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)

We evaluated the efficacy of alpha-phenyl-N-tertbutylnitrone as an adjunctive therapy in 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. Alpha-Phenyl-N-tert-butylnitrone 100 mg/kg was given as a bolus intravenous injection 30 min before induction of meningitis. Although it completely abolished the elevated CSF tumor necrosis factor-a level observed in the meningitis group, alpha-phenyl-N-tert-butylnitrone did not down-modulate parameters of inflammatory responses such as increased intracranial pressure, hypoglycorrhachia, elevated CSF lactate level, and CSF leukocytosis observed in this group. However, alpha-phenyl-N-tert-butylnitrone treatment mitigated alterations in brain cell membrane structure and function during meningitis, evidenced by amelioration of increased brain cell membrane lipid peroxidation products (conjugated dienes) and decreased Na+, K+-ATPase activity. Reduced mean arterial blood pressure, cerebral perfusion pressure, brain glucose concentration, and cerebral energy stores and marginally increased brain lactate level observed in the meningitis group were also ameliorated. These results suggest that although it failed to attenuate the inflammatory responses, alpha-phenyl-N-tert-butylnitrone was effective in ameliorating brain injury in neonatal bacterial meningitis.
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PMID:Effect of alpha-phenyl-N-tert-butylnitrone on brain cell membrane function and energy metabolism in experimental Escherichia coli meningitis in the newborn piglet. 1064 28

This study was done to evaluate the anti-inflammatory effect and the ensuing neuroprotective effect of pentoxifylline in neonatal experimental bacterial meningitis. Newborn piglets were divided into three groups: 10 in the control group (CG), 13 in the meningitis group (MG), and 13 in the meningitis with pentoxifylline group (PG). Meningitis was induced by intracisternal injection of 10(8) colony-forming units of Escherichia coli in 100 microl of saline. In PG, 20 mg/kg of pentoxifylline was given as a bolus intravenous injection 30 min before induction of meningitis and 6 mg/kg/h was given continuously throughout the experiment. In PG, the increase of CSF TNF-alpha level observed in MG was abolished. Reduced brain glucose and ATP concentrations observed in MG were significantly increased in PG. However, other parameters of inflammatory responses such as increased intracranial pressure, reduced glucose and increased lactate concentrations in the CSF observed in MG were not significantly down-modulated. The extent of CSF leukocytosis was even higher in PG than in MG. Increased cerebral cortical cell membrane lipid peroxidation products and decreased Na(+),K(+)-ATPase activity observed in MG, indicative of meningitis-induced brain cell membrane dysfunction, tended to improve without statistical significance in PG. In summary, although some anti-inflammatory effects have been observed, the overall anti-inflammatory effects of pentoxifylline was very weak, and it failed to significantly reduce the brain damage in experimental neonatal bacterial meningitis.
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PMID:The efficacy of pentoxifylline as an anti-inflammatory agent in experimental Escherichia coli meningitis in the newborn piglet. 1082 75

An important goal of cancer immunology is the identification of antigens associated with tumor destruction. Vaccination with irradiated tumor cells engineered to secrete granulocyte/macrophage colony-stimulating factor (GM-CSF) generates potent, specific, and long-lasting antitumor immunity in multiple murine tumor models. A phase I clinical trial of this vaccination strategy in patients with advanced melanoma demonstrated the consistent induction of dense CD4(+) and CD8(+) T lymphocyte and plasma cell infiltrates in distant metastases, resulting in extensive tumor destruction, fibrosis, and edema. Antimelanoma antibody and cytotoxic T cell responses were associated with tumor cell death. To characterize the targets of these responses, we screened an autologous cDNA expression library prepared from a densely infiltrated metastasis with postvaccination sera from a long-term responding patient. High-titer IgG antibodies detected ATP6S1, a putative accessory unit of the vacuolar H(+)-ATPase complex. A longitudinal analysis of this patient revealed an association between the vaccine-induced increase in antibodies to ATP6S1 and tumor destruction. Three additional vaccinated melanoma patients and three metastatic non-small cell lung carcinoma patients vaccinated with autologous GM-CSF-secreting tumor cells similarly showed a correlation between humoral responses to ATP6S1 and tumor destruction. Moreover, a chronic myelogenous leukemia patient who experienced a complete remission after CD4(+) donor lymphocyte infusions also developed high-titer antibodies to ATP6S1. Lastly, vaccination with GM-CSF-secreting B16 melanoma cells stimulated high-titer antibodies to ATPS1 in a murine model. Taken together, these findings demonstrate that potent humoral responses to ATP6S1 are associated with immune-mediated destruction of diverse tumors.
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PMID:ATP6S1 elicits potent humoral responses associated with immune-mediated tumor destruction. 1198 66

Granulocyte/macrophage colony-stimulating factor (GM-CSF) is a key cytokine in myelopoiesis and aberrant expression is associated with chronic inflammatory disease and myeloid leukemias. This aberrant expression is often associated with constitutive nuclear factor (NF)-kappaB activation. To investigate the relationship between NF-kappaB and GM-CSF transcription in a chromatin context, we analyzed the chromatin structure of the GM-CSF gene in T cells and the role of NF-kappaB proteins in chromatin remodeling. We show here that chromatin remodeling occurs across a region of the GM-CSF gene between -174 and +24 upon T cell activation, suggesting that remodeling is limited to a single nucleosome encompassing the proximal promoter. Nuclear NF-kappaB levels appear to play a critical role in this process. In addition, using an immobilized template assay we found that the ATPase component of the SWI/SNF chromatin remodeling complex, brg1, is recruited to the GM-CSF proximal promoter in an NF-kappaB-dependent manner in vitro. These results suggest that chromatin remodeling across the GM-CSF promoter in T cells is a result of recruitment of SWI/SNF type remodeling complexes by NF-kappaB proteins binding to the CD28 response region of the promoter.
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PMID:Changes in chromatin accessibility across the GM-CSF promoter upon T cell activation are dependent on nuclear factor kappaB proteins. 1259

Phospholemman (FXYD1) is a homolog of the Na,K-ATPase gamma subunit (FXYD2), a small accessory protein that modulates ATPase activity. Here we show that phospholemman is highly expressed in selected structures in the CNS. It is most abundant in cerebellum, where it was detected in the molecular layer, in Purkinje neurons, and in axons traversing the granule cell layer. Phospholemman was particularly enriched in choroid plexus, the organ that secretes CSF in the ventricles, where it colocalized with Na,K-ATPase in the apical membrane. It was also enriched, with Na,K-ATPase, in certain tanycytes or ependymal cells of the ventricle wall. Two different experimental approaches demonstrated that phospholemman physically associated with the Na,K-ATPase in cerebellum and choroid plexus: the proteins copurified after detergent treatment and co-immunoprecipitated from solubilized crude membranes using either anti-phospholemman or anti-Na,K-ATPase antibodies. Phospholemman antibodies precipitated all three Na,K-ATPase alpha subunit isoforms (alpha1-alpha3) from cerebellum, indicating that the interaction is not specific to a particular alpha isoform and consistent with the presence of phospholemman in both neurons and glia. Antibodies against the C-terminal domain of phospholemman reduced Na,K-ATPase activity in vitro without effect on Na+ affinity. At least two other FXYD family members have been detected in the CNS, suggesting that additional complexity of sodium pump regulation will be found.
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PMID:Phospholemman, a single-span membrane protein, is an accessory protein of Na,K-ATPase in cerebellum and choroid plexus. 1265 75

The human polyomaviruses BK (BKV) and JC (JCV) affect immunosuppressed patients and are associated with urogenital tract (BKV) and CNS disorders (JCV) and in humans, the pathogenic role of the rhesus monkey virus, Simian virus 40 (SV40), is uncertain. These three viruses have somewhat overlapping tissue pathogenicity and detection of all three polyomaviruses is desirable. A broadly targeted, simple, single tube real-time degenerated quantitative PCR (QPCR) technique for detection of JCV, BKV and SV40 DNA was developed. To avoid false positive results, due to contamination with commonly used SV40 T-antigen plasmids, a conserved region of the VP2 gene was targeted. Down to 1-10 copies of target DNA per PCR reaction were detected. The QPCR was compared with a nested PCR on 41 clinical samples (urine, serum and plasma): 24 (58.5%) tested positive by nested PCR, whereas 31 (75.6%) were positive with QPCR. One CSF sample, from a patient with progressive multifocal leukoencephalopathy, was negative with the nested PCR but determined as positive by QPCR. Sera from 24 blood donors were negative with QPCR. The QPCR described had a high sensitivity. Its specificity was confirmed sequencing. The QPCR is simple to perform and is valuable for diagnosis of polyomavirus infection.
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PMID:Quantitative real-time PCR assay for detection of human polyomavirus infection. 1667 18

Knowledge of the diversity of ion channel form and function has increased enormously over the last 25 years. The initial impetus in channel discovery came with the introduction of the patch clamp method in 1981. Functional data from patch clamp experiments have subsequently been augmented by molecular studies which have determined channel structures. Thus the introduction of patch clamp methods to study ion channel expression in the choroid plexus represents an important step forward in our knowledge understanding of the process of CSF secretion.Two K+ conductances have been identified in the choroid plexus: Kv1 channel subunits mediate outward currents at depolarising potentials; Kir 7.1 carries an inward-rectifying conductance at hyperpolarising potentials. Both K+ channels are localised at the apical membrane where they may contribute to maintenance of the membrane potential while allowing the recycling of K+ pumped in by Na+-K+ ATPase. Two anion conductances have been identified in choroid plexus. Both have significant HCO3- permeability, and may play a role in CSF secretion. One conductance exhibits inward-rectification and is regulated by cyclic AMP. The other is carried by an outward-rectifying channel, which is activated by increases in cell volume. The molecular identity of the anion channels is not known, nor is it clear whether they are expressed in the apical or basolateral membrane. Recent molecular evidence indicates that choroid plexus also expresses the non-selective cation channels such as transient receptor potential channels (TRPV4 and TRPM3) and purinoceptor type 2 (P2X) receptor operated channels. In conclusion, good progress has been made in identifying the channels expressed in the choroid plexus, but determining the precise roles of these channels in CSF secretion remains a challenge for the future.
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PMID:Ion channel diversity, channel expression and function in the choroid plexuses. 1788 37

Intracerebroventricular (ICV) infusion of NaCl mimics the effects of a high-salt diet in salt-sensitive hypertension, raising the sodium concentration in the cerebrospinal fluid (CSF [Na]) and subsequently increasing the concentration of an endogenous ouabain-like substance (OLS) in the brain. The OLS, in turn, inhibits the brain Na(+)-K(+)-ATPase, causing increases in the activity of the brain renin-angiotensin system (RAS) and blood pressure. The Na(+)-K(+)-ATPase alpha (catalytic)-isoform(s) that mediates the pressor response to increased CSF [Na] is unknown, but it is likely that one or more isoforms that bind ouabain with high affinity are involved (e.g., the Na(+)-K(+)-ATPase alpha(2)- and/or alpha(3)-subunits). We hypothesize that OLS-induced inhibition of the alpha(2)-subunit mediates this response. Therefore, a chronic reduction in alpha(2) expression via a heterozygous gene knockout (alpha(2) +/-) should enhance the pressor response to increased CSF [Na]. Intracerebroventricular (ICV) infusion of artificial CSF containing 0.225 M NaCl increased mean arterial pressure (MAP) in both wild-type (+/+) and alpha(2) +/- mice, but to a greater extent in alpha(2) +/-. Likewise, the pressor response to ICV ouabain was enhanced in alpha(2) +/- mice, demonstrating enhanced sensitivity to brain Na(+)-K(+)-ATPase inhibition per se. The pressor response to ICV ANG I but not ANG II was also enhanced in alpha(2) +/- vs. alpha(2)+/+ mice, suggesting an enhanced brain RAS activity that may be mediated by increased brain angiotensin converting enzyme (ACE). The latter hypothesis is supported by enhanced ACE ligand binding in the organum vasculosum laminae terminalis. These studies demonstrate that chronic downregulation of Na(+)-K(+)-ATPase alpha(2)-isoform expression by heterozygous knockout increases the pressor response to increased CSF [Na] and activates the brain RAS. Since these changes mimic those produced by the endogenous brain OLS, the brain alpha(2)-isoform may be a target for the brain OLS during increases in CSF [Na], such as in salt-dependent hypertension.
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PMID:Enhanced pressor response to increased CSF sodium concentration and to central ANG I in heterozygous alpha2 Na+ -K+ -ATPase knockout mice. 1924 89

Autoimmune disease and/or autoantibodies have been reported in mood disorder patients. We screened for autoantibodies to glutamic acid decarboxylase (GAD65), thyroid peroxidase (TPO), gastric H+/K+ ATPase (ATP4B), and Ro52 in a psychiatric patient cohort. A 24-year-old woman with major depressive disorder (MDD) with reduced psychomotor activity was identified with unusually high serum GAD65 and Ro52 autoantibody titers. Anti-GAD65 and anti-Ro52 autoantibodies were also elevated in the CSF from this patient. Longitudinal examination revealed a four-fold increase in anti-GAD65 serum antibody titers which correlated with exacerbation of psychomotor symptomatology. These results suggest the possibility that CNS autoimmunity may be responsible for the psychomotor impairment in this MDD patient.
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PMID:High levels of Anti-GAD65 and Anti-Ro52 autoantibodies in a patient with major depressive disorder showing psychomotor disturbance. 2022 14

Dystonia-plus syndromes represent a heterogeneous group of diseases, where dystonia is accompanied by other neurological features and gene mutations can be detected frequently. Symptomatic dystonias and complex neurodegenerative diseases with dystonia as part of the clinical presentation are excluded from this category. At present, the following disorders are categorized as dystonia-plus syndromes: Dopa-responsive dystonia (DRD) is a mostly pediatric-onset, neurometabolic disorder with two different modes of inheritance: in its autosomal-dominant form, heterozygous mutations of GTP-cyclohydrolase I (GCH1, DYT5) cause DRD with reduced penetrance and excellent and lasting response to levodopa. Autosomal-recessive (AR) forms of DRD are caused by homozygous or compound heterozygous mutations of the tyrosine hydroxylase (TH) or the sepiapterin reductase (SPR) gene. In AR-DRD, the phenotype is generally more severe including cognitive deficits and developmental delay. Diagnosis can be confirmed by analysis of CSF pterine metabolites. Alternatively, comprehensive genetic testing yields causative mutations in up to 80% of patients. Myoclonus-dystonia (M-D) is caused by heterozygous mutations of the epsilon-sarcoglycan gene (SGCE). Dystonia is generally only mild to moderate, and 'lightning-like' myoclonic jerks occur rarely at rest and can be triggered by complex motor tasks like writing and drawing. Both features together with an age at onset below 25 years strongly predict SGCE mutation in M-D and differentiate this genetic disease from other 'jerky' dystonias. The combination of dystonia and parkinsonism can only be rarely observed in non-degenerative syndromes. Besides DRD, two additional syndromes have been classified. Rapid-onset dystonia-parkinsonism (RPD, DYT12) is a rare disorder with an abrupt onset of symptoms over minutes to days, prominent bulbar involvement and parkinsonism with a lack of response to levodopa. Patients with this rare phenotype should be screened for mutation in the Na(+)/K(+) ATPase alpha3-subunit (ATP1A3) gene, even if family history is negative. Recently, a novel form of dystonia-parkinsonism (DYT16) has been found to be linked to mutations in the PRKRA gene, whose relation to basal ganglia disorders is yet unknown .
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PMID:Dystonia-plus syndromes. 2059 Aug 7


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