for estimation of insulin sensitivity), oxidative stress-generating enzyme myeloperoxidase and marker 8-isoprostaglandin F2alpha, the inflammatory protein C-reactive protein, soluble ICAM-1 as an indicator of endothelial activation, sP-selectin as a marker of platelet activation, the chemokine macrophage inflammatory protein-1alpha, and total matrix metalloproteinase-9. Using subject sera and human aortic endothelial cell culture systems, we measured VCAM-1 cell surface abundance and monocyte chemotactic protein-1, nitric oxide, superoxide, and hydrogen peroxide production in vitro by fluorometric detection. Also determined in vitro was serum-induced, monocyte adhesion and monocyte chemotactic activity. After 3 wk, significant reductions (P < 0.05) in body mass index, all serum lipids and lipid ratios, fasting glucose, insulin, homeostasis model assessment for insulin resistance, myeloperoxidase, 8-isoprostaglandin F2alpha, C-reactive protein, soluble ICAM-1, soluble P-selectin, macrophage inflammatory protein-1alpha, and matrix metalloproteinase-9 were noted. In vitro, serum-stimulated cellular VCAM-1 expression, monocyte chemotactic protein-1 production, and fluorometric detection of superoxide and hydrogen peroxide production decreased, whereas a concomitant increase in NO production was noted (all P < 0.01). Additionally, both monocyte adhesion (P < 0.05) and MCA (P < 0.01) decreased. Nine of 15 were no longer positive for metabolic syndrome postintervention. Intensive lifestyle modification may ameliorate novel coronary artery disease risk factors in men with metabolic syndrome factors before reversal of obesity.
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PMID:Effect of a short-term diet and exercise intervention on oxidative stress, inflammation, MMP-9, and monocyte chemotactic activity in men with metabolic syndrome factors. 1661 61

Low plasma levels of adiponectin (hypoadiponectinemia) and elevated circulating concentrations of plasminogen activator inhibitor (PAI)-1 are causally associated with obesity-related insulin resistance and cardiovascular disease. However, the mechanism that mediates the aberrant production of these two adipokines in obesity remains poorly understood. In this study, we investigated the effects of hypoxia and reactive oxygen species (ROS) on production of adiponectin and PAI-1 in 3T3-L1 adipocytes. Quantitative PCR and immunoassays showed that ambient hypoxia markedly suppressed adiponectin mRNA expression and its protein secretion, and increased PAI-1 production in mature adipocytes. Dimethyloxallyl glycine, a stabilizer of hypoxia-inducible factor 1alpha (HIF-1alpha), mimicked the hypoxia-mediated modulations of these two adipokines. Hypoxia caused a modest elevation of ROS in adipocytes. However, ablation of intracellular ROS by antioxidants failed to alleviate hypoxia-induced aberrant production of adiponectin and PAI-1. On the other hand, the antioxidants could reverse hydrogen peroxide (H2O2)-induced dysregulation of adiponectin and PAI-1 production. H2O2 treatment decreased the expression levels of peroxisome proliferator-activated receptor gamma (PPARgamma) and CCAAT/enhancer binding protein (C/EBPalpha), but had no effect on HIF-1alpha, whereas hypoxia stabilized HIF-1alpha and decreased expression of C/EBPalpha, but not PPARgamma. Taken together, these data suggest that hypoxia and ROS decrease adiponectin production and augment PAI-1 expression in adipocytes via distinct signaling pathways. These effects may contribute to hypoadiponectinemia and elevated PAI-1 levels in obesity, type 2 diabetes, and cardiovascular diseases.
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PMID:Hypoxia dysregulates the production of adiponectin and plasminogen activator inhibitor-1 independent of reactive oxygen species in adipocytes. 1642 6

In the formation of gallstone diseases, there are numerous genes, that are held responsible for liver disorders primarily and diseases of bile flow and bile formation, modification of lipid metabolism diabetes mellitus, obesity, glutene sensitive enteropathy, Crohn-disease, Down syndrome, Gucher syndrome, cystic fibrosis as well as haematological disorders and state following ileum resection. In the development of these, bacterial infections, inflammatory reactions, metal element power and free radicals play an important role. Fatty acids, lipid oxides, diene conjugates and other lipid peroxidation products are moving from the liver to the bile, and they initiate primer and secondary free radical reactions in the bile duct and gallbladder. The inflammation processes in the gallbladder wall produce free radicals. The free bilirubin content of the bile behaves pro- and antioxidant molecules. The ambivalent property of free bilirubin, which is detected concentration in the gallbladder bile -- from microsomal leakage or as a consequence of bacterial deglucuronidation -- increases the free radical reactions in the gallbladder. The gallstone formation of free bilirubin with metal ions, primarily Ca ++ ions makes calcium hydrogen bilirubinate in the bile. Calcium ions can react with fatty acids and hereby modify the bile viscosity. The lipids, free bilirubin and metal elements are all components in stone formation. Antioxidants, concerning their derivates or molecules, medicines, which increase antioxidant property can influence the bile composition or inhibit the gallstone formation on several levels.
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PMID:[Gallstone disease: free radical reactions and the ambivalent role of bilirubin in the pathomechanism of gallstone formation]. 1738 52

Zonisamide and topiramate are two antiepileptic drugs known to induce weight loss in epilepsy patients. These molecules were recently shown to act as carbonic anhydrase (CA) inhibitors, being presumed that the weight loss may be due to the inhibition of the mitochondrial isozymes CA VA and CA VB involved in metabolic processes, among which lipid biosynthesis. To better understand the interaction of these compounds with CAs, here, we report a homology modeling and molecular dynamics simulations study on their adducts with human carbonic anhydrase VA (hCA VA). According to our results, in both cases the inhibitor sulfamate/sulfonamide moiety participates in the canonical interactions with the catalytic zinc ion, whereas the organic scaffold establishes a large number of van der Waals and polar interactions with the active site cleft. A structural comparison of these complexes with the corresponding homologues with human carbonic anhydrase II (hCA II) provides a rationale to the different affinities measured for these drugs toward hCA VA and hCA II. In particular, our data suggest that a narrower active site cleft, together with a different hydrogen bond network arrangement of hCA VA compared to hCA II, may account for the different Kd values of zonisamide and topiramate toward these physiologically relevant hCA isoforms. These results provide useful insights for future design of more isozyme-selective hCA inhibitors with potential use as anti-obesity drugs possessing a novel mechanism of action.
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PMID:Molecular modeling study for the binding of zonisamide and topiramate to the human mitochondrial carbonic anhydrase isoform VA. 1742 Jan 32


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