Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Through chemical screening, we identified a pyrazolone that reversibly blocked the activation of phagocyte oxidase (phox) in human neutrophils in response to tumor necrosis factor (TNF) or formylated peptide. The pyrazolone spared activation of phox by phorbol ester or bacteria, bacterial killing, TNF-induced granule exocytosis and phox assembly, and endothelial transmigration. We traced the pyrazolone's mechanism of action to inhibition of TNF-induced intracellular Ca2+ elevations, and identified a nontransmembrane ("soluble") adenylyl cyclase (sAC) in neutrophils as a Ca2+-sensing source of cAMP. A sAC inhibitor mimicked the pyrazolone's effect on phox. Both compounds blocked TNF-induced activation of Rap1A, a phox-associated guanosine triphosphatase that is regulated by cAMP. Thus, TNF turns on phox through a Ca2+-triggered, sAC-dependent process that may involve activation of Rap1A. This pathway may offer opportunities to suppress oxidative damage during inflammation without blocking antimicrobial function.
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PMID:Calcium-sensing soluble adenylyl cyclase mediates TNF signal transduction in human neutrophils. 1604 20

There is very little evidence on the value of giving corticoids in cases of seawater drowning induced acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Therefore, this study aimed to investigate whether dexamethasone treatment can attenuate seawater instillation-induced acute lung injury in rabbits. Seawater (4 ml/kg body weight) was instilled into the lower trachea of ventilated, anesthetized rabbits. Then these rabbits were assigned randomly 20 min later to receive intravenous injection of 1mg/kg body weight of dexamethasone (dissolving in 2 ml of normal saline) or 2 ml of normal saline. All animals demonstrated immediate drops in arterial oxygen tension (PaO2) and the total thoracic compliance, which were significantly improved after 2 h of dexamethasone treatment. Histopathological study also indicated that dexamethasone treatment markedly attenuated lung histopathological changes, alveolar hemorrhage and inflammatory cells infiltration with evidence of decreasing of myeloperoxidase (MPO) activity and tumor necrosis factor-alpha (TNF-alpha) concentration in lung tissue. In addition, dexamethasone treatment reduced extravascular lung water and lung epithelial-endothelial barrier permeability, up-regulated the expression of surfactant protein-A (SP-A) and alpha-epithelial Na+ channel, and increased Na+/K+-adenosine triphosphatase (Na+/K+-ATPase) activity and Na+/K+-ATPase-alpha1 protein abundance. Thus, these data indicate that dexamethasone treatment might be of benefit in patients with seawater aspiration-induced ALI.
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PMID:Dexamethasone treatment attenuates early seawater instillation-induced acute lung injury in rabbits. 1650 35

Previous investigations indicate that some of the metabolites of the hemorheological agent pentoxifylline (PTX), namely 1-(5-hydroxyhexyl)-3,7-dimethylxanthine (M1), 1-(4-carboxybutyl)-3,7-dimethylxanthine (M4) and 1-(3-carboxypropyl)-3,7-dimethylxanthine (M5), concur to some of the biological effects of the drug. However, information on the bioactivity of the major circulating oxidative metabolites of PTX (M4 and M5) is scanty. Here, we compared the effects of M4 and M5 with that of PTX and its major reductive metabolite, M1, on TNF-alpha production and cytotoxicity, endothelial cell proliferation and on the ATPase activity related to some ATP-binding cassette (ABC) transporters. Unlike PTX and M1, M4 and M5 poorly inhibited lipopolysaccaride-stimulated tumor necrosis factor-alpha (TNF-alpha) release by RAW 264.7 murine macrophages, and did not affect at all cell proliferation and upregulation of TNF-alpha-induced vascular cell adhesion molecule-1 (VCAM-1) in H5V endothelioma cells. By contrast, M4 and M5 were more effective than PTX and M1 in protecting WC/1 murine fibrosarcoma cells from TNF-alpha cytotoxicity. Moreover, results from ATP hydrolase assays indicated that neither PTX nor its tested metabolites interacted significantly with the human multidrug resistance transporters p-glycoprotein/multidrug resistance 1 (MDR1), multidrug resistance-related protein 1 (MRP1), and breast cancer resistance protein (BCRP). Based on these results and literature data, M5, retaining some of the PTX effects but lacking in significant inhibition of TNF-alpha production, may be a promising candidate drug for certain pathologic conditions.
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PMID:Pentoxifylline and its major oxidative metabolites exhibit different pharmacological properties. 1654 99

Ion transport is essential for maintenance of transmembranous and transcellular electric potential, fluid transport and cellular volume. Disturbance of ion transport has been associated with cellular dysfunction, intra and extracellular edema and abnormalities of epithelial surface liquid volume. There is increasing evidence that conditions characterized by an intense local or systemic inflammatory response are associated with abnormal ion transport. This abnormal ion transport has been involved in the pathogenesis of conditions like hypovolemia due to fluid losses, hyponatremia and hypokalemia in diarrhoeal diseases, electrolyte abnormalities in pyelonephritis of early infancy, septicemia induced pulmonary edema, and in hypersecretion and edema induced by inflammatory reactions of the mucosa of the upper respiratory tract. Components of membranous ion transport systems, which have been shown to undergo a change in function during an inflammatory response include the sodium potassium ATPase, the epithelial sodium channel, the Cystic Fibrosis Transmembrane Conductance Regulator and calcium activated chloride channels and the sodium potassium chloride co-transporter. Inflammatory mediators, which influence ion transport are tumor necrosis factor, gamma interferon, interleukins, transforming growth factor, leukotrienes and bradykinin. They trigger the release of specific messengers like prostaglandins, nitric oxide and histamine which alter ion transport system function through specific receptors, intracellular second messengers and protein kinases. This review summarizes data on in vivo measurements of changes in ion transport in acute inflammatory conditions and in vitro studies, which have explored the underlying mechanisms. Potential interventions directed at a correction of the observed abnormalities are discussed.
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PMID:Changes in ion transport in inflammatory disease. 1657 Nov 16

Resistance training results in muscle hypertrophy and improves glycemic control in patients with type 2 diabetes. Whether resistance training modulates inflammation in muscles of diabetic patients remains unknown. We examined the expression of genes encoding the cytokines, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and transforming growth factor-beta1 (TGF-beta1) as well as the pan-leukocyte marker CD18. Thirty men and women (67+/-7 years) were randomized to either 16 weeks of resistance training and usual diabetes care (EX) or to usual diabetes care only (CON). Muscle biopsies were obtained from the vastus lateralis muscle prior to the 16-week intervention, and 72 h following the maximal strength test post-intervention. Fiber cross-sectional area (CSA) was determined following ATPase staining. Cytokine and CD18 transcript levels were assessed by real-time PCR. Resistance training increased CSA of type I and II fibers (both P <0.05) and IL-1beta transcript levels (P = 0.05). TNF-alpha (P<0.05) and TGF-beta1 transcripts (P<0.05) increased over time in the EX group, but these increases did not differ from those in the CON group. In both groups, the increase in CD18 transcripts remained minimal. The two groups differ by the relationship between changes in CD18 and changes in cytokine transcripts, suggesting that resistance training affects the source of cytokines in muscle. Our studies establish that resistance training in older adults with type 2 diabetes results in muscle fiber hypertrophy, despite a greater accumulation of inflammatory cytokine transcripts in muscle.
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PMID:Resistance training alters cytokine gene expression in skeletal muscle of adults with type 2 diabetes. 1716 96

Alpha-melanocyte-stimulating hormone (alpha-MSH) is a peptide with broad anti-inflammatory effects. The present research was designed to determine production and effects of alpha-MSH in acute bleomycin-induced lung injury in rats. Intratracheal bleomycin instillation induced alpha-MSH expression in lung infiltrating cells and a marked peptide increase in the circulation. In experiments on the therapeutic potential of alpha-MSH on lung injury, we determined influences of the synthetic alpha-MSH analogue [Nle4-dPhe7]-alpha-MSH (NDP-alpha-MSH) on pulmonary edema, circulating nitric oxide, and gene expression profile in lungs 8 and 24 h after bleomycin instillation. Three main gene categories, known to be involved in the development of acute lung injury, were explored: stress response, inflammation, and fluid homeostasis. Peptide treatment was associated with a significant reduction in interstitial edema, with a virtually normal wet/dry weight ratio. Several stress-related genes, which were either upregulated or reduced by bleomycin, were only marginally altered during NDP-alpha-MSH treatment. NDP-alpha-MSH prevented bleomycin-related transcriptional alterations in genes involved in lung fluid homeostasis, including upregulation of Na/K-transporting ATPase and epithelial sodium channels and downregulation of cystic fibrosis transmembrane conductance regulator. Bleomycin-induced expression of proinflammatory and profibrotic factors (interleukin 6, tumor necrosis factor-alpha, transforming growth factor-beta1, and inducible nitric oxide synthase) and chemokines (chemokine [C-C motif] ligand 2 and chemokine [C-C motif] ligand 5) was likewise significantly reduced by NDP-alpha-MSH. In conclusion, treatment with the alpha-MSH analogue NDP-alpha-MSH greatly improved the clinical and molecular picture of bleomycin-induced lung injury. Treatment with alpha-MSH-related agents can exert beneficial effects in acute lung injury.
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PMID:Production and effects of alpha-melanocyte-stimulating hormone during acute lung injury. 1730 15

Toll-like receptor 4 (TLR4) initiates both myeloid differentiation factor 88 (MyD88)-dependent and Toll/interleukin (IL)-1R domain-containing adapter, inducing interferon (IFN)-beta-dependent signaling, leading to production of proinflammatory mediators and type I interferon (IFN) to eliminate pathogens. However, uncontrolled TLR4 activation may contribute to pathogenesis of autoimmune and inflammatory diseases. TLR4 is transported from the plasma membrane to the endosome for ubiqutination and to the lysosome for degradation, and downregulation of TLR4 expression or promotion of TLR4 degradation are important ways for negative regulation of TLR4 signaling. We previously identified a lysosome-associated small guanosine triphosphatase (GTPase) Rab7b that may be involved in lysosomal trafficking and degradation of proteins. Here we demonstrate that Rab7b can negatively regulate lipopolysaccharide (LPS)-induced production of tumor necrosis factor (TNF)-alpha, IL-6, nitric oxide, and IFN-beta, and potentiate LPS-induced activation of mitogen-activated protein kinase, nuclear factor kappaB, and IFN regulatory factor 3 signaling pathways in macrophages by promoting the degradation of TLR4. Rab7b is localized in LAMP-1-positive subcellular compartments and colocalized with TLR4 after LPS treatment and can decrease the protein level of TLR4. Our findings suggest that Rab7b is a negative regulator of TLR4 signaling, potentially by promoting the translocation of TLR4 into lysosomes for degradation.
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PMID:Lysosome-associated small Rab GTPase Rab7b negatively regulates TLR4 signaling in macrophages by promoting lysosomal degradation of TLR4. 1739 80

Sepsis and multiple organ failure are characterized by an excessive release of inflammatory mediators and a marked stimulation of stress hormones. These in turn have profound effects on energy and substrate metabolism: energy expenditure is generally increased, and increased lipolysis and fat oxidation are observed. Net protein breakdown occurs and leads to accelerated wasting. Most of these effects can be produced in healthy humans by administration of bacterial endotoxin or by tumor necrosis factor-alpha. Hyperlactatemia is a hallmark of sepsis and critical illness, and its severity is related to mortality. An increased lactate production, possibly secondary to activation of Na-K adenosine 5'-triphosphatase and to muscle mitochondrial dysfunction, is involved. Lactate production by immune cells and wound tissue may also play a role. Long-chain, n-3 polyunsaturated fatty acids have anti-inflammatory effects that may be beneficial in sepsis. They also decrease the stimulation of stress hormones induced by bacterial endotoxin, possibly through an effect exerted at the level of the central nervous sytem. Their use in patients with sepsis does not lead to adverse metabolic effects.
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PMID:Substrate utilization in sepsis and multiple organ failure. 1771 4

When cardiomyocytes were subjected to hypoxia, tumor necrosis factor-alpha (TNF-alpha; 3-50 ng/ml) or adenosine (1-100 microM), decreased hypoxic damage as was detected by lactate dehydrogenase (LDH) release, MTT (3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) absorbance, ROS (reactive oxygen species) measurement or desmin immunostaining. This cardioprotection was not prevented in TNF-alpha-treated cultures by 5-hydroxydecanoic acid (5-HD). Our aim was to elucidate whether adenosine and TNF-alpha mediate a similar protective mechanism against hypoxia in primary heart cultures and in H9c2 cardiomyocytes. Adenosine and TNF-alpha are known for their negative inotropic effects on the heart. We have suggested that deoxyglucose uptake reflects heart contractility in cell cultures; therefore, we assayed its accumulation under various conditions. Treatment for 20 min with adenosine, R-PIA [(-)-N(6)-phenylisopropyladenosine] (10 microM), or TNF-alpha reduced (3)H-deoxyglucose uptake in primary heart cultures and also in H9c2 cardiomyocytes by 30-50%. Isoproterenol accelerated (3)H-deoxyglucose uptake by 50%. Adenosine, R-PIA, or TNF-alpha attenuated the stimulatory effect of isoproterenol on (3)H-deoxyglucose uptake to control levels. Hypoxia reduced (3)H-deoxyglucose uptake by 50%, as in the treatment of the hypoxic cultures with TNF-alpha or adenosine. Glibenclamide (2 microM), 5-HD (300 microM), or diazoxide (50 microM) increased (3)H-deoxyglucose uptake by 50-80%. Adenosine (100 microM) and TNF-alpha (50 ng/ml) stimulated (86)Rb efflux. Glibenclamide attenuated this effect. We demonstrate that TNF-alpha, like adenosine, accelerated Ca(2+) uptake into the sarcoplasmic reticulum (SR) by 50-100% and therefore prevented cardiomyocyte Ca(2+) overload. Our findings further suggest that TNF-alpha, as well as adenosine, may mediate an adaptive effect in the heart by preventing Ca(2+) overload via activation of SR Ca-ATPase (SERCA(2)a).
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PMID:Adenosine and TNF-alpha exert similar inotropic effect on heart cultures, suggesting a cardioprotective mechanism against hypoxia. 1776 3

Hepatic injury after cardiac surgery was considered to be a consequence of cardiopulmonary bypass (CPB). This study tested the hypothesis that melatonin could attenuate the hepatic injury in a rat CPB model. Male Sprague-Dawley rats were randomly divided into four groups: sham-operation group, control group (given an equal volume of vehicle), low dose melatonin (10 mg/kg) treated group and high dose melatonin (20 mg/kg) treated group. Blood samples were collected at the beginning, at the cessation of CPB, and at 30 min, 1, 2, 3 and 24 h post-operation. Liver samples were harvested at 24 h after operation. The serum indices of the liver enzymes and systemic inflammation, as well as oxidative stress indices and the Ca++-ATPase activity of liver tissues were determined. In the control animals, the indices of liver enzymes, tumor necrosis factor-alpha (TNF-alpha) increased after operation, and liver inducible nitric oxide synthase (iNOS), malondialdehyde (MDA), myeloperoxidase (MPO) increased as well. However, the activities of liver antioxidative enzymes and the concentration of glutathione (GSH) decreased remarkably. Results in melatonin group showed that melatonin reversed all the biochemical changes, but there was no significant difference between the melatonin-treated groups. In addition, histological findings further supported these results. All results indicated that application of exogenous melatonin during operation preserves liver function by reducing oxidative stress and the systemic inflammatory response.
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PMID:Exogenous melatonin ameliorates hepatic injury in a rat cardiopulmonary bypass model. 1805 82


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