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)

This study was done to evaluate the efficacy of anti-tumor necrosis factor alpha (anti-TNF-alpha) antibody as an adjunctive therapy in neonatal bacterial meningitis. Newborn piglets were divided into three groups: 8 in the control group, 13 in the meningitis group (MG), and 10 in the meningitis with anti-TNF-alpha antibody group (AG). Meningitis was induced by intracisternal injection of 10(8) colony-forming units of Escherichia coli in 100 microl of saline. In the AG, 200 microl of anti-TNF-alpha antibody was also given intracisternally. In the AG, the elevated cerebrospinal fluid TNF-alpha level observed in the MG was completely abolished, and increased intracranial pressure, hypoglycorrhachia, and CSF pleocytosis observed in the MG were downmodulated. But blood, brain, and CSF lactate levels remained elevated in both MG and AG. Increased brain cell membrane lipid peroxidation products and decreased Na+,K+-ATPase activity observed in the MG were not attenuated in the AG. These results indicate that anti-TNF-alpha antibody was not particularly effective as an adjunctive therapy in attenuating acute inflammatory responses and ameliorating brain damage in neonatal bacterial meningitis.
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PMID:Efficacy of anti-tumor necrosis factor-alpha antibody as an adjunctive therapy in experimental Escherichia coli meningitis in the newborn piglet. 1032 41

While effector molecules produced by activated macrophages (including nitric oxide, tumor necrosis factor alpha, interleukin 1, etc.) help to eliminate pathogens, high levels of these molecules can be deleterious to the host itself. Despite their importance, the mechanisms modulating macrophage effector functions are poorly understood. This work introduces two key negative regulators that control the levels and duration of macrophage cytokine production. Vacuolar-type H+-ATPase (V-ATPase) and calcineurin (Cn) constitutively act in normal macrophages to suppress expression of inflammatory cytokines in the absence of specific activation and to inhibit macrophage cytokine responses induced by bacterial lipopolysaccharide (V-ATPase), interferon gamma (V-ATPase and Cn), and calcium (Ca2+) flux (Cn). Cn and V-ATPase modulate effector gene expression at the mRNA level by inhibiting transcription factor NF-kappaB. This negative regulation by Cn is opposite to its crucial positive role in T cells, where it activates NFAT transcription factor(s) leading to expression of interleukin 2, tumor necrosis factor alpha, and other cytokine genes. The negative effects of V-ATPase and Cn on NF-kappaB-dependent gene expression are not limited to the macrophage lineage, as similar effects have been seen with a murine fibroblast cell line and with primary astrocytes.
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PMID:Calcineurin and vacuolar-type H+-ATPase modulate macrophage effector functions. 1033 86

Arterial hypertension (HBP) is a very important cardiovascular risk factor. According to the data from the Framingham Study, 90% of the patients with chronic heart failure (CHF) have a clinical history of HBP, and the risk of developing CHF is 2 to 3 times greater in hypertensive persons. Studies of general population by multivariate analysis have shown that HBP is responsible for 39% of CHF cases in males and 59% in females. On the other hand, there is a significant relation between HBP and coronary artery disease (CAD), another very important cause of CHF. HBP very frequently originates left ventricular hypertrophy (LVH) and this is one of the most important links between HBP, myocardium ischaemia, CAD, and sudden death from arrhythmias, to which it can lead. Recent studies on left ventricle systolic function in hypertensive patients indicate that about 1/6 of HBP patients with LVH present systolic dysfunction. Even more frequently, diastolic function is prematurely deteriorated in HBP. In spite of the existence of a significant relation between the grade of LVH and the severity of this disfunction, it may be present even before LVH is detectable. The transition from LVH would be related to quantitative and qualitative changes in the three compartments of the myocardium: hypertrophy of cardiomyocytes with reinduction of fetal genetic program, reactive and cicatricial fibrosis of the interstice, and functional and structural changes of coronary arteries. These modifications will progressively increase, leading to LV dilation which seems to signal transition to heart failure. In recent papers the transition from LVH to CHF has been related to a marked increase in microtubular intracytoplasmic structure, the reduction of Ca++ ATPase concentration of the sarcoplasmic reticulum, and the increased myocardial expression of growth factor TGF beta 1, which influences interstitial fibrosis. In the same way, stimulation of apoptosis by myocardial expression of tumor necrosis factor alpha and the subquent increase in inducible NO-synthase and oxidative stress has been related to the progression for CHF. Prevention of CHF will not only consist in the treatment of HBP but, very probably, also in the prevention of regression of LVH, and normalization of myocardial components, as well as the correction of all the factors involved in CHF establishment. In accordance with form of treatment, we must give special emphasis to drugs interfering with the renin-angiotensin system and, possibly in the near future, to gene therapy.
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PMID:[Hypertensive cardiopathy. From arterial hypertension to congestive heart failure]. 1042 61

Dietary potassium supplementation lowers blood pressure (BP) and attenuates complications in hypertensive subjects, particularly those with the low renin volume expanded (LRVE) variety. We and others have shown that the plasma level of a digitalis like substance (DLS) is elevated in this type of hypertension. We therefore, examined the effect of increases in dietary potassium on the plasma level of endogenous DLS, myocardial and renal Na+, K+-ATPase (NKA) activities, BP, and renal excretory function in reduced renal mass (RRM)-salt hypertension in the rat, a classical model of LRVE hypertension. 70% RRM rats were divided in 4 groups, namely those consuming: 1) a sodium free and normal potassium (1.3% as KCl) diet (RRM-0 Na), 2) a normal sodium and normal potassium diet (RRM-NaK), 3) a normal sodium and high potassium (2 X normal) diet (RRM-Na2K), and 4) a normal sodium and 4 times normal potassium diet (RRM-Na4K). At the end of 4 weeks of dietary treatment, direct BP was recorded, plasma level of DLS determined by bioassay and with a radioimmunoassay for digoxin (DIF) and myocardial and renal NKA activities were measured. As expected, compared to RRM-0Na rats, RRM-NaK rats developed hypertension. BP increased significantly less in RRM-Na2K, whereas BP did not increase in RRM-Na4K rats. Hypertension in RRM-NaK rats was associated with an increase in plasma DLS and DIF and decrease in renal and myocardial NKA activities. DLS was increased (DIF was not changed) and myocardial NKA also decreased in rats consuming double potassium. However, quadrupling potassium in the diet (RRM-Na4K) normalized DLS and DIF and increased myocardial and renal NKA activities, compared to RRM-0Na rats. Also compared to RRM-0Na, water consumption, urinary volume excretion, sodium, and potassium increased in the other 3 groups, more so in RRM-Na4K rats. These data show that quadrupling the potassium in the diet prevents the BP increase in RRM rats and this is associated with diuresis/natriuresis and normalization of DLS, perhaps because the diuresis/natriuresis normalizes blood volume.
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PMID:Mechanism of antihypertensive effect of dietary potassium in experimental volume expanded hypertension in rats. 1097 61

We evaluated the anti-inflammatory and neuroprotective effects of the selective neuronal nitric oxide synthase inhibitor 7-nitroindazole and aminoguanidine, which predominantly inhibits inducible nitric oxide synthase, during the early phase of experimental bacterial meningitis in the newborn piglet. Meningitis was induced by intracisternal injection of 10(8) colony-forming units of Escherichia coli in 100 microl of saline. 7-Nitroindazole significantly attenuated the meningitis-induced acute inflammatory responses such as increased intracranial pressure, decreased cerebrospinal fluid (CSF) glucose concentration, and CSF leukocytosis at 2 h. However, meningitis-induced CSF leukocytosis at 4 h and increased CSF lactate and tumor necrosis factor alpha levels were not significantly attenuated. Reduced cerebral cortical cell membrane Na(+),K(+)-ATPase activity and increased lipid peroxidation products, indicative of meningitis-induced brain cell membrane dysfunction, were also significantly improved with 7-nitroindazole treatment. In contrast, although aminoguanidine significantly attenuated the increase in the CSF tumor necrosis factor alpha level, it failed to attenuate the acute inflammation and the ensuing brain injury in bacterial meningitis. In summary, 7-nitroindazole, but not aminoguanidine, significantly attenuated the acute inflammatory responses and brain injury during the early phase of neonatal bacterial meningitis.
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PMID:7-Nitroindazole, but not aminoguanidine, attenuates the acute inflammatory responses and brain injury during the early phase of Escherichia coli meningitis in the newborn piglet. 1147 50

Since a release of intracellular contents can induce local inflammatory responses, mechanisms that lead to loss of plasma membrane integrity in cell death are important to know. We showed previously that deficiency of the plasma membrane Ca2+ ATPase 4 (PMCA4) in L929 cells impaired tumor necrosis factor alpha (TNF-alpha)-induced enlargement of lysosomes and reduced cell death. The lysosomal changes can be determined by measuring the total volume of intracellular acidic compartments per cell (VAC), and we show here that inhibition of the increase in VAC due to PMCA4 deficiency not only reduced cell death but also converted TNF-alpha-induced cell death from a process involving disruption of the plasma membrane to a cell demise with a nearly intact plasma membrane. The importance of the size of lysosomes in determining plasma membrane integrity during cell death was supported by the observations that chemical inhibitors that reduce VAC also reduced the plasma membrane disruption induced by TNF-alpha in wild-type L929 cells, while increases in VAC due to genetic mutation, senescence, cell culture conditions, and chemical inhibitors all changed the morphology of cell death from one with an originally nearly intact plasma membrane to one with membrane disruption in a number of different cells. Moreover, the ATP depletion-mediated change from apoptosis to necrosis is also associated with the increases of VAC. The increase in lysosomal size may due to intracellular self-digestion of dying cells. Big lysosomes are easy to rupture, and the release of hydrolytic enzymes from ruptured lysosomes can cause plasma membrane disruption.
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PMID:Susceptibility of lysosomes to rupture is a determinant for plasma membrane disruption in tumor necrosis factor alpha-induced cell death. 1250 64

P68 nuclear RNA helicase is essential for normal cell growth. The protein plays a very important role in cell development and proliferation. However, the molecular mechanism by which the p68 functions in cell developmental program is not clear. We previously observed that bacterially expressed his-p68 was phosphorylated at multiple sites including serine/threonine and tyrosine [L. Yang, Z.R. Liu, Protein Expr. Purif., 35: 327]. Here we report that p68 RNA helicase is phosphorylated at tyrosine residue(s) in HeLa cells. Phosphorylation of p68 at threonine or tyrosine residues responds differently to tumor necrosis factor alpha (TNF-alpha)induced cell signal. Kinase inhibition and in vitro kinase assays demonstrate that p68 RNA helicase is a cellular target of p38 MAP kinase. Phosphorylation of p68 affects the ATPase and RNA unwinding activities of the protein. In addition, we demonstrate here that phosphorylation of p68 RNA helicase controls the function of the protein in the pre-mRNA splicing process. Interestingly, phosphorylation at different amino acid residues exhibits different regulatory effects. The data suggest that function(s) of p68 RNA helicase may be subjected to the regulation of multiple cell signal pathways.
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PMID:Signaling to the DEAD box--regulation of DEAD-box p68 RNA helicase by protein phosphorylations. 1592 48

To perform effectively as a molecular chaperone, DnaK (Hsp70) necessitates the assistance of its DnaJ (Hsp40) co-chaperone partner, which efficiently stimulates its intrinsically weak ATPase activity and facilitates its interaction with polypeptide substrates. In this study, we address the function of the conserved glycine- and phenylalanine-rich (G/F-rich) region of the Escherichia coli DnaJ in the DnaK chaperone cycle. We show that the G/F-rich region is critical for DnaJ co-chaperone functions in vivo and that despite a significant degree of sequence conservation among the G/F-rich regions of Hsp40 homologs from bacteria, yeast, or humans, functional complementation in the context of the E. coli DnaJ is limited. Furthermore, we found that the deletion of the whole G/F-rich region is mirrored by mutations in the conserved Asp-Ile/Val-Phe (DIF) motif contained in this region. Further genetic and biochemical analyses revealed that this amino acid triplet plays a critical role in regulation of the DnaK chaperone cycle, possibly by modulating a crucial step subsequent to DnaK-mediated ATP hydrolysis.
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PMID:The role of the DIF motif of the DnaJ (Hsp40) co-chaperone in the regulation of the DnaK (Hsp70) chaperone cycle. 1653 11

There has been increasing evidence that tumor necrosis factor alpha (TNF-alpha) is synthesized by cardiomyoctes and contributes to their impaired function and to cardiac failure. Because the Na(+)-K(+) ATPase is a key player in the contraction of cardiomyocytes, this work was undertaken to study the effect of TNF-alpha on the Na(+)-K(+) ATPase in rat heart. Sprague Dawley rats (Rattus norvegicus) were injected with TNF-alpha (270 ng/100 g body weight) and 4 h later the ventricles were isolated, homogenized and assayed for their Na(+)-K(+) ATPase activity. The effect of TNF-alpha on the pump was studied also in isolated myocytes treated in suspension. The involvement of PGE2 was investigated by pre-treating animals or cells with indomethacin, an inhibitor of COX enzymes. The involvement of NF-kappaB and AP-1 was studied using their respective inhibitors PDTC and curcumin. A time response study showed an increase in the activity of the Na(+)-K(+) ATPase in the left and right ventricles of animals treated with the cytokine, with no change in its protein expression. This effect disappeared in the presence of indomethacin suggesting an involvement of PGE(2) in the action of TNF-alpha. Rats and cells treated directly with PGE(2) showed a dose-dependent response. A decrease in the activity of the Na(+)-K(+) ATPase was observed at a low dose and an increase at a high dose in both ventricles. Since PGE(2) is suspected to be the active mediator in TNF-alpha signaling, inhibiting its synthesis by inhibiting some suspected transcription factors was attempted. PDTC abrogated fully, and curcumin partially the effect of the cytokine. It was concluded that TNF-alpha activates NF-kappaB and AP-1 and induces PGE(2) release which alters dose-dependently the activity of the pump by activating different EP receptors with different affinities for PGE(2).
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PMID:Tumor necrosis factor alpha alters Na+-K+ ATPase activity in rat cardiac myocytes: involvement of NF-kappaB, AP-1 and PGE2. 1702 35

The pathogenesis of Mycoplasma pneumoniae infection is considered to be in part attributable to excessive immune responses. In this study, we investigated whether synthetic lipopeptides of subunit b of F0F1-type ATPase (F0F1-ATPase), NF-kappaB-activating lipoprotein 1 (N-ALP1), and N-ALP2 (named FAM20, sN-ALP1, and sN-ALP2, respectively) derived from M. pneumoniae induce cytokine and chemokine production and leukocyte infiltration in vivo. Intranasal administration of FAM20 and sN-ALP2 induced infiltration of leukocyte cells and production of chemokines and cytokines in bronchoalveolar lavage fluid, but sN-ALP1 failed to do so. The activity of FAM20 was notably higher than that of sN-ALP2. FAM20 and sN-ALP2 induced tumor necrosis factor alpha (TNF-alpha) through Toll-like receptor 2 in mouse peritoneal macrophages. Moreover, in the range of low concentrations of lipopeptides, FAM20 showed relatively high activity of inducing TNF-alpha in mouse peritoneal macrophages compared to synthetic lipopeptides such as MALP-2 and FSL-1, derived from Mycoplasma fermentans and Mycoplasma salivarium, respectively. These findings indicate that the F0F1-ATPase might be a key molecule in inducing cytokines and chemokines contributing to inflammatory responses during M. pneumoniae infection in vivo.
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PMID:Mycoplasma pneumoniae-derived lipopeptides induce acute inflammatory responses in the lungs of mice. 1795 22


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