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:3.1.1.7 (acetylcholinesterase)
28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A significant increase in the ratio of serum pseudocholinesterase/high density lipoprotein cholesterol (the Complementary Risk Factor ratio) was found in individuals classified as high risk for cardiovascular disease on the basis of the ratio of total cholesterol/high density lipoprotein cholesterol (the Established Risk Factor ratio) compared to the individuals with average and low risks. This Complementary Risk Factor ratio also showed good correlation with serum low density lipoprotein, triglycerides and the Established Risk Factor ratio. These results indicate that serum cholinesterase has a parallel relationship with low density lipoproteins and a reciprocal relationship with high density lipoproteins. We propose that the Complementary Risk Factor ratio may be an additional marker in predicting the risks for cardiovascular disease.
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PMID:Serum pseudocholinesterase: high density lipoprotein cholesterol ratio as an index of risk for cardiovascular disease. 726 7

The rate of acetylcholine hydrolysis of mammalian heart muscle influences cardiac responses to vagal innervation. We characterized cholinesterases of human left ventricular heart muscle with respect to both substrate specificity and irreversible inhibition kinetics with the organophosphorus inhibitor N,N'-di-isopropylphosphorodiamidic fluoride (mipafox). Specimens were obtained postmortem from three men and four women (61 +/- 5 years) with no history of cardiovascular disease. Myocardial choline ester hydrolyzing activity was determined with acetylthiocholine (ASCh; 1.25 mM), acetyl-beta-methylthiocholine (AbetaMSCh; 2.0 mM), and butyrylthiocholine (BSCh; 30 mM). After irreversible and covalent inhibition (60 min; 25 degrees C) with a wide range of mipafox concentrations (50 nM-5 mM), residual choline ester hydrolyzing activities were fitted to a sum of up to five exponentials using weighted least-squares non-linear curve fitting. In each ease, quality of curve fitting reached its optimum on the basis of a four component model. Final classification of heart muscle cholinesterases was achieved according to substrate hydrolysis patterns (nmol/min per g wet weight) and to second-order organophosphate inhibition rate constants k2 (1/mol per min); one choline ester hydrolyzing enzyme was identified as acetylcholinesterase (AChE; k2/mipafox = 6.1 (+/- 0.8) x 10(2)), and one as butyrylcholinesterase (BChE; k2/mipafox = 5.3 (+/- 1.1) x 10(3)). An enzyme exhibiting both ChE-like substrate specificity and relative resistance to mipafox inhibition (k2/mipafox = 5.2 (+/- 1.0) x 10(-1)) was classified as atypical cholinesterase.
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PMID:Organophosphate inhibition of human heart muscle cholinesterase isoenzymes. 1042 52

Susceptibility to organophosphorus (OP) insecticides and nerve agents is strongly influenced by genetic and developmental factors. A number of organophosphorothioate insecticides are detoxified in part via a two-step pathway involving bioactivation of the parent compound by the cytochrome P450 systems, then hydrolysis of the resulting oxygenated metabolite (oxon) by serum and liver paraoxonases (PON1). Serum PON1 has been shown to be polymorphic in human populations. The Arg192 isoform (PON1R192) of this HDL-associated protein hydrolyzes paraoxon (POX) at a high rate, while the Gln192 isoform (PON1Q192) hydrolyzes paraoxon at a low rate. The effect of the polymorphism is reversed for the hydrolysis of diazoxon (DZO), soman and particularly sarin. Phenylacetate is hydrolyzed at approximately the same rate by both PON1 isoforms and chlorpyrifos oxon (CPO) slightly faster by the PON1R192 isoform. In addition to the effect of the amino acid substitution on rates of toxicant hydrolysis, two other factors influence these rates. The expression of PON1 is developmentally regulated. Newborns have very low levels of PON1. Adult levels in rats and mice are reached at 3 weeks of age and in humans, sometime after 6 months of age. In addition, among individuals of a given genotype, there is at least a 13-fold difference in expression of PON1 that is stable over time. Dose/response experiments with normal mice injected with purified PON1 and with PON1 knockout mice have clearly demonstrated that the observed differences of in vitro rates of hydrolysis are significant in determining differential sensitivities to specific insecticides processed through the P450/PON1 pathway. Injection of purified rabbit PON1 protects mice from cholinesterase inhibition by chlorpyrifos (CPS) and CPO. Knockout mice are much more sensitive to CPO and DZO than are their PON1+/+ littermates or wild-type mice. A number of recent reports have also indicated that the PON1R192 isoform may be a risk factor for cardiovascular disease. Studies with PON1 knockout mice are also consistent with a role of PON1 in preventing vascular disease.
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PMID:Genetic and temporal determinants of pesticide sensitivity: role of paraoxonase (PON1). 1079 89

Neural and stem cell transplantation is emerging as a potential treatment for neurodegenerative diseases. Transplantation of specific committed neuroblasts (fetal neurons) to the adult brain provides such scientific exploration of these new potential therapies. Huntington's disease (HD) is a fatal, incurable autosomal dominant (CAG repeat expansion of huntingtin protein) neurodegenerative disorder with primary neuronal pathology within the caudate-putamen (striatum). In a clinical trial of human fetal striatal tissue transplantation, one patient died 18 months after transplantation from cardiovascular disease, and postmortem histological analysis demonstrated surviving transplanted cells with typical morphology of the developing striatum. Selective markers of both striatal projection and interneurons such as dopamine and c-AMP-related phosphoprotein, calretinin, acetylcholinesterase, choline acetyltransferase, tyrosine hydroxylase, calbindin, enkephalin, and substance P showed positive transplant regions clearly innervated by host tyrosine hydroxylase fibers. There was no histological evidence of immune rejection including microglia and macrophages. Notably, neuronal protein aggregates of mutated huntingtin, which is typical HD neuropathology, were not found within the transplanted fetal tissue. Thus, although there is a genetically predetermined process causing neuronal death within the HD striatum, implanted fetal neural cells lacking the mutant HD gene may be able to replace damaged host neurons and reconstitute damaged neuronal connections. This study demonstrates that grafts derived from human fetal striatal tissue can survive, develop, and are unaffected by the disease process, at least for 18 months, after transplantation into a patient with HD.
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PMID:Transplanted fetal striatum in Huntington's disease: phenotypic development and lack of pathology. 1113 40

Donepezil, a selective acetylcholinesterase inhibitor, is approved for the symptomatic treatment of mild to moderate Alzheimer's disease (AD). In a post-marketing surveillance (PMS) study in Germany, patients under routine treatment conditions were observed while treatment was switched from other antidementia drugs (i.e., nootropics) to donepezil. A total of 913 patients were enrolled (60.1% female, mean+/-S.D. age 73.4+/-8.6 years, mean Mini-Mental Status Examination [MMSE] 18.0+/-5.3), and were treated with donepezil (5 or 10 mg/day according to recommended dosing). 709/913 (77.1%) of patients had been pretreated with other antidementive drugs (piracetam, memantine, ginkgo, and others). In 29.6% of patients, investigators documented concomitant cerebrovascular disease (CVD+) according to their clinical judgment. Observation period was 3 months for the individual patient. Efficacy parameters were changes in MMSE, global clinical (investigators) judgment of efficacy, and a clinical judgment about the patients' quality of life (QoL). Adverse events were also analyzed. The objective of the present investigation was to compare-in a "real-life" setting-the differential efficacy and tolerability of donepezil in AD patients with and without concomitant cerebrovascular disease. After 3 months, patients had improved by a mean MMSE change from baseline of 2.2 points (CVD+: 2.4 pts, CVD-: 2.1 pts). QoL was judged "improved" in 70.0% of patients (CVD+: 72.5%, CVD-: 69.6%). Adverse events were reported in 85/913 (9.3%) of patients (CVD+: 11.2%, CVD-: 7.9%). Reported adverse events were substantially less than reported previously in controlled clinical trials. This suggests that donepezil therapy is effective and well tolerated in AD patients, both with and without concomitant cerebrovascular disease.
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PMID:Treatment with donepezil in Alzheimer patients with and without cerebrovascular disease. 1241 72

To investigate the distribution of autonomic nerves in the human heart, six autopsied hearts without cardiovascular disease were studied by a histochemical method for acetylcholinesterase (AChE) and by an immunohistochemical method for tyrosine hydroxylase (TH). The density of nerve distribution was microscopically calculated by the point-counting method to evaluate regional distribution of the autonomic nerves. There were more AChE-positive nerves and TH-positive nerves in the atrium than in the ventricle, and more at the base than at the apex in the ventricle. There were more AChE-positive nerves in the subendocardial area than in the subepicardial area of the myocardium. In the atrium, AChE-positive nerves were more numerous than TH-positive nerves. On the other hand, there were more TH-positive nerves than AChE-positive nerves in the ventricle. Predominancy of the distribution density at the anterior to the posterior wall of the ventricle was observed for TH-positive nerves. The different distribution patterns of sympathetic and parasympathetic nerves could modify cardiac performance under both physiologic and pathologic conditions.
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PMID:Histological study on the distribution of autonomic nerves in the human heart. 1264 79

Vascular dementia (VaD) is the second-most-common cause of dementia in the elderly, after Alzheimer's disease (AD). VaD is defined as loss of cognitive function resulting from ischemic, hypoperfusive, or hemorrhagic brain lesions due to cerebrovascular disease or cardiovascular pathology. Diagnosis requires the following criteria: cognitive loss, often predominantly subcortical; vascular brain lesions demonstrated by imaging; a temporal link between stroke and dementia; and exclusion of other causes of dementia. Poststroke VaD may be caused by large-vessel disease with multiple strokes (multiinfarct dementia) or by a single stroke (strategic stroke VaD). A common form is subcortical ischemic VaD caused by small-vessel occlusions with multiple lacunas and by hypoperfusive lesions resulting from stenosis of medullary arterioles, as in Binswanger's disease. Unlike with AD, in VaD, executive dysfunction is commonly seen, but memory impairment is mild or may not even be present. The cholinesterase inhibitors used for AD are also useful in VaD. Prevention strategies should focus on reduction of stroke and cardiovascular disease, with attention to control of risk factors such as hypertension, diabetes mellitus, hypercholesterolemia, and hyperhomocysteinemia.
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PMID:Vascular dementia: distinguishing characteristics, treatment, and prevention. 1280 86

Cerebrovascular disease (CVD), as well as secondary ischemic brain injury from cardiovascular disease, are common causes of dementia and cognitive decline in the elderly. Also, CVD frequently contributes to cognitive loss in patients with Alzheimer's disease (AD). Progress in understanding the pathogenetic mechanism involved in vascular cognitive impairment and vascular dementia (VaD) has resulted in promising treatments of these conditions. Cholinergic deficits in VaD are due to ischemia of basal forebrain nuclei and of cholinergic pathways and can be treated with the use of the cholinesterase inhibitors used in AD. Controlled clinical trials with donepezil, galantamine, and rivastigmine in VaD, as well as in patients with AD plus CVD, have demonstrated improvement in cognition, behavior and activities of daily living.
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PMID:Treatment of vascular dementia-evidence from clinical trials with cholinesterase inhibitors. 1526 82

Cerebrovascular disease (CVD), as well as secondary ischemic brain injury from cardiovascular disease, are common causes of dementia and cognitive decline in the elderly. In addition, CVD frequently contributes to cognitive loss in patients with Alzheimer's disease (AD). Progress in understanding the pathogenetic mechanism involved in vascular cognitive impairment (VCI) and vascular dementia (VaD) has resulted in promising treatments of these conditions. Cholinergic deficits in VaD are due to ischemia of basal forebrain nuclei and of cholinergic pathways and can be treated with the use of the cholinesterase inhibitor agents used in AD. Controlled clinical trials with donepezil, galantamine and rivastigmine in VaD, as well as in patients with AD plus CVD, have demonstrated improvements in cognition, behavior and activities of daily living.
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PMID:Treatment of vascular dementia--evidence from clinical trials with cholinesterase inhibitors. 1553 22

Ischemic or hemorrhagic cerebrovascular disease (CVD) produces injury of brain regions important for executive function, behavior, and memory leading to decline in cognitive functions and vascular dementia (VaD). Cardiovascular disease may cause VaD from hypoperfusion of susceptible brain areas. CVD may worsen degenerative dementias such as Alzheimer disease (AD). Currently, the global diagnostic category for cognitive impairment of vascular origin is vascular cognitive disorder (VCD). VCD ranges from vascular cognitive impairment (VCI) to VaD. The term VCI is limited to cases of cognitive impairment of vascular etiology, without dementia; VCI is equivalent to vascular mild cognitive impairment (MCI). Risk factors for VaD include age, hypertension, diabetes, smoking, cardiovascular disease (coronary heart disease, congestive heart failure, peripheral vascular disease), atrial fibrillation, left ventricular hypertrophy, hyperhomocysteinemia, orthostatic hypotension, cardiac arrhythmias, hyperfibrinogenemia, sleep apnea, infection, and high C-reactive protein. Research on biomarkers revealed increased CSF-NFL levels in VaD, whereas CSF-tau was normal. CSF-TNF-alpha, VEGF, and TGF-beta were increased in both AD and VaD. VaD shows low CSF acetylcholinesterase levels. This condition responds to acetylcholinesterase inhibitors, confirming the central role of cholinergic deficit in its pathogenesis. Evidence strongly suggests that control of vascular risk factors, in particular hypertension, could prevent VaD.
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PMID:Vascular dementia. Advances in nosology, diagnosis, treatment and prevention. 1587 77


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