Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.5 (neuropathy target esterase)
 1,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The development of new treatments to slow or arrest the progression of diabetic polyneuropathy (DPN) has increased the importance of the early and accurate identification of this complication. It is likely that effective intervention will be possible only during the subclinical or early phase of dysfunction. Accurate diagnosis of DPN is a formidable task because of the diversity of presentations, involvement of different nerve fiber types, and the common dissociation of symptoms from objective measures of neural function. Several diagnostic tools are available or in development, each with strengths and limitations. Electrophysiology is a sensitive, objective, and targeted measure of DPN, but it reflects, almost exclusively, the activity of large-caliber, myelinated axons. Newly refined skin-punch biopsy procedures use morphometric and immunohistochemical methods to examine thinly myelinated and unmyelinated nerve fibers. The integrity, density, and distribution of these fibers may provide a sensitive index of small-fiber distal axonopathy. Improvements in quantitative sensory testing include better control of stimulation characteristics and the use of computer-assisted testing algorithms (e.g., CASE IV), as well as the ability to examine a distal to proximal gradient of sensation (Physitemp NTE-2a). Composite scales, which combine the assessment of signs, symptoms, electrophysiology, and specific quantitative sensory measures, have also been proposed and, in some cases, validated. The existing diagnostic tools and newly emerging methods provide a battery of tests that can be used to assess multiple aspects of neural function and increase sensitivity to detect the onset and progression of DPN.
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PMID:New developments in the diagnosis of diabetic neuropathy. 1048 40

The integrity of the host cell may represent an important prerequisite for the intracellular survival and development of obligate intracellular pathogens. In the present study, we investigated the influence of infections with the protozoan parasite Toxoplasma gondii on the rate of apoptosis in the human leukemia cell line HL-60. After infection with T. gondii tachyzoites of the strain NTE and in uninfected controls, less than 2% of the host cells showed typical signs of apoptosis, i.e. condensation of chromatin after staining with Hoechst 33258 or internucleosomal DNA fragmentation after agarose gel electrophoresis of genomic DNA. After treatment with 0.1 to 0.5 microg/ml actinomycin D for up to 16 hours, HL-60 cells considerably underwent apoptosis. However, this actinomycin D-induced apoptosis was clearly reduced after concomitant infection with T. gondii as shown by staining with Hoechst 33258 and by DNA fragmentation assay. Inhibition of apoptosis by the intracellular pathogen T. gondii might be recognized as an evasion mechanism that enables intracellular survival and establishes long-lasting persistence.
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PMID:Toxoplasma gondii inhibits the in vitro induced apoptosis of HL-60 cells. 1062 33

Sulfonylureas are generally used in the therapeutic treatment of non-insulin-dependent diabetes mellitus. Little is known, however, whether they also affect the lipid metabolism. Using glibenclamide (GB), a typical sulfonylurea, we have investigated its effects on the lipid metabolism in macrophages, J774 and phorbol ester-treated THP-1 cells. In the whole-cell assay system for cholesteryl ester (CE) accumulation that is induced by addition of chemically modified low-density lipoprotein (LDL), such as Ac-LDL and ox-LDL, GB effectively inhibited the CE accumulation of J774 cells in dose-dependent manners. The inhibition was resulted from increase in free cholesterol but not from change in total cholesterol amount. The results suggest that GB acts on acyl-CoA: cholesterol acyltransferase (ACAT) and inhibits its activity. To confirm the possibility, we then tested GB by another assay system using ACAT that was solubilized from the cells and reconstituted into the liposome composed of phosphatidyl choline- cholesterol. GB inhibition was not so much effective as those by CI-976 and NTE-122, known ACAT inhibitors, but the inhibition was complete in the presence of 100 microM GB. Using cell homogenates of PMA-stimulated THP-1 cells, GB also inhibited the ACAT activity to the level of undifferentiated THP-1 cells. These results indicate that GB acts as ACAT inhibitor but the chemical structure is quite different from the conventional ACAT inhibitors, suggesting it can be a seed to generate potential ACAT inhibitors which do not exhibit toxicity in adrenal gland.
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PMID:[Glibenclamide inhibits cholesterol metabolism in macrophage]. 1062 72

The Drosophila neurodegeneration gene swiss-cheese encodes a neuronal protein apparently involved in glia-neuron interaction and is homologous to human NTE, the molecular target of organophosphate-induced neuropathy. The isolated Msws/NTE gene is 96% identical to NTE. During development the Msws transcript is expressed in the embryonic respiratory system, different epithelial structures and strongly in the spinal ganglia. Postnatally, Msws mRNA is expressed in all brain areas, with an increasingly restrictive pattern. In adult mice expression is most prominent in Purkinje cells, granule cells and pyramidal neurons of the hippocampus and some large neurons in the medulla oblongata, nucleus dentatus and pons.
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PMID:Cloning and expression of the murine sws/NTE gene. 1064 Jul 12

Neuropathy target esterase (neurotoxic esterase, NTE), a protein thought to be involved in the production of organophosphorus compound-induced delayed neurotoxicity (OPIDN), has been postulated to be a component of endogenous neuronal protein phosphorylation systems. The purpose of this work was to test this hypothesis as well as to investigate further the role of endogenous protein phosphorylation in toxic neuropathies. White Leghorn hens were dosed with the neuropathic compounds di-1-butyl-2,2-dichlorovinyl phosphate (dibutyl dichlorvos, DBDCV), tri-o-cresyl phosphate (TOCP), or acrylamide, and regions from brain were fractionated into axolemmal, synaptosomal, and microsomal preparations. Radiolabeling of NTE or endogenously phosphorylated proteins was carried out by incubation with [14C]-DFP or gamma-[32P]-ATP, respectively. Radiolabeled proteins were separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and visualized by autoradiography. Relative amounts of phosphoproteins were quantified by densitometry of the autoradiographs. Changes in endogenous phosphorylation of a protein exhibiting the characteristics of NTE were not observed in these experiments. However, levels of a [32P]-labeled 50-kDa brainstem axolemmal protein were decreased significantly on d 15, but not on d 1, 3, 7, or 10 after dosing with 2.8 mg/kg DBDCV. Clinical signs of ataxia and histopathological findings of axonal degeneration in the spinocerebellar tracts of the brainstem were evident on d 10-15, and hens were unable to perch on a horizontal wooden rod from d 12 after dosing with DBDCV. The decrease in the 50-kDa phosphoprotein was not observed on d 15 after the production of clinically evident neuropathy with either 14 daily doses of 50 mg/kg acrylamide or with a single dose of 500 mg/kg TOCP. These results suggest that NTE is not an endogenously phosphorylated protein under the conditions of these experiments. However, an effect on endogenous phosphorylation limited to a 50-kDa axolemmal protein was selectively produced by treatment with a neuropathic dose of DBDCV that was in evidence only after clinical signs and histopathological findings of axonopathy were apparent.
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PMID:Brainstem axolemmal protein phosphorylation in vitro in hens dosed with di-1-butyl-2,2-dichlorovinyl phosphate. 1070 44

The cholesterol-lowering and anti-atherosclerotic effects of NTE-122 (trans-1,4-bis[[1-cyclohexyl-3-(4-dimethylaminophenyl)ureido]methyl]cyclohexane), an acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, were evaluated in 1% cholesterol diet-fed rabbits. NTE-122 (1, 3 and 10 mg/kg per day) lowered the total cholesterol levels in both plasma and liver dose-dependently (by 99% and 94% at 10 mg/kg per day, respectively). In the aortic wall of the rabbits given NTE-122, the atherosclerotic lesion area in both aortic arch and thoracic aorta were dose-dependently reduced (by 100% at 10 mg/kg per day), and the total cholesterol content in aortic arch was also lowered significantly at more than 3 mg/kg per day. These results suggest that NTE-122 is capable of exhibiting anti-atherosclerotic effects.
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PMID:NTE-122, an acyl-coa:cholesterol acyltransferase inhibitor, prevents the progression of atherogenesis in cholesterol-fed rabbits. 1143 Apr 63

Net CO2 exchange in a 35-year-old boreal Norway spruce (Picea abies (L.) Karst.) forest in northern Sweden was measured at the shoot (NSE), tree (NTE) and ecosystem levels (NEE) by means of shoot cuvettes, whole-tree chambers and the eddy covariance technique, respectively. We compared the dynamics of gross primary production (GPP) at the three levels during the course of a single week. The diurnal dynamics of GPP at each level were estimated by subtracting half-hourly or hourly model-estimated values of total respiration (excluding light-dependent respiration) from net CO(2) exchange. The relationship between temperature and total respiration at each level was derived from nighttime measurements of NSE, NTE and NEE over the course of 1 month. There was a strong linear relationship (r2 = 0.93) between the hourly estimates of GPP at the shoot and tree levels, but the correlation between shoot- and ecosystem-level GPP was weaker (r2 = 0.69). However, the correlation between shoot- and ecosystem-level GPP was improved (r2 = 0.88) if eddy covariance measurements were restricted to periods when friction velocity was > or = 0.5 m s(-1). Daily means were less dependent on friction velocity, giving an r2 value of 0.94 between shoot- and ecosystem-level GPP. The correlation between shoot and tree levels also increased when daily means were compared (r2 = 0.98). Most of the measured variation in carbon exchange rate among the shoot, tree and ecosystem levels was the result of periodic low coupling between vegetation and the atmosphere at the ecosystem level. The results validate the use of measurements at the shoot and tree level for analyzing the contribution of different compartments to net ecosystem CO2 exchange.
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PMID:Carbon dioxide exchange in Norway spruce at the shoot, tree and ecosystem scale. 1149 44

Measurements of plasma cholinesterase (pl.ChE), brain cholinesterase (Br.ChE) and brain Neuropathy Target Esterase (Br.NTE) were made in three different lineages of chickens. All birds received toxicants through gavage in a single oral dose between 08:00 and 09:00 h, after overnight fast. Babcock chickens were treated with 800 mg/kg tri-ortho-cresyl phosphate (TOCP) or 80 mg/kg trichlorfon. The TOCP group had 82% Br.NTE inhibition, when compared to the control group, and no birds displayed symptoms of clinical organophosphate-induced delayed neuropathy (OPIDN). Hy-line w36 lineage chickens were given 1600 mg/kg TOCP and despite this higher dose, Br.NTE inhibition was similar that presented by Babcock chickens. Isabrown chickens were given 1600 mg/kg TOCP or 80 mg/kg trichlorfon. At 36 h all trichlorfon treated birds had from 80 to 90% inhibition of Pl.ChE and Br.ChE, when compared to controls. However, Br.NTE was inhibited less than 20%, and there were no clinical signs of OPIDN. All TOCP treated isabrown chickens had more than 80% Br.NTE inhibition while one of them exhibited just light signs of OPIDN, two chickens became totally paralyzed. This finding suggested that chicken strain was important in the appearance of OPIDN. In addition, 70-80% of NTE inhibition was necessary but was not sufficient to produce OPIDN in chickens, since babcock and hy-line w36 chickens exhibited NTE inhibition in the range of 70-80% without clinical signs of OPIDN.
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PMID:Organophosphate induced delayed neuropathy in genetically dissimilar chickens: studies with tri-ortho-cresyl phosphate (TOCP) and trichlorfon. 1242 64

These studies were intended to explore the relationship between autonomic neuropathy and erectile dysfunction (ED). Sensory thresholds reflecting the integrity of both large diameter, myelinated neurons (ie pressure, touch, vibration) and small diameter axons (ie hot and cold thermal sensation) were determined on the penis and finger. Data were compared across subjects with and without ED, controlling for age, hypertension and diabetes. The correlation of specific thresholds scores and IIEF values were also examined. Seventy-three patients who visited the academic urology clinics at Montefiore hospital were evaluated. All patients were required to complete the erectile function domain of the International Index of Erectile Function (IIEF) questionnaire: 20 subjects had no complaints of ED and scored within the 'normal' range on the IIEF. Patients were subsequently tested on their index finger and glans penis for vibration (Biothesiometer), pressure (Semmes-Weinstein monofilaments), spatial perception (Tactile Circumferential Discriminator), and warm and cold thermal thresholds (Physitemp NTE-2). Sensation of the glans penis, as defined by the examined sensory thresholds, was significantly diminished in patients with ED and these differences remained significant when controlling for age, diabetes and hypertension. In contrast, thresholds on the index finger were equivalent in the ED and non-ED groups. Threshold and IIEF scores were highly correlated, consistent with an association between diminished sensation and decreasing IIEF score (worse erectile functioning). These relations also remained significant when controlling for age, diabetes and hypertension. The findings demonstrate dysfunction of large and small diameter nerve fibers in patients with ED of all etiologies. Further, the neurophysiologic measures validate the use of the IIEF as an index of ED, as objective findings of sensory neuropathy were highly correlated with worse IIEF scores. The sensory threshold methods utilized represent novel, non-invasive and relatively simple procedures, which can be used in a longitudinal fashion to assess a patient's neurological response to therapies.
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PMID:The neuropathy of erectile dysfunction. 1249 74

Potent cannabinoid CB1 receptor ligands include anandamide [N-(2-hydroxyethyl)arachidonamide], Delta9-tetrahydrocannabinol, and 3H-CP 55,940 at the agonist site and selected organophosphorus esters (including some pesticides) and organosulfur compounds at a proposed closely coupled "nucleophilic" site. This study considers the toxicological and structural features of alkylfluorophosphonates, benzodioxaphosphorin oxides, alkanesulfonyl fluorides, and analogs acting at the nucleophilic site. Binding at the agonist site, using3H-CP 55,940 in assays with mouse brain membranes, is inhibited byO-isopropyl dodecylfluorophosphonate (compound 2), dodecanesulfonyl fluoride (compound 14) and dodecylbenzodioxaphosphorin oxide with IC50 values of 2-11 nM. Compounds 2 and 14 are also effectivein vivo, with 84% inhibition of mouse brain CB1 binding 4 h after intraperitoneal dosage at 30 mg/kg. Compound 14-inhibited CB1 in mouse brain requires about 3-4 days for recovery of 50% activity, suggesting covalent derivatization. Delayed toxicity (mortality in 0.3-5 days) from compounds 2, 14, and octanesulfonyl fluoride (18) is more closely associated with in vivo inhibition of brain neuropathy target esterase-lysophospholipase (NTE-LysoPLA) than with that of CB1 or acetylcholinesterase. NTE-LysoPLA inhibited by sulfonyl fluorides 14 and 18 cannot "age," a proposed requirement for NTE phosphorylated by organophosphorus-delayed neurotoxicants. Several octane- and dodecanesulfonamides with N-(2-hydroxyethyl) and other substituents based on anandamide give depressed mobility and recumbent posture in mice, but the effects do not correlate with potency for CB1 inhibition in vitro. Specific toxicological responses are not clearly associated with organophosphorus- or organosulfur-induced inhibition of the proposed CB1 nucleophilic site in mouse brain. On the other hand, the most potent CB1 inhibitors examined here are also NTE-LysoPLA inhibitors and cause delayed toxicity in mice.
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PMID:Toxicological and structural features of organophosphorus and organosulfur cannabinoid CB1 receptor ligands. 1294 86


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