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Sample records for cholinesterase inhibitors

  1. Cholinesterase inhibitors from botanicals

    Directory of Open Access Journals (Sweden)

    Faiyaz Ahmed

    2013-01-01

    Full Text Available Alzheimer′s disease (AD is a progressive neurodegenerative disease, wherein a progressive loss of cholinergic synapses occurs in hippocampus and neocortex. Decreased concentration of the neurotransmitter, acetylcholine (ACh, appears to be critical element in the development of dementia, and the most appropriate therapeutic approach to treat AD and other form of dementia is to restore acetylcholine levels by inhibiting both major form of cholinesterase: Acetylcholinesterase (AChE and butyrylcholinesterase (BChE. Consequently, researches have focused their attention towards finding cholinesterase inhibitors from natural products. A large number of such inhibitors have been isolated from medicinal plants. This review presents a comprehensive account of the advances in field of cholinesterase inhibitor phytoconstituents. The structures of some important phytoconstituents (collected through www.Chemspider.com are also presented and the scope for future research is discussed.

  2. Cholinesterase inhibitors and memory.

    Science.gov (United States)

    Pepeu, Giancarlo; Giovannini, Maria Grazia

    2010-09-06

    A consensus exists that cholinesterase inhibitors (ChEIs) are efficacious for mild to moderate Alzheimer's Disease (AD). Unfortunately, the number of non-responders is large and the therapeutic effect is usually short-lasting. In experimental animals, ChEIs exert three main actions: inhibit cholinesterase (ChE), increase extracellular levels of brain acetylcholine (ACh), improve cognitive processes, particularly when disrupted in models of AD. In this overview we shall deal with the cognitive processes that are improved by ChEI treatment because they depend on the integrity of brain cholinergic pathways and their activation. The role of cholinergic system in cognition can be investigated using different approaches. Microdialysis experiments demonstrate the involvement of the cholinergic system in attention, working, spatial and explicit memory, information encoding, sensory-motor gating, skill learning. No involvement in long-term memory has yet been demonstrated. Conversely, memory consolidation is facilitated by low cholinergic activity. Experiments on healthy human subjects, notwithstanding caveats concerning age, dose, and different memory tests, confirm the findings of animal experiments and demonstrate that stimulation of the cholinergic system facilitates attention, stimulus detection, perceptual processing and information encoding. It is not clear whether information retrieval may be improved but memory consolidation is reduced by cholinergic activation. ChEI effects in AD patients have been extensively investigated using rating scales that assess cognitive and behavioural responses. Few attempts have been made to identify which scale items respond better to ChEIs and therefore, presumably, depend on the activity of the cholinergic system. Improvement in attention and executive functions, communication, expressive language and mood stability have been reported. Memory consolidation and retrieval may be impaired by high ACh levels. Therefore, considering

  3. A review on cholinesterase inhibitors for Alzheimer's disease.

    Science.gov (United States)

    Anand, Preet; Singh, Baldev

    2013-04-01

    Alzheimer's disease (AD), a progressive neurodegenerative disorder, is characterized by the deficits in the cholinergic system and deposition of beta amyloid (Aβ) in the form of neurofibrillary tangles and amyloid plaques. Since the cholinergic system plays an important role in the regulation of learning and memory processes, it has been targetted for the design of anti-Alzheimer's drugs. Cholinesterase inhibitors enhance cholinergic transmission directly by inhibiting the enzyme acetylcholinesterase (AChE) which hydrolyses acetylcholine. Furthermore, it has been also demonstrated that both acetylcholinesterase and butrylcholinesterase (BuChE) play an important role in Aβ-aggregation during the early stages of senile plaque formation. Therefore, AChE and BuChE inhibition have been documented as critical targets for the effective management of AD by an increase in the availability of acetylcholine in the brain regions and decrease in the Aβ deposition. This review discusses the different classes of cholinesterase inhibitors including tacrine, donepezil, rivastigmine, galantamine, xanthostigmine, para-aminobenzoic acid, coumarin, flavonoid, and pyrrolo-isoxazole analogues developed for the treatment of AD.

  4. New method for the determination of the half inhibition concentration (IC50) of cholinesterase inhibitors.

    Science.gov (United States)

    Kovárová, Markéta; Komers, Karel; Stepánková, Sárka; Parík, Patrik; Cegan, Alexander

    2013-01-01

    A new and simple analytical method is described for the determination of the IC50 values of the inhibitors of the hydrolysis of acetylcholine (ACh) or acetylthiocholine (ATCh) by cholinesterases. The method is based on monitoring the time course of the pH value during the uninhibited and inhibited reaction. It requires only a pH meter with a suitable pH measuring cell and a small thermostated stirred batch reactor. The method has been validated for twelve different types of cholinesterase inhibitors. The determined IC50 values are comparable to those obtained by independent, more complicated, and expensive methods (Ellman's and pH-stat).

  5. Effects of Cholinesterase Inhibitors in Parkinson's Disease Dementia : A Review of Clinical Data

    NARCIS (Netherlands)

    van Laar, Teus; De Deyn, Peter Paul; Aarsland, Dag; Barone, Paolo; Galvin, James E.

    2011-01-01

    Aims: Cognitive impairment and dementia are common features of Parkinson's disease (PD). Patients with Parkinson's disease dementia (PDD) often have significant cholinergic defects, which may be treated with cholinesterase inhibitors (ChEIs). The objective of this review was to consider available ef

  6. Potentially hazardous substances in surface waters. II. Cholinesterase inhibitors in Dutch surface waters

    NARCIS (Netherlands)

    Greve, P.A.; Freudenthal, J.; Wit, S.L.

    1972-01-01

    Several analytical methods were employed to determine the concentrations of cholinesterase inhibitors in several Dutch surface waters. An Auto-Analyzer method was used for screening purposes; thin-layer chromatography and gas-liquid chromatography-mass spectrometry were used for identification and q

  7. Effect of apolipoprotein E and butyrylcholinesterase genotypes on cognitive response to cholinesterase inhibitor treatment at different stages of Alzheimer's disease.

    Science.gov (United States)

    Patterson, C E; Todd, S A; Passmore, A P

    2011-12-01

    Factors that influence response to drug treatment are of increasing importance. We report an analysis of genetic factors affecting response to cholinesterase inhibitor therapy in 165 subjects with Alzheimer's disease (AD). The presence of apolipoprotein E ε4 (APOE ε4) allele was associated with early and late cognitive response to cholinesterase inhibitor treatment in mild AD (Mini-Mental State Examination (MMSE) ≥21) (P<0.01). In moderate-to-severe AD (MMSE ≤15), presence of the BCHE-K variant was associated with late response to cholinesterase inhibitor treatment (P=0.02). Testing for APOE and BCHE genotypes may be useful in therapeutic decision making.

  8. Cholinesterase inhibitors and add-on nutritional supplements in Alzheimer's disease: a systematic review of randomized controlled trials.

    Science.gov (United States)

    Rijpma, A; Meulenbroek, O; Olde Rikkert, M G M

    2014-07-01

    To date, single drug and nutrient-based interventions have failed to show a clinically relevant effect on Alzheimer's disease (AD). Multidomain interventions may alleviate symptoms and alter the disease course in a synergistic manner. This systematic review examines the effect of adding nutritional supplementation to cholinesterase inhibitors. A systematic PubMed and Cochrane search resulted in nine high quality studies. The studies had low to moderate risk of bias and focused on oxidative stress, homocysteine levels, membrane fluidity, inflammation and acetylcholine levels. Only the use of vitamin E supplements could reduce the rate of functional decline when combined with cholinesterase inhibitors in one study, whereas cognition was not affected in both this and other studies. None of the other nutritional supplements showed convincing evidence of a beneficial effect when combined with cholinesterase inhibitors. This shows that cognitive and functional improvement is difficult to achieve in patients with AD, despite epidemiological data and evidence of biological effects of nutritional supplements. Addressing one disease pathway in addition to cholinesterase inhibitor therapy is probably insufficient to alter the course of the disease. Personalized, multifactorial interventions may be more successful in improving cognition and daily functioning.

  9. Mild versus moderate stages of Alzheimer's disease: three-year outcomes in a routine clinical setting of cholinesterase inhibitor therapy.

    OpenAIRE

    Wattmo, Carina; Minthon, Lennart; Wallin, Åsa

    2016-01-01

    BACKGROUND: There is an increasing interest in cognitive and functional outcomes in the respective stages of Alzheimer's disease (AD) and in novel therapies particularly for the milder phases of AD. Our aim was to describe and compare various aspects of disease progression in patients with mild versus moderate AD in routine clinical practice of cholinesterase inhibitor (ChEI) therapy. METHODS: This 3-year, prospective, observational, multicentre study included 1021 participants. Of the...

  10. Novel Cholinesterase Inhibitors Based on O-Aromatic N,N-Disubstituted Carbamates and Thiocarbamates

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    Martin Krátký

    2016-02-01

    Full Text Available Based on the presence of carbamoyl moiety, twenty salicylanilide N,N-disubstituted (thiocarbamates were investigated using Ellman’s method for their ability to inhibit acetylcholinesterase (AChE and butyrylcholinesterase (BChE. O-Aromatic (thiocarbamates exhibited weak to moderate inhibition of both cholinesterases with IC50 values within the range of 1.60 to 311.0 µM. IC50 values for BChE were mostly lower than those obtained for AChE; four derivatives showed distinct selectivity for BChE. All of the (thiocarbamates produced a stronger inhibition of AChE than rivastigmine, and five of them inhibited BChE more effectively than both established drugs rivastigmine and galantamine. In general, 5-chloro-2-hydroxy-N-[4-(trifluoromethyl-phenyl]benzamide, 2-hydroxy-N-phenylbenzamide as well as N-methyl-N-phenyl carbamate derivatives led to the more potent inhibition. O-{4-Chloro-2-[(4-chlorophenylcarbamoyl]phenyl} dimethylcarbamothioate was identified as the most effective AChE inhibitor (IC50 = 38.98 µM, while 2-(phenylcarbamoylphenyl diphenylcarbamate produced the lowest IC50 value for BChE (1.60 µM. Results from molecular docking studies suggest that carbamate compounds, especially N,N-diphenyl substituted representatives with considerable portion of aromatic moieties may work as non-covalent inhibitors displaying many interactions at peripheral anionic sites of both enzymes. Mild cytotoxicity for HepG2 cells and consequent satisfactory calculated selectivity indexes qualify several derivatives for further optimization.

  11. Cognitive and affective changes in mild to moderate Alzheimer's disease patients undergoing switch of cholinesterase inhibitors: a 6-month observational study.

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    Gianfranco Spalletta

    Full Text Available Patients with Alzheimer's disease after an initial response to cholinesterase inhibitors may complain a later lack of efficacy. This, in association with incident neuropsychiatric symptoms, may worsen patient quality of life. Thus, the switch to another cholinesterase inhibitor could represent a valid therapeutic strategy. The aim of this study was to investigate the effectiveness of the switch from one to another cholinesterase inhibitor on cognitive and affective symptoms in mild to moderate Alzheimer disease patients. Four hundred twenty-three subjects were included from the EVOLUTION study, an observational, longitudinal, multicentre study conducted on Alzheimer disease patients who switched to different cholinesterase inhibitor due either to lack/loss of efficacy or response, reduced tolerability or poor compliance. All patients underwent cognitive and neuropsychiatric assessments, carried out before the switch (baseline, and at 3 and 6-month follow-up. A significant effect of the different switch types was found on Mini-Mental State Examination score during time, with best effectiveness on mild Alzheimer's disease patients switching from oral cholinesterase inhibitors to rivastigmine patch. Depressive symptoms, when measured using continuous Neuropsychiatric Inventory values, decreased significantly, while apathy symptoms remained stable over the 6 months after the switch. However, frequency of both depression and apathy, when measured categorically using Neuropsychiatric Inventory cut-off scores, did not change significantly during time. In mild to moderate Alzheimer disease patients with loss of efficacy and tolerability during cholinesterase inhibitor treatment, the switch to another cholinesterase inhibitor may represent an important option for slowing cognitive deterioration. The evidence of apathy stabilization and the positive tendency of depressive symptom improvement should definitively be confirmed in double-blind controlled

  12. Cognitive and affective changes in mild to moderate Alzheimer's disease patients undergoing switch of cholinesterase inhibitors: a 6-month observational study.

    Science.gov (United States)

    Spalletta, Gianfranco; Caltagirone, Carlo; Padovani, Alessandro; Sorbi, Sandro; Attar, Mahmood; Colombo, Delia; Cravello, Luca

    2014-01-01

    Patients with Alzheimer's disease after an initial response to cholinesterase inhibitors may complain a later lack of efficacy. This, in association with incident neuropsychiatric symptoms, may worsen patient quality of life. Thus, the switch to another cholinesterase inhibitor could represent a valid therapeutic strategy. The aim of this study was to investigate the effectiveness of the switch from one to another cholinesterase inhibitor on cognitive and affective symptoms in mild to moderate Alzheimer disease patients. Four hundred twenty-three subjects were included from the EVOLUTION study, an observational, longitudinal, multicentre study conducted on Alzheimer disease patients who switched to different cholinesterase inhibitor due either to lack/loss of efficacy or response, reduced tolerability or poor compliance. All patients underwent cognitive and neuropsychiatric assessments, carried out before the switch (baseline), and at 3 and 6-month follow-up. A significant effect of the different switch types was found on Mini-Mental State Examination score during time, with best effectiveness on mild Alzheimer's disease patients switching from oral cholinesterase inhibitors to rivastigmine patch. Depressive symptoms, when measured using continuous Neuropsychiatric Inventory values, decreased significantly, while apathy symptoms remained stable over the 6 months after the switch. However, frequency of both depression and apathy, when measured categorically using Neuropsychiatric Inventory cut-off scores, did not change significantly during time. In mild to moderate Alzheimer disease patients with loss of efficacy and tolerability during cholinesterase inhibitor treatment, the switch to another cholinesterase inhibitor may represent an important option for slowing cognitive deterioration. The evidence of apathy stabilization and the positive tendency of depressive symptom improvement should definitively be confirmed in double-blind controlled studies.

  13. Functional response to cholinesterase inhibitor therapy in a naturalistic Alzheimer’s disease cohort

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    Wattmo Carina

    2012-11-01

    Full Text Available Abstract Background Activities of daily living (ADL are an essential part of the diagnostic criteria for Alzheimer’s disease (AD. A decline in ADL affects independent living and has a strong negative impact on caregiver burden. Functional response to cholinesterase inhibitor (ChEI treatment and factors that might influence this response in naturalistic AD patients need investigating. The aim of this study was to identify the socio-demographic and clinical factors that affect the functional response after 6 months of ChEI therapy. Methods This prospective, non-randomised, multicentre study in a routine clinical setting included 784 AD patients treated with donepezil, rivastigmine or galantamine. At baseline and after 6 months of treatment, patients were assessed using several rating scales, including the Instrumental Activities of Daily Living (IADL scale, Physical Self-Maintenance Scale (PSMS and Mini-Mental State Examination (MMSE. Demographic and clinical characteristics were investigated at baseline. The functional response and the relationships of potential predictors were analysed using general linear models. Results After 6 months of ChEI treatment, 49% and 74% of patients showed improvement/no change in IADL and in PSMS score, respectively. The improved/unchanged patients exhibited better cognitive status at baseline; regarding improved/unchanged PSMS, patients were younger and used fewer anti-depressants. A more positive functional response to ChEI was observed in younger individuals or among those having the interaction effect of better preserved cognition and lower ADL ability. Patients with fewer concomitant medications or those using NSAIDs/acetylsalicylic acid showed a better PSMS response. Conclusions Critical characteristics that may influence the functional response to ChEI in AD were identified. Some predictors differed from those previously shown to affect cognitive response, e.g., lower cognitive ability and older age

  14. Cholinesterase inhibitors in mild cognitive impairment: a systematic review of randomised trials.

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    Roberto Raschetti

    2007-11-01

    Full Text Available BACKGROUND: Mild cognitive impairment (MCI refers to a transitional zone between normal ageing and dementia. Despite the uncertainty regarding the definition of MCI as a clinical entity, clinical trials have been conducted in the attempt to study the role of cholinesterase inhibitors (ChEIs currently approved for symptomatic treatment of mild to moderate Alzheimer disease (AD, in preventing progression from MCI to AD. The objective of this review is to assess the effects of ChEIs (donepezil, rivastigmine, and galantamine in delaying the conversion from MCI to Alzheimer disease or dementia. METHODS AND FINDINGS: The terms "donepezil", "rivastigmine", "galantamine", and "mild cognitive impairment" and their variants, synonyms, and acronyms were used as search terms in four electronic databases (MEDLINE, EMBASE, Cochrane, PsycINFO and three registers: the Cochrane Collaboration Trial Register, Current Controlled Trials, and ClinicalTrials.gov. Published and unpublished studies were included if they were randomized clinical trials published (or described in English and conducted among persons who had received a diagnosis of MCI and/or abnormal memory function documented by a neuropsychological assessment. A standardized data extraction form was used. The reporting quality was assessed using the Jadad scale. Three published and five unpublished trials met the inclusion criteria (three on donepezil, two on rivastigmine, and three on galantamine. Enrolment criteria differed among the trials, so the study populations were not homogeneous. The duration of the trials ranged from 24 wk to 3 y. No significant differences emerged in the probability of conversion from MCI to AD or dementia between the treated groups and the placebo groups. The rate of conversion ranged from 13% (over 2 y to 25% (over 3 y among treated patients, and from 18% (over 2 y to 28% (over 3 y among those in the placebo groups. Only for two studies was it possible to derive point

  15. Adverse Drug Reactions Reported With Cholinesterase Inhibitors : An Analysis of 16 Years of Individual Case Safety Reports From VigiBase

    NARCIS (Netherlands)

    Kroeger, Edeltraut; Mouls, Marie; Wilchesky, Machelle; Berkers, Mieke; Carmichael, Pierre-Hugues; van Marum, Rob; Souverein, Patrick; Egberts, Toine; Laroche, Marie-Laure

    2015-01-01

    Background: No worldwide pharmacovigilance study evaluating the spectrum of adverse drug reactions (ADRs) induced by cholinesterase inhibitors (ChEI) in Alzheimer's disease has been conducted since their emergence on the market. Objective: To describe ChEI related ADRs in Alzheimer's disease (donepe

  16. Impact of cholinesterase inhibitors on behavioral and psychological symptoms of Alzheimer’s disease: A meta-analysis

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    Noll Campbell

    2008-12-01

    Full Text Available Noll Campbell1, Amir Ayub2, Malaz A Boustani2, Chris Fox3, Martin Farlow4, Ian Maidment3, Robert Howard51Wishard Health Services, Indianapolis, Indiana; 2Indiana University Center for Aging Research, Regenstrief Institute, Inc., Indianapolis, Indiana; 3University of Kent, Kent, United Kingdom; 4Indiana University School of Medicine, Indianapolis, Indiana; 5King’s College, London, United KingdomObjective: To determine the efficacy of cholinesterase inhibitors (ChEIs in improving the behavioral and psychological symptoms of dementia (BPSD in patients with Alzheimer’s disease (AD.Data sources: We searched MEDLINE, Cochrane Registry, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL from 1966 to 2007. We limited our search to English Language, full text, published articles and human studies.Data extraction: We included randomized, double-blind, placebo-controlled trials evaluating the efficacy of donepezil, rivastigmine, or galantamine in managing BPSD displayed by AD patients. Using the United States Preventive Services Task Force (USPSTF guidelines, we critically appraised all studies and included only those with an attrition rate of less than 40%, concealed measurement of the outcomes, and intention to treat analysis of the collected data. All data were imputed into pre-defined evidence based tables and were pooled using the Review Manager 4.2.1 software for data synthesis.Results: We found 12 studies that met our inclusion criteria but only nine of them provided sufficient data for the meta-analysis. Among patients with mild to severe AD and in comparison to placebo, ChEIs as a class had a beneficial effects on reducing BPSD with a standard mean difference (SMD of −0.10 (95% confidence interval [CI]; −0.18, −0.01 and a weighted mean difference (WMD of −1.38 neuropsychiatry inventory point (95% CI; −2.30, −0.46. In studies with mild AD patients, the WMD was −1.92 (95% CI; −3.18, −0.66; and in studies

  17. Effect of cholinesterase inhibitor galanthamine on circulating tumor necrosis factor alpha in rats with lipopolysaccharide induced peritonitis

    Institute of Scientific and Technical Information of China (English)

    LIU Zhi-hai; MA Yue-feng; WU Jun-song; GAN Jian-xin; XU Shao-wen; JIANG Guan-yu

    2010-01-01

    Background The nervous system, through the vagus nerve and its neurotransmitter acetylcholine, can down-regulate the systemic inflammation in vivo, and recently, a role of brain cholinergic mechanisms in activating this cholinergic anti-inflammatory pathway has been indicated. Galanthamine is a cholinesterase inhibitor and one of the centrally acting cholinergic agents available in clinic. This study aimed to evaluate the effect of galanthamine on circulating tumor necrosis factor alpha (TNF-α) in rats with lipopolysaccharide-induced peritonitis and the possible role of the vagus nerve in the action of galanthamine.Methods Rat models of lipopolysaccharide-induced peritonitis and bilateral cervical vagotomy were produced. In the experiment 1, the rats were randomly divided into control group, peritonitis group, and peritonitis groups treated with three dosages of galanthamine. In the experiment 2, the rats were randomly divided into sham group, sham plus peritonitis group, sham plus peritonitis group treated with galanthamine, vagotomy plus peritonitis group, and vagotomy plus peritonitis group treated with galanthamine. The levels of plasma TNF-α were determined in every group. Results The level of circulating TNF-α was significantly increased in rats after intraperitoneal injection of endotoxin. Galanthamine treatment decreased the level of circulating TNF-α in rats with lipopolysaccharide-induced peritonitis, and there was significant difference compared with rats with lipopolysaccharide-induced peritonitis without treatment. The 3 mg/kg dosage of galanthamine had the most significant inhibition on circulating TNF-α level at all the three tested doses. Galanthamine obviously decreased the TNF-α level in rats with lipopolysaccharide-induced peritonitis with sham operation, but could not decrease the TNF-α level in rats with lipopolysaccharide-induced peritonitis with vagotomy. Conclusion Cholinesterase inhibitor galanthamine has an inhibitory effect on TNF

  18. Transthyretin as a potential CSF biomarker for Alzheimer's disease and dementia with Lewy bodies: effects of treatment with cholinesterase inhibitors

    DEFF Research Database (Denmark)

    Schultz, K; Nilsson, K; Nielsen, Jørgen Erik

    2010-01-01

    BACKGROUND: Previous studies have indicated that transthyretin (TTR) levels in cerebrospinal fluid (CSF) are altered in depression and dementia. The present study aimed to investigate whether CSF TTR can be used to discriminate between patients with Alzheimer's disease (AD) and patients with deme......BACKGROUND: Previous studies have indicated that transthyretin (TTR) levels in cerebrospinal fluid (CSF) are altered in depression and dementia. The present study aimed to investigate whether CSF TTR can be used to discriminate between patients with Alzheimer's disease (AD) and patients...... with dementia with Lewy bodies (DLB) with or without medication, as well as to reveal whether CSF TTR correlates with depression in dementia. METHODS: CSF samples from 59 patients with AD, 13 patients with DLB and 13 healthy controls were collected, and biochemical analysis was performed. Subjects were assessed...... for the presence of depression. RESULTS: No significant differences in CSF TTR were found between AD, DLB, and control subjects or between depressed and non-depressed dementia patients. Interestingly, we found a significant reduction in CSF TTR (14%) in AD patients who were medicated with cholinesterase inhibitors...

  19. Recent Knowledge on Medicinal Plants as Source of Cholinesterase Inhibitors for the Treatment of Dementia.

    Science.gov (United States)

    Tundis, Rosa; Bonesi, Marco; Menichini, Francesco; Loizzo, Monica R

    2016-01-01

    Dementia is becoming a major public health problem worldwide. The most common form of dementia is Alzheimer's disease (AD), characterized by a deficient cholinergic transmission, deposition of amyloid plaques and neurofibrillary tangles, and neuro-inflammation that result in progressive degeneration and/or death of nerve cells and cognitive impairment. At present, AD cannot be prevented or cured, so the symptomatic relief obtainable by the use of acetylcholinesterase (AChE) inhibitors is one of the therapeutic strategies. Accumulated evidence suggests that naturally occurring compounds may potentially improve memory and cognitive function, and prevent neurodegeneration. Even today the search for new neuroprotective agents of natural origin is very active. The neuroprotective effects of medicinal plants covering studies of the last years will be summarized and discussed in this review choosing a family classification with particular emphasis on extracts and isolated compounds as promising new drugs. The search of a multifunctional potential anti-AD agent able to act on different crucial targets, such as galanthamine, quercetin and timosaponin AIII, could be a useful approach to recognizing therapeutics against AD.

  20. Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine

    Institute of Scientific and Technical Information of China (English)

    Rui WANG; Han YAN; Xi-can TANG

    2006-01-01

    Huperzine A (HupA), a novel alkaloid isolated from the Chinese herb Huperzia serrata, is a potent, highly specific and reversible inhibitor of acetylcholinesterase (AChE). Compared with tacrine, donepezil, and rivastigmine, HupA has better penetration through the blood-brain barrier, higher oral bioavailability, and longer duration of AChE inhibitory action. HupA has been found to improve cognitive deficits in a broad range of animal models. HupA possesses the ability to protect cells against hydrogen peroxide, β-amyloid protein (or peptide), glutamate,ischemia and staurosporine-induced cytotoxicity and apoptosis. These protective effects are related to its ability to attenuate oxidative stress, regulate the expression of apoptotic proteins Bcl-2, Bax, P53, and caspase-3, protect mitochondria, upregulate nerve growth factor and its receptors, and interfere with amyloid precursor protein metabolism. Antagonizing effects of HupA on N-methyl-D-aspartate receptors and potassium currents may also contribute to its neuroprotection as well. Pharmacokinetic studies in rodents, canines, and healthy human volunteers indicated that HupA was absorbed rapidly, distributed widely in the body, and eliminated at a moderate rate with the property of slow and prolonged release after oral administration. Animal and clinical safety tests showed that HupA had no unexpected toxicity, particularly the dose-limiting hepatotoxicity induced by tacrine. The phase Ⅳ clinical trials in China have demonstrated that HupA significantly improved memory deficits in elderly people with benign senescent forgetfulness, and patients with Alzheimer disease and vascular dementia, with minimal peripheral cholinergic side effects and no unexpected toxicity. HupA can also be used as a protective agent against organophosphate intoxication.

  1. Kinetics and molecular docking studies of loganin, morroniside and 7-O-galloyl-D-sedoheptulose derived from Corni fructus as cholinesterase and β-secretase 1 inhibitors.

    Science.gov (United States)

    Bhakta, Himanshu Kumar; Park, Chan Hum; Yokozawa, Takako; Min, Byung-Sun; Jung, Hyun Ah; Choi, Jae Sue

    2016-06-01

    We evaluated the major active components isolated from Corni Fructus: loganin, morroniside, and 7-O-galloyl-D-sedoheptulose as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) for use in Alzheimer's disease treatment. These compounds exhibited predominant cholinesterase (ChEs) inhibitory effects with IC50 values of 0.33, 3.95, and 10.50 ± 1.16 µM, respectively, for AChE, and 33.02, 37.78, and 87.94 ± 4.66 µM, respectively, for BChE. Kinetics studies revealed that loganin and 7-O-galloyl-D-sedoheptulose inhibited AChE with characteristics typical of mixed inhibitors, while morroniside was found to be a noncompetitive inhibitor against AChE and also exerted mixed BChE inhibitory activities. For BACE1, loganin showed noncompetitive type inhibitory effects, while morroniside and 7-O-galloyl-D-sedoheptulose were found to be mixed inhibitors. Furthermore, these compounds exhibited dose-dependent inhibitory activity with ONOO(-)-mediated protein tyrosine nitration. Molecular docking simulation of these compounds demonstrated negative binding energies for ChEs, and BACE1, indicating high affinity and tighter binding capacity for the active site of the enzyme. Loganin was the most potent inhibitor against both ChEs and BACE1. The data suggest that these compounds together can act as a triple inhibitor of AChE, BChE, and BACE1, providing a preventive and therapeutic strategy for Alzheimer's disease treatment.

  2. Qualitative and quantitative two-dimensional thin-layer chromatography/high performance liquid chromatography/diode-array/electrospray-ionization-time-of-flight mass spectrometry of cholinesterase inhibitors.

    Science.gov (United States)

    Mroczek, Tomasz

    2016-09-10

    Recently launched thin-layer chromatography-mass spectrometry (TLC-MS) interface enabling extraction of compounds directly from TLC plates into MS ion source was unusually extended into two-dimensional thin-layer chromatography/high performance liquid chromatography (2D, TLC/HPLC) system by its a direct connection to a rapid resolution 50×2.1mm, I.D. C18 column compartment followed by detection by diode array (DAD) and electrospray ionisation time-of-flight mass spectrometry (ESI-TOF-MS). In this way, even not separated bands of complicated mixtures of natural compounds could be analysed structurally, only within 1-2min after development of TLC plates. In comparison to typically applied TLC-MS interface, no ion suppression for acidic mobile phases was observed. Also, substantial increase in ESI-TOF-MS sensitivities and quality of spectra, were noticed. It has been utilised in combination with TLC- based bioautographic approaches of acetylcholinesterase (AChE) inhibitors, However, it can be also applied in any other procedures related to bioactivity (e.g. 2,2-Diphenyl-1-picryl-hydrazyl-DPPH screen test for radicals). This system has been also used for determination of half maximal inhibitory concentration (IC50 values) of the active inhibitor-galanthamine, as an example. Moreover, AChE inhibitory potencies of some of purified plant extracts, never studied before, have been quantitatively measured. This is first report of usage such the 2D TLC/HPLC/MS system both for qualitative and quantitative evaluation of cholinesterase inhibitors in biological matrices.

  3. Effect of APOE and CHRNA7 genotypes on the cognitive response to cholinesterase inhibitor treatment at different stages of Alzheimer's disease.

    Science.gov (United States)

    Braga, Ianna Lacerda Sampaio; Silva, Patricia Natalia; Furuya, Tatiane Katsue; Santos, Leonardo Caires; Pires, Belisa Caldana; Mazzotti, Diego Robles; Bertolucci, Paulo Henrique; Cendoroglo, Maysa Seabra; Smith, Marília Cardoso

    2015-03-01

    The loss of cholinergic transmission is considered to be an important cause of Alzheimer's disease (AD). Treatment with acetyl cholinesterase inhibitors (ChEIs) shows benefits; however, great heterogeneity has been observed in patient responses. We evaluated apolipoprotein E (APOE) and α7 nicotinic receptor (CHRNA7) single-nucleotide polymorphisms (SNPs) and associated these SNPs with pharmacological responses to ChEIs in a Brazilian population with AD. We studied 177 outpatients using ChEIs, and they were classified as responders and nonresponders according to variation in Mini-Mental State Examination (MMSE) status. The analysis of APOE genotypes showed that patients with the ε4 allele had a worse response than those without the ε4 allele. We observed an association between the CHRNA7 T allele and a better response to treatment with ChEIs in patients with mild AD (MMSE ≥ 20). The SNP rs6494223 of CHRNA7 as well as APOEε4 could be useful for understanding the response to ChEI treatment in patients with AD.

  4. A longitudinal study of risk factors for community-based home help services in Alzheimer’s disease: the influence of cholinesterase inhibitor therapy

    Directory of Open Access Journals (Sweden)

    Wattmo C

    2013-03-01

    Full Text Available Carina Wattmo, Elisabeth Paulsson, Lennart Minthon, Elisabet LondosClinical Memory Research Unit, Department of Clinical Sciences, Malmö, Lund University, Malmö, SwedenBackground: To investigate the long-term effects of cholinesterase inhibitor (ChEI therapy and the influence of sociodemographic and clinical factors on the use of community-based home help services (HHS by patients with Alzheimer’s disease (AD.Methods: This 3-year, prospective, multicenter study included 880 AD patients treated with donepezil, rivastigmine, or galantamine in a routine clinical setting. At baseline and every 6 months, the patients were assessed with several rating scales, including the Mini-Mental State Examination, Instrumental Activities of Daily Living (IADL, and Physical Self-Maintenance Scale. Doses of ChEI and amounts of HHS per week were recorded. Cox regression models were used to predict the time to HHS, and multiple linear regression was used to predict the volume of HHS used.Results: During the study, 332 patients (38% used HHS. Factors that both postponed HHS use and predicted lower amounts of HHS were higher doses of ChEIs, better IADL ability, and living with family. Men, younger individuals, and those with a slower IADL decline showed a longer time to HHS, whereas female sex, a lower cognitive status, or more medications at baseline predicted fewer hours of HHS.Conclusions: Higher doses of ChEI might reduce the use of HHS, possibly reducing the costs of community-based care. Female spouses provide more informal care than do male spouses, so the likelihood of using HHS is greater among women with AD. The "silent group" of more cognitively impaired and frail elderly AD patients receives less HHS, which might precipitate institutionalization.Keywords: cognition, activities of daily living, treatment effect, gender, predictors

  5. Evaluation of Candidate Genes for cholinesterase Activity in Farmworkers Exposed to organophosphorous Pesticides-Association of SNPs in BCHE

    Science.gov (United States)

    Background: Organophosphate pesticides act as cholinesterase inhibitors, and as such may give rise to potential neurological effects. Cholinesterase activity is a useful, indirect measurement of pesticide exposure, especially in high-risk individuals such as farmworkers. To und...

  6. Kinetics and molecular docking studies of cholinesterase inhibitors derived from water layer of Lycopodiella cernua (L.) Pic. Serm. (II).

    Science.gov (United States)

    Hung, Tran Manh; Lee, Joo Sang; Chuong, Nguyen Ngoc; Kim, Jeong Ah; Oh, Sang Ho; Woo, Mi Hee; Choi, Jae Sue; Min, Byung Sun

    2015-10-05

    Acetylcholinesterase (AChE) inhibitors increase the availability of acetylcholine in central cholinergic synapses and are the most promising drugs currently available for the treatment of Alzheimer's disease (AD). Our screening study indicated that the water fraction of the methanolic extract of Lycopodiella cernua (L.) Pic. Serm. significantly inhibited AChE in vitro. Bioassay-guided fractionation led to the isolation of a new lignan glycoside, lycocernuaside A (12), and fourteen known compounds (1-11 and 13-15). Compound 7 exhibited the most potent AChE inhibitory activity with an IC50 value of 0.23 μM. Compound 15 had the most potent inhibitory activity against BChE and BACE1 with IC50 values of 0.62 and 2.16 μM, respectively. Compounds 4 and 7 showed mixed- and competitive-type AChE inhibition. Compound 7 noncompetitively inhibited BChE whereas 15 showed competitive and 8, 13, and 14 showed mixed-type inhibition. The docking results for complexes with AChE or BChE revealed that inhibitors 4, 7, and 15 stably positioned themselves in several pocket/catalytic domains of the AChE and BChE residues.

  7. Prophylactic administration of non-organophosphate cholinesterase inhibitors before acute exposure to organophosphates: assessment using terbufos sulfone.

    Science.gov (United States)

    Lorke, Dietrich E; Nurulain, Syed M; Hasan, Mohamed Y; Kuča, Kamil; Petroianu, Georg A

    2014-10-01

    Poisoning with organophosphorus compounds (OPCs) poses a serious threat worldwide. OPC-induced mortality can be significantly reduced by prophylactic administration of reversible acetylcholinesterase (AChE) inhibitors. The only American Food and Drug Administration (FDA)-approved substance for such pre-treatment (to soman exposure) is presently pyridostigmine, although its efficacy is controversial. In search for more efficacious and broad-spectrum alternatives, we have assessed in vivo the mortality-reducing efficacy of a group of five compounds with known AChE inhibitory activity (pyridostigmine, physostigmine, ranitidine, tacrine and K-27), when given in equitoxic dosage (25% of LD01 ) 30 min before exposure to the OPC terbufos sulfone. Protection was quantified in rats by determining the relative risk of death (RR) using Cox analysis, with RR = 1 for animals given only terbufos sulfone, but no pre-treatment. All tested AChE inhibitors reduced terbufos sulfone-induced mortality significantly (p ≤ 0.05) as compared with the non-treatment group (RR = 1: terbufos sulfone only). Best in vivo protection from terbufos sulfone-induced mortality was achieved, when K-27 was given before terbufos sulfone exposure (RR = 0.06), which was significantly (P ≤ 0.05) superior to the pre-treatment with all other tested compounds, for example tacrine (RR = 0.21), pyridostigmine (RR = 0.28), physostigmine (RR = 0.29) and ranitidine (RR = 0.33). The differences in efficacy between tacrine, pyridostigmine, physostigmine and ranitidine were not statistically significant. Prophylactic administration of an oxime (such as K-27) in case of imminent OPC exposure may be a viable option.

  8. Pulmonary Toxicity of Cholinesterase Inhibitors

    Science.gov (United States)

    2006-01-01

    to the more active and potent form (paraoxon) was demon-1956; Lubash and Clark, 1960; Sidell, 1967). strated to take place in the liver (Diggle and...chlorpyrifos, parathion, and diazinon inhibit this M2 muscarinic stimulation and 2-PAM to reactivate the inhib- receptor population. ited AChE. For the

  9. Design, synthesis and biological evaluation of multifunctional tacrine-curcumin hybrids as new cholinesterase inhibitors with metal ions-chelating and neuroprotective property.

    Science.gov (United States)

    Liu, Zhikun; Fang, Lei; Zhang, Huan; Gou, Shaohua; Chen, Li

    2017-03-06

    Total sixteen tacrine-curcumin hybrid compounds were designed and synthesized for the purpose of searching for multifunctional anti-Alzheimer agents. In vitro studies showed that these hybrid compounds showed good cholinesterase inhibitory activity. Particularly, the potency of K3-2 is even beyond tacrine. Some of the compounds exhibited different selectivity on acetylcholinesterase or butyrylcholinesterase due to the structural difference. Thus, the structure and activity relationship is summarized and further discussed based on molecular modeling studies. The ORAC and MTT assays indicated that the hybrid compounds possessed pronounced antioxidant activity and could effectively protect PC12 cells from the H2O2/Aβ42-induced toxicity. Moreover, the hybrid compounds also showed positive metal ions-chelating ability in vitro, suggesting a potential to halt ion-induced Aβ aggregation. All the obtained results demonstrated that the tacrine-curcumin hybrid compounds, in particular compound K3-2, can be considered as potential therapeutic agents for Alzheimer's disease.

  10. Nonquaternary Cholinesterase Reactivators.

    Science.gov (United States)

    1982-08-30

    1978, 34, 523. 30. Lehninger , A. L., " Biochemistry ," Worth Publ. Inc., New York, 1970, p. 161. 31. Green, A. L.; Smith, H. J.; Biochem. J., 1958, 68...nerve agent antidotes focuses on nonquaternary cholinesterase reactivators. In principle , it should be possible to find nonquaternary hydroximic acid...elicit pronounced physiological responses. In principle , it should be possible to develop nonquaternary AChE reactivators that would not only equal

  11. Depressão vascular no idoso: resposta ao tratamento antidepressivo associado a inibidor das colinesterases Vascular depression in elderly: response to treatment with antidepressant associated to cholinesterase inhibitor

    Directory of Open Access Journals (Sweden)

    Ricardo Barcelos

    2007-01-01

    Full Text Available CONTEXTO: Entre os transtornos neuropsiquiátricos ocasionados por eventos cerebrovasculares, a depressão vascular é pouco diagnosticada por médicos não especialistas, causando aumento da morbimortalidade de pacientes idosos. CASO CLÍNICO: Trata-se de um paciente com 67 anos que apresentou resposta parcial a tratamento com inibidores da recaptura de serotonina e efeitos adversos autonômicos graves com outros antidepressivos. A adição de rivastigmina ao citalopram promoveu sucesso terapêutico, com redução de 23 para 7 pontos, na escala de Hamilton para depressão. DISCUSSÃO: O resultado obtido traz novas perspectivas para o tratamento da depressão vascular, sendo necessários ensaios clínicos controlados que evidenciem o benefício da adição dos inibidores das colinesterases aos antidepressivos no tratamento destes pacientes.CONTEXT: Among neuropsychiatric disorders caused by cerebrovascular factors, vascular depression is diagnosed in a small degree by general practitioners, causing morbid-mortality increase in elderly. CASE REPORT: That is a case of a 67 year-old-man with partial response after treatment with a Selective Serotonin Receptors Inhibitor, and severe autonomic adverse effects with other antidepressants. The addition of rivastigmine to citalopram resulted in a therapeutic success, with a reduction of 23 to 7 points on the Hamilton Depressive Scale (HAM-D. DISCUSSION: The result obtained brings new perspectives to the treatment of vascular depression, providing that randomized controlled trials with larger sample sizes confirm the positive effect of the addition of a cholinesterase inhibitor to antidepressants in the treatment of these patients.

  12. Synthesis and Biological Evaluation of Benzochromenopyrimidinones as Cholinesterase Inhibitors and Potent Antioxidant, Non-Hepatotoxic Agents for Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Youssef Dgachi

    2016-05-01

    Full Text Available We report herein the straightforward two-step synthesis and biological assessment of novel racemic benzochromenopyrimidinones as non-hepatotoxic, acetylcholinesterase inhibitors with antioxidative properties. Among them, compound 3Bb displayed a mixed-type inhibition of human acetylcholinesterase (IC50 = 1.28 ± 0.03 μM, good antioxidant activity, and also proved to be non-hepatotoxic on human HepG2 cell line.

  13. Synthesis and evaluation of 7-substituted coumarin derivatives as multimodal monoamine oxidase-B and cholinesterase inhibitors for the treatment of Alzheimer's disease.

    Science.gov (United States)

    Joubert, Jacques; Foka, Germaine B; Repsold, Benjamin P; Oliver, Douglas W; Kapp, Erika; Malan, Sarel F

    2017-01-05

    A series of 7-substituted coumarin derivatives were designed and synthesised to display ChE and MAO-B inhibitory activity. The compounds consisted out of a coumarin structure (MAO-B inhibitor) and benzyl-, piperidine-, N-benzylpiperidine- or p-bromo-N-benzylpiperizine moiety, resembling the N-benzylpiperidine function of donepezil (ChE inhibitor), connected via an alkyl ether linkage at the 7 position. The biological assay results indicated that all the compounds (1-25) displayed selective inhibition to hMAO-B over hMAO-A, with the benzyloxy series (1-8, 10-13) showing nano-molar hMAO-B inhibition (IC50: 0.5-73 nM). Limited ChE inhibitory activity was however observed for the benzyloxy series with the exception of 2 and especially 3 showing selective BuChE inhibition. From this series 3 showed the best multifunctional activity (eqBuChE IC50 = 0.96 μM, hMAO-A IC50 = 2.13 μM, hMAO-B IC50 = 0.0021 μM). Within the N-benzylpiperidine (16-19) and p-bromo-N-benzylpiperizine (21-24) series the compounds in general showed moderate ChE and MAO-B inhibitory activity. Of these compounds 19 was the most potent multifunctional agent showing good eeAChE and eqBuChE inhibition (IC50 = 9.10 μM and 5.90 μM, respectively), and relatively potent and selective hMAO-B inhibition (IC50 = 0.30 μM, SI = >33). Molecular modeling revealed that 19 was able to bind simultaneously to the CAS, mid-gorge and PAS sites of AChE and BuChE suggesting that it will be able to inhibit AChE induced Aβ aggregation. From this study, compounds that 3 and 19 can be considered as promising multifunctional lead compounds.

  14. Multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer’s disease: design, synthesis, biochemical evaluation, ADMET, molecular modeling, and QSAR analysis of novel donepezil-pyridyl hybrids

    Directory of Open Access Journals (Sweden)

    Bautista-Aguilera OM

    2014-10-01

    Full Text Available Oscar M Bautista-Aguilera,1,* Gerard Esteban,2,* Mourad Chioua,1 Katarina Nikolic,3 Danica Agbaba,3 Ignacio Moraleda,4 Isabel Iriepa,4 Elena Soriano,5 Abdelouahid Samadi,1 Mercedes Unzeta,2 José Marco-Contelles1 1Laboratory of Medicinal Chemistry (Institute of General Organic Chemistry [IQOG], National Research Council [CSIC], Madrid, Spain; 2Department of Biochemistry and Molecular Biology, Institute of Neurosciences, Autonomous Barcelona University, Barcelona, Spain; 3Institute of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia; 4Department of Organic Chemistry, Faculty of Pharmacy, University of Alcalá, Ctra Barcelona, Alcalá de Henares, Spain; 5Synthesis, and Structure of Organic Compounds (SEPCO (IQOG, CSIC, Madrid, Spain *These authors have equally contributed to this work Abstract: The design, synthesis, and biochemical evaluation of donepezil-pyridyl hybrids (DPHs as multipotent cholinesterase (ChE and monoamine oxidase (MAO inhibitors for the potential treatment of Alzheimer’s disease (AD is reported. The 3D-quantitative structure-activity relationship study was used to define 3D-pharmacophores for inhibition of MAO A/B, acetylcholinesterase (AChE, and butyrylcholinesterase (BuChE enzymes and to design DPHs as novel multi-target drug candidates with potential impact in the therapy of AD. DPH14 (­Electrophorus electricus AChE [EeAChE]: half maximal inhibitory concentration [IC50] =1.1±0.3 nM; equine butyrylcholinesterase [eqBuChE]: IC50 =600±80 nM was 318-fold more potent for the inhibition of AChE, and 1.3-fold less potent for the inhibition of BuChE than the reference compound ASS234. DPH14 is a potent human recombinant BuChE (hBuChE inhibitor, in the same range as DPH12 or DPH16, but 13.1-fold less potent than DPH15 for the inhibition of human recombinant AChE (hAChE. Compared with donepezil, DPH14 is almost equipotent for the inhibition of hAChE, and 8.8-fold more potent for h

  15. Molecular Biological Studies on the Biogenesis of Human Cholinesterases in vivo and as Directed by Cloned Cholinesterase DNA Sequences

    Science.gov (United States)

    1990-10-24

    potentially be analogous to the well-known amplification of other genes that encode target proteins to toxic compounds. As such, it could provide cells the...occurring CHE inhibitors, including the steroidal glycoalkaloid solanine and its hydrolytic aglycone derivative solanidine, both of which may be...present in toxic concentrations in potatoes (63,64). 4.5 Suggestions for peptidase activity of cholinesterases Carboxy- and aminopeptidase activity from a

  16. Exposure of nonbreeding migratory shorebirds to cholinesterase-inhibiting contaminants in the western hemisphere

    Science.gov (United States)

    Strum, K.M.; Hooper, M.J.; Johnson, K.A.; Lanctot, Richard B.; Zaccagnini, M.E.; Sandercock, B.K.

    2010-01-01

    Migratory shorebirds frequently forage and roost in agricultural habitats, where they may be exposed to cholinesterase-inhibiting pesticides. Exposure to organophosphorus and carbamate compounds, common anti-cholinesterases, can cause sublethal effects, even death. To evaluate exposure of migratory shorebirds to organophosphorus and carbamates, we sampled birds stopping over during migration in North America and wintering in South America. We compared plasma cholinesterase activities and body masses of individuals captured at sites with no known sources of organophosphorus or carbamates to those captured in agricultural areas where agrochemicals were recommended for control of crop pests. In South America, plasma acetylcholinesterase and butyrylcholinesterase activity in Buff-breasted Sandpipers was lower at agricultural sites than at reference sites, indicating exposure to organophosphorus and carbamates. Results of plasma cholinesterase reactivation assays and foot-wash analyses were inconclusive. A meta-analysis of six species revealed no widespread effect of agricultural chemicals on cholinesterase activity. however, four of six species were negative for acetylcholinesterase and one of six for butyrylcholinesterase, indicating negative effects of pesticides on cholinesterase activity in a subset of shorebirds. Exposure to cholinesterase inhibitors can decrease body mass, but comparisons between treatments and hemispheres suggest that agrochemicals did not affect migratory shorebirds' body mass. Our study, one of the first to estimate of shorebirds' exposure to cholinesterase-inhibiting pesticides, suggests that shorebirds are being exposed to cholinesterase- inhibiting pesticides at specific sites in the winter range but not at migratory stopover sites. future research should examine potential behavioral effects of exposure and identify other potential sitesand levels of exposure. ?? The Cooper Ornithological Society 2010.

  17. Cholinesterase inhibitory activity of chlorophenoxy derivatives-Histamine H3 receptor ligands.

    Science.gov (United States)

    Łażewska, Dorota; Jończyk, Jakub; Bajda, Marek; Szałaj, Natalia; Więckowska, Anna; Panek, Dawid; Moore, Caitlin; Kuder, Kamil; Malawska, Barbara; Kieć-Kononowicz, Katarzyna

    2016-08-15

    In recent years, multitarget-directed ligands have become an interesting strategy in a search for a new treatment of Alzheimer's disease. Combination of both: a histamine H3 receptor antagonist/inverse agonist and a cholinesterases inhibitor in one molecule could provide a new therapeutic opportunity. Here, we present biological evaluation of histamine H3 receptor ligands-chlorophenoxyalkylamine derivatives against cholinesterases: acetyl- and butyrylcholinesterase. The target compounds showed cholinesterase inhibitory activity in a low micromolar range. The most potent in this group was 1-(7-(4-chlorophenoxy)heptyl)homopiperidine (18) inhibiting the both enzymes (EeAChE IC50=1.93μM and EqBuChE IC50=1.64μM). Molecular modeling studies were performed to explain the binding mode of 18 with histamine H3 receptor as well as with cholinesterases.

  18. Motor endplate cholinesterase in human skeletal muscle.

    Directory of Open Access Journals (Sweden)

    Fujii,Masafumi

    1982-08-01

    Full Text Available The activity and properties of cholinesterase (ChE of the motor endplate and its fractions were studied in isolated human skeletal muscle. This preparation was used since the ChE activity of the membrane preparation was localized only in the motor endplate. The endplate ChE was stable in the isolated membrane for 4 weeks at 4 degrees C. The specific activity of the extracted ChE of human muscle membrane was 29.6% higher than that of the original membrane. Studies with specific substrates and ChE inhibitors indicated that most of the ChE of human muscle membrane and its fractions was acetylcholinesterase, and that the minor component was pseudocholinesterase. A Michaelis-Menten constant of 3.82 mM was estimated in the endplate ChE, and 0.88 mM in the extracted ChE of the endplate. The extracted human endplate ChE was separated into three fractions by Sephadex G-200 chromatography, and into two fractions by acrylamide gel electrophoresis.

  19. Central cholinesterase inhibition enhances glutamatergic synaptic transmission.

    Science.gov (United States)

    Kozhemyakin, Maxim; Rajasekaran, Karthik; Kapur, Jaideep

    2010-04-01

    Central cholinergic overstimulation results in prolonged seizures of status epilepticus in humans and experimental animals. Cellular mechanisms of underlying seizures caused by cholinergic stimulation remain uncertain, but enhanced glutamatergic transmission is a potential mechanism. Paraoxon, an organophosphate cholinesterase inhibitor, enhanced glutamatergic transmission on hippocampal granule cells synapses by increasing the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) in a concentration-dependent fashion. The amplitude of mEPSCs was not increased, which suggested the possibility of enhanced action potential-dependent release. Analysis of EPSCs evoked by minimal stimulation revealed reduced failures and increased amplitude of evoked responses. The ratio of amplitudes of EPSCs evoked by paired stimuli was also altered. The effect of paraoxon on glutamatergic transmission was blocked by the muscarinic antagonist atropine and partially mimicked by carbachol. The nicotinic receptor antagonist α -bungarotoxin did not block the effects of paraoxon; however, nicotine enhanced glutamatergic transmission. These studies suggested that cholinergic overstimulation enhances glutamatergic transmission by enhancing neurotransmitter release from presynaptic terminals.

  20. The Inhibitory Effect of Propranolol and Isoproterenol on Human Plasma Cholinesterase

    Directory of Open Access Journals (Sweden)

    Ali Awsat Mellati

    2002-10-01

    Full Text Available The effect of propranolol and isoproterenol on the hydrolysis of 4- nitrophenylbutyrate (PNPB by the purified human plasma cholinesterase was studied. During the hydrolysis of PNPB, enzyme obeyed to Michaelis-Menten model. Propranolol was found to be a competitive inhibitor, and isoproterenol yielded a complex inhibition pattern. It could be explained that the inhibitory effect of propranolol shows noncooperativity between subunits of human plasma cholinesterase upon binding of PNPB. In contrast, isoproternol inhibitory effects indicate more than one type of binding sites on this enzyme.

  1. TLC Bioautographic Method for Activity Screening of Natural Acetyl Cholinesterase In-hibitors from Xinjiang Mohe-Tobacco%薄层色谱生物自显影法筛选新疆莫合烟天然乙酰胆碱酯酶抑制剂的活性成分

    Institute of Scientific and Technical Information of China (English)

    王健; 朱萍萍; 倪国柱; 温琳豫; 支玲; 胡曙晨

    2014-01-01

    Objective To explain nicotine in tobacco can reduce the incidence of degenerative diseases,perform the activity screening of acetyl cholinesterase inhibitors of Xinjiang's unique Mohe-tobacco for illuminating the action mechanism. Methods The thin layer chromatography(TLC)bioautographic method combining TLC with biological activity assay was used to conduct the activity screening of extract solution of Xinjiang Mohe-tobacco. Results Nicotine in the extract solution of Xinjiang Mohe-tobacco appeared the white spots on the purple background by the TLC bioautography,indicating that which possesses the activity,but the white spots were weak, indicating that the nicotine content in the extract solution was unable to reach the significant inhibiting concentration,its activity was lower than that of the reference substance huperzine A;the DPPH development method revealed that the extraction solution of Xinjiang Mohe-tobacco simultaneously possesses the better antioxidant activity. Conclusion Nicotine in Xinjiang Mohe-tobacco can be com-bined with acetyl cholinesterase and inhibits its activity. The TLC bioautographic method is easy to operate with high sensitivity and specificity in the activity screening for natural acetyl cholinesterase inhibitor.%目的:为阐明烟草中的烟碱降低退行性疾病发病率的作用机理,对新疆特有的莫合烟进行天然乙酰胆碱酯酶抑制剂的活性筛选。方法采用薄层色谱分离和生物活性测定相结合的薄层色谱生物自显影技术,对新疆莫合烟提取液进行活性筛选。结果新疆莫合烟提取液中的烟碱通过薄层色谱生物自显影,在紫色背景下出现白色斑点,表明具有活性;但白色斑点较弱,表明提取液中的烟碱含量无法达到显著的抑制浓度,较对照品石杉碱甲活性偏低;2,2-二苯基苦基苯肼自由基( DPPH )显色法表明新疆莫合烟提取液同时具有较好的抗氧化活性。结论新疆莫合烟中的

  2. Cholinesterase modulations in patients with acute bacterial meningitis

    DEFF Research Database (Denmark)

    Berg, Ronan M G; Ofek, Keren; Qvist, Tavs;

    2011-01-01

    The circulating cholinesterases acetyl- and butyrylcholinesterase may be suppressed and subsequently released from the brain in acute bacterial meningitis.......The circulating cholinesterases acetyl- and butyrylcholinesterase may be suppressed and subsequently released from the brain in acute bacterial meningitis....

  3. The Multileveled Regulation of the Human Cholinesterase Genes and Their Protein Products

    Science.gov (United States)

    1993-09-30

    present in all members of the Solanua plant family, including Solanin tuberosa (potatoes), and are likely to be present in extremely high and toxic ...and solanine -derived alkaloids 120 33. Conservation of substrate specificity and loss of substrate activation in AChE-BuChE chimera 121 34. Inhibition...for inhibition of the insect enzyme, with particular emphasis on low toxicity to humans. In addition, cholinesterase (ChZ) inhibitors are employed

  4. Early appearance and possible roles of non-neuromuscular cholinesterases.

    Directory of Open Access Journals (Sweden)

    Carla eFalugi

    2012-04-01

    Full Text Available The biological function of the cholinesterase (ChE enzymes is well known and has been studied since the beginning of the XXth century; in particular, acetylcholinesterase (AChE, E.C. 3.1.1.7 is an enzyme playing a key role in the modulation of neuromuscular impulse transmission. However, in the past decades, there has been increasing interest concerning its role in regulating non-neuromuscular cell-to-cell interactions mediated by intracellular ion concentration changes, like the ones occurring during gamete interaction and embryonic development. An understanding of the mechanisms of the cholinergic regulation of these events can help us foresee the possible impact on environmental and human health, including gamete efficiency and possible teratogenic effects on different models, and help elucidate the extent to which exposure to ChE inhibitors may affect human health.

  5. Partial purification and properties of flyhead cholinesterase

    NARCIS (Netherlands)

    Dauterman, W.C.; Talens, A; Asperen, K. van

    1962-01-01

    Housefly head cholinesterase was purified using the following steps: (1) freeze-drying of flyheads, (2) solubilization of the enzyme by butanol extraction, (3) ammonium sulphate precipitation at pH 7, (4) heat denaturation of proteins in the presence of acetylcholine for protection of the cholineste

  6. MEASURING CHOLINESTERASE ACTIVITY IN HUMAN SALIVA.

    Science.gov (United States)

    To assess the potential for using saliva in pesticide biomonitoring, the consistency of cholinesterase activity in human saliva collected over time was examined. In this pilot study, saliva was collected from 20 healthy adults once per week for 5 consecutive weeks using 2 differe...

  7. Cholinesterases: structure of the active site and mechanism of the effect of cholinergic receptor blockers on the rate of interaction with ligands

    Energy Technology Data Exchange (ETDEWEB)

    Antokhin, A M; Gainullina, E T; Taranchenko, V F [Federal State Agency ' 27 Scientific Centre of Ministry of Defence of the Russian Federation' (Russian Federation); Ryzhikov, S B; Yavaeva, D K [Department of Physics, M.V.Lomonosov Moscow State University (Russian Federation)

    2010-10-19

    Modern views on the structure of cholinesterase active sites and the mechanism of their interaction with organophosphorus inhibitors are considered. The attention is focused on the mechanism of the effect of cholinergic receptor blockers, acetylcholine antagonists, on the rate of interaction of acetylcholine esterase with organophosphorus inhibitors.

  8. In vitro antioxidant, cholinesterase and tyrosinase inhibitory activities of Calophyllum symingtonianum and Calophyllum depressinervosum (Guttiferae)

    Institute of Scientific and Technical Information of China (English)

    Nurul Iman Aminudin; Farediah Ahmad; Muhammad Taher

    2015-01-01

    Objective:To screen the antioxidant, cholinesterase and tyrosinase enzymatic inhibition activities of the leaves and heartwood of Calophyllum symingtonianum (C. symingtonianum), and the bark of Calophyllum depressinervosum (C. depressinervosum). Methods: Samples of leaves and heartwood of C. symingtonianum and bark of C. depressinervosum were tested for their total phenolic content and in vitro antioxidant assay by 2,2-diphenyl-1-picrylhydrazyl radical scavenging andβ-carotene bleaching. Cholinesterase inhibition by Ellman’s method and tyrosinase inhibition using L-3,4-dihydroxyphenylalanine as a substrate were also tested. Results:All methanol extracts were found to exhibit strong 2,2-diphenyl-1-picrylhydrazyl radical scavenging effects. Extracts from the heartwood of C. symingtonianum gave a low IC50 (5.17±0.04) µg/mL followed by bark of C. depressinervosum [(7.30±0.14) µg/mL] and C. symingtonianum leaves [(15.70±1.43) µg/mL]. The methanol extract of C. depressinervosum bark showed 95.08% inhibition of β-carotene bleaching. All extracts showed moderate inhibition towards tyrosinase activity with an IC50 of more than 100 µg/mL. The methanol extract of C. depressinervosum stem bark showed the highest inhibition (78.46%) against butyrylcholinesterase. Conclusions:These results showed that both Calophyllum species are potential sources of antioxidant and cholinesterase inhibitors. Further study is needed for the isolation and characterization of the active metabolites responsible for both activities.

  9. Synthesis, cholinesterase inhibition and molecular modelling studies of coumarin linked thiourea derivatives.

    Science.gov (United States)

    Saeed, Aamer; Zaib, Sumera; Ashraf, Saba; Iftikhar, Javeria; Muddassar, Muhammad; Zhang, Kam Y J; Iqbal, Jamshed

    2015-12-01

    Alzheimer's disease is among the most widespread neurodegenerative disorder. Cholinesterases (ChEs) play an indispensable role in the control of cholinergic transmission and thus the acetylcholine level in the brain is enhanced by inhibition of ChEs. Coumarin linked thiourea derivatives were designed, synthesized and evaluated biologically in order to determine their inhibitory activity against acetylcholinesterases (AChE) and butyrylcholinesterases (BChE). The synthesized derivatives of coumarin linked thiourea compounds showed potential inhibitory activity against AChE and BChE. Among all the synthesized compounds, 1-(2-Oxo-2H-chromene-3-carbonyl)-3-(3-chlorophenyl)thiourea (2e) was the most potent inhibitor against AChE with an IC50 value of 0.04±0.01μM, while 1-(2-Oxo-2H-chromene-3-carbonyl)-3-(2-methoxyphenyl)thiourea (2b) showed the most potent inhibitory activity with an IC50 value of 0.06±0.02μM against BChE. Molecular docking simulations were performed using the homology models of both cholinesterases in order to explore the probable binding modes of inhibitors. Results showed that the novel synthesized coumarin linked thiourea derivatives are potential candidates to develop for potent and efficacious acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors.

  10. 21 CFR 862.3240 - Cholinesterase test system.

    Science.gov (United States)

    2010-04-01

    ... is present at nerve endings and in erythrocytes (red blood cells) but is not present in plasma... obtained by this device are used in the diagnosis and treatment of cholinesterase inhibition disorders...

  11. Gravidade das intoxicações por inseticidas inibidores das colinesterases no noroeste do estado do Paraná, Brasil Gravedad de las intoxicaciones por insecticidas inhibidores de colinesterasa en el noroeste del estado do Paraná, Brasil Severity of the intoxications by cholinesterase inhibitor insecticides registered in the nothwest of the state of Paraná, Brasil

    Directory of Open Access Journals (Sweden)

    Magda Lúcia Félix de Oliveira

    2009-12-01

    clasificadas como severas. La alta incidencia de intoxicación grave y mortalidad sugieren estrategias preventivas referidas a la utilización de estos insecticidas, objetivando restringir el acceso indiscriminado a estos potentes agentes tóxicos.This article has as objective the discussion of the severity of intoxications by cholinesterase inhibitor insecticides, which happened in the Northwest of Paraná, Brasil, starting from an exploratory descriptive study, with retrospective analysis of epidemiological data sheets of the Intoxications Control Center in the University Hospital of Maringá, Paraná, Brasil, referring to patients intoxicated from January, 1994 to December, 2005. 529 cases were analyzed, 168 (31,7% for organophosphates and 167 (31,5% for carbamates. The suicide attempt represented 257 cases (48,5%, the occupational exposure 140 (26,5%, and the accidental 124 (23,5%. Comparing the number of severe intoxications and deaths, it was verified from 100% of deaths to cases severe occupational exposure, 20% for the suicide attempt and 7,5% deaths for the accidental intoxications classified as severe. The high incidence of serious intoxication and mortality suggest preventive strategies in respect of the usage of the insecticides, aiming to restrict the indiscriminate access to these powerful toxic agents.

  12. Study of Serum Amylase and Serum Cholinesterase in Organophosphorus Poisoning

    Directory of Open Access Journals (Sweden)

    Sharan Badiger

    2016-04-01

    Full Text Available Background: Poisoning due to organophosphorus compounds is most commonly seen. Earlier plasma cholinesterase level was used to assess the severity of poisoning. Presently serum amylase is being recommended as a better indicator of severity. Aims and Objectives: To study plasma cholinesterase and serum amylase levels in acute organophosphorus and to correlate serum amylase levels with clinical severity and outcome. Material and Methods: A total of 80 patients in the study admitted to a tertiary care centre within 24 hours with a history of organophosphorus poisoning were included in study. Estimation of plasma cholinesterase and serum rd amylase was done at the time of admission, and on 3 th day and on 5 day. Results: Occurrence of organophosphorus poisoning was more common among age group 21-30 years and among males (57.5%. They were 25 (31.2% farmers, 23 (28.8% st u d e n ts, a n d 2 2 ( 2 7 . 5% h o u s ewi v e s. Monocrotophos (45.0% was commonly used compound. Mean value of plasma cholinesterase and serum amylase at admission are 3693 U/L, and 185.4 U/L. There was significant inhibition of plasma cholinesterase and elevation of serum amylase at th admission with return to normal values on 5 day. Conclusion: Plasma cholinesterase inhibition 200 U/L has been associated with poor prognosis and proneness to respiratory failure.

  13. Oxidation of cholinesterase-inhibiting pesticides: A simple experiment to illustrate the role of bioactivation in the toxicity of chemicals.

    Science.gov (United States)

    Arufe; Romero; Gamero; Moreno

    2000-05-01

    A simple undergraduate laboratory experiment that can be used in Biochemistry and Toxicology courses to illustrate the importance of metabolic reactions in the toxicity of chemical substances is reported. It involves the experimental confirmation that oxidized phosphorothionate esters, commonly used as insecticides, are stronger cholinesterase inhibitors and therefore exhibit higher toxicity than do their sulphur analogs starting from which the first are formed by in vivo oxidative desulphuration. Two separated aliquots of a bovine blood sample are incubated with parathion and paraoxon, its oxygen analog, and compared for cholinesterase activity with "normal" blood. Previously, a standard sample of paraoxon was obtained by oxidation of the thiono group of parathion with bromine vapour by reaction TLC. The comparison of the inhibitory capacity of both compounds is made by a colorimetric procedure using acetylthiocholine as substrate of the enzyme and 5,5'-dithiobis-(2-nitrobenzoic acid) as chromogen.

  14. Characterization and in vitro sensitivity of cholinesterases of gilthead seabream (Sparus aurata) to organophosphate pesticides.

    Science.gov (United States)

    Albendín, G; Arellano, J M; Mánuel-Vez, M P; Sarasquete, C; Arufe, M I

    2016-10-06

    The characterization of cholinesterase activity in brain and muscle of gilthead seabream was carried out using four specific substrates and three selective inhibitors. In addition, K m and V max were calculated from the Michaelis-Menten equation for ASCh and BSCh substrates. Finally, the in vitro sensitivity of brain and muscle cholinesterases to three organophosphates (OPs) was also investigated by estimating inhibition kinetics. The results indicate that AChE is the enzyme present in the brain, whereas in muscle, a typical AChE form is present along with an atypical form of BChE. Very low ChE activity was found in plasma with all substrates used. The inhibitory potency of the studied OPs on brain and muscle AChEs based on bimolecular inhibition constants (k i ) was: omethoate < dichlorvos < azinphosmethyl-oxon. Furthermore, muscle BChE was found to be several orders of magnitude (from 2 to 4) more sensitive than brain and muscle AChE inhibition by dichlorvos and omethoate.

  15. Chemical and molecular aspects on interactions of galanthamine and its derivatives with cholinesterases.

    Science.gov (United States)

    Gulcan, Hayrettin O; Orhan, Ilkay E; Sener, Bilge

    2015-01-01

    Dual action of galanthamine as potent cholinesterase inhibitor and nicotinic modulator has attracted a great attention to be used in the treatment of AD. Consequently, galanthamine, a natural alkaloid isolated from a Galanthus species (snowdrop, Amaryllidaceae), has become an attractive model compound for synthesis of its novel derivatives to discover new drug candidates. Numerous studies have been done to elucidate interactions between galanthamine and its different derivatives and the enzymes; acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using in vitro and in silico experimental models. The in vitro studies revealed that galanthamine inhibits AChE in strong, competitive, long-acting, and reversible manner as well as BChE, although its selectivity towards AChE is much higher than BChE. The in silico studies carried out by employing molecular docking experiments as well as molecular dynamics simulations pointed out to existence of strong interactions of galanthamine with the active gorge of AChE, mostly of Torpedo californica (the Pasific electric ray) origin. In this review, we evaluate the mainstays of cholinesterase inhibitory action of galanthamine and its various derivatives from the point of view of chemical and molecular aspects.

  16. Evaluation of Antioxidant, Anti-cholinesterase, and Anti-inflammatory Effects of Culinary Mushroom Pleurotus pulmonarius

    Science.gov (United States)

    Nguyen, Trung Kien; Im, Kyung Hoan; Choi, Jaehyuk; Shin, Pyung Gyun

    2016-01-01

    Culinary mushroom Pleurotus pulmonarius has been popular in Asian countries. In this study, the anti-oxidant, cholinesterase, and inflammation inhibitory activities of methanol extract (ME) of fruiting bodies of P. pulmonarius were evaluted. The 1,1-diphenyl-2-picryl-hydrazy free radical scavenging activity of ME at 2.0 mg/mL was comparable to that of butylated hydroxytoluene, the standard reference. The ME exhibited significantly higher hydroxyl radical scavenging activity than butylated hydroxytoluene. ME showed slightly lower but moderate inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase than galantamine, a standard AChE inhibitor. It also exhibited protective effect against cytotoxicity to PC-12 cells induced by glutamate (10~100 µg/mL), inhibitory effect on nitric oxide (NO) production and inducible nitric oxide synthase protein expression in lipopolysaccharide-stimulated RAW 264.7 macrophages, and carrageenan-induced paw edema in a rat model. High-performance liquid chromatography analysis revealed the ME of P. pulmonarius contained at least 10 phenolic compounds and some of them were identified by the comparison with known standard phenolics. Taken together, our results demonstrate that fruiting bodies of P. pulmonarius possess antioxidant, anti-cholinesterase, and inflammation inhibitory activities.

  17. Effect of temperature and pH on carbamoylation and phosphorylation of serum cholinesterases. Theoretical interpretation of activation energies in complex reactions

    Science.gov (United States)

    Simeon, Vera; Reiner, Elsa; Vernon, C. A.

    1972-01-01

    1. The effect of temperature and pH was studied on the kinetics of inhibition of horse serum and human serum cholinesterase by four organophosphorus compounds and five carbamates. 2. For all compounds, and at each pH and temperature, the inhibition followed the kinetics of a bimolecular reaction with the inhibitor in excess, and with a negligible concentration of the Michaelis complex. 3. The second-order rate constants (ka) for inhibition of human serum cholinesterase by one organophosphate and one carbamate increased from 5° to 40°C with an apparent activation energy of 46kJ/mol (11kcal/mol). 4. The ka constant for inhibition of horse serum cholinesterase increased with temperature from 5° to 30°C, and then decreased from 30° to 40°C. The theoretical interpretation of such an unusual effect of temperature is derived. 5. The increase of ka with pH (human serum cholinesterase) followed the dissociation curve for a single group on the enzyme (pK7.5). 6. Rate constants for decarbamoylation (k+3) were determined, and the time-course of inhibition was calculated from the ka and k+3 constants. PMID:4677141

  18. Analysis of Amaryllidaceae alkaloids from Zephyranthes grandiflora by GC/MS and their cholinesterase activity

    Directory of Open Access Journals (Sweden)

    Lucie Cahlíková

    2011-08-01

    Full Text Available Amaryllidaceae are known as ornamental plants, furthermore some species of this family contain galanthamine, an acetylcholinesterase inhibitor approved for the treatment of Alzheimer's disease, and other alkaloids with interesting pharmacological activity. The chemical composition of alkaloids from Zephyranthes grandiflora Lindl. was analyzed by GC/MS. Seven known compounds, belonging to five structural types of Amaryllidaceae alkaloids, were identified. The alkaloid extract from the bulbs showed promising cholinesterase inhibitory activities against human blood acetylcholinesterase (HuAChE; IC50 39.2±3.0 µg/mL and human plasma butyrylcholinesterase (HuBuChE; IC50 356±9.3 µg/mL.

  19. Different sensitivities of rat skeletal muscles and brain to novel anti-cholinesterase agents, alkylammonium derivatives of 6-methyluracil (ADEMS)

    Science.gov (United States)

    Petrov, Konstantin A; Yagodina, Lilia O; Valeeva, Guzel R; Lannik, Natalya I; Nikitashina, Alexandra D; Rizvanov, Albert A; Zobov, Vladimir V; Bukharaeva, Ellya A; Reznik, Vladimir S; Nikolsky, Eugeny E; Vyskočil, František

    2011-01-01

    BACKGROUND AND PURPOSE The rat respiratory muscle diaphragm has markedly lower sensitivity than the locomotor muscle extensor digitorum longus (EDL) to the new acetylcholinesterase (AChE) inhibitors, alkylammonium derivatives of 6-methyluracil (ADEMS). This study evaluated several possible reasons for differing sensitivity between the diaphragm and limb muscles and between the muscles and the brain. EXPERIMENTAL APPROACH Increased amplitude and prolonged decay time of miniature endplate currents were used to assess anti-cholinesterase activity in muscles. In hippocampal slices, induction of synchronous network activity was used to follow cholinesterase inhibition. The inhibitor sensitivities of purified AChE from the EDL and brain were also estimated. KEY RESULTS The intermuscular difference in sensitivity to ADEMS is partly explained caused by a higher level of mRNA and activity of 1,3-bis[5(diethyl-o-nitrobenzylammonium)pentyl]-6-methyluracildibromide (C-547)-resistant BuChE in the diaphragm. Moreover, diaphragm AChE was more than 20 times less sensitive to C-547 than that from the EDL. Sensitivity of the EDL to C-547 dramatically decreased after treadmill exercises that increased the amount of PRiMA AChE(G4), but not ColQ AChE(A12) molecular forms. The A12 form present in muscles appeared more sensitive to C-547. The main form of AChE in brain, PRiMA AChE(G4), was apparently less sensitive because brain cholinesterase activity was almost three orders of magnitude more resistant to C-547 than that of the EDL. CONCLUSIONS AND IMPLICATIONS Our findings suggest that ADEMS compounds could be used for the selective inhibition of AChEs and as potential therapeutic tools. PMID:21232040

  20. [Pesticide detection in Costarican vegetables based on the inhibition of serum and erythrocytic human cholinesterases].

    Science.gov (United States)

    Nevermann, Karl Schosinsky; Guzmán, Eugenia Quintana

    2004-12-01

    A simple and low cost method able to detect the presence of pesticides, organophosphates and carbamates based on the inhibition of serum and erythrocytic cholinesterases, was used in lettuce (Lactuca sativa), cilantro (Coriandum santivum) and celery (Apium graveolens) obtained from the Ferias del Agricultor from Valle Central of Costa Rica. The percentage inhibition of cholinesterases is related to the presence of plaguicide in the vegetable. Thirteen percent of the analyzed samples were positive for plaguicides using serum cholinesterase and 33% for erythrocytic cholinesterase. Washing and cooking the vegetables does not eliminate the presence of plaguicides but they lower slightly the concentration. Statistical evidence (p = 0.0001) indicates that erythrocytic cholinesterase has higher analytical sensitivity than serum cholinesterase. It is very important to establish the degree of contamination with pesticides in these agricultural products because they are exposed to direct contamination by fumigation, soil contamination and irrigation water, and are products that are often consumed without adequate cooking and washing.

  1. Cholinesterase activity in gilthead seabream (Sparus aurata) larvae: Characterization and sensitivity to the organophosphate azinphosmethyl.

    Science.gov (United States)

    Arufe, M Isabel; Arellano, Juana M; García, Leticia; Albendín, Gemma; Sarasquete, Carmen

    2007-10-15

    Assessment of cholinesterase (ChE) inhibition is widely used as a specific biomarker for evaluating the exposure and effects of non-target organisms to anticholinesterase agents. Cholinesterase and carboxylesterase activities have been measured in larvae of gilthead seabream, Sparus aurata, during the endogenous feeding stage, and ChE was characterized with the aid of diagnostic substrates and inhibitors. The results of the present study showed that whole-body ChE of yolk-sac seabream larvae possesses typical properties of acetylcholinesterase (AChE) with a apparent affinity constant (K(m)) of 0.163+/-0.008 mM and a maximum velocity (V(max)) of 332.7+/-2.8 nmol/min/mg protein. Moreover, sensibility of this enzyme was investigated using the organophosphorus insecticide azinphosmethyl. Static-renewal toxicity tests were conducted over 72 h and larval survival and AChE inhibition were recorded. Mean mortality of seabream larvae increased with increasing concentrations of azinphosmethyl and exposure duration. The estimated 72-h LC50 value to azinphosmethyl was 4.59 microg/l (95% CI=0.46-8.71 microg/l) and inhibition of ChE activity gave an IC50 of 3.04 microg/l (95% CI=2.73-3.31 microg/l). Larvae exposed to azinphosmethyl for 72h showed a 70% inhibition of the whole-body acetylcholinesterase activity at approximately the LC50. In conclusion, the results of the present study suggested that monitoring ChE activity is a valuable tool indicating OP exposure in S. aurata larvae and that acetylthiocholine is the most appropriate substrate for assessing ChE inhibition in this early-life stage of the fish.

  2. Tracking the origin and divergence of cholinesterases and neuroligins: the evolution of synaptic proteins

    OpenAIRE

    Lenfant, Nicolas; Hotelier, Thierry; Bourne, Yves; Marchot, Pascale; Chatonnet, Arnaud

    2014-01-01

    14. International Symposium on Cholinergic Mechanisms (ISCM), Hangzhou, 2013/05/05-9; A cholinesterase activity can be found in all kingdoms of living organism, yet cholinesterases involved in cholinergic transmission appeared only recently in the animal phylum. Among various proteins homologous to cholinesterases, one finds neuroligins. These proteins, with an altered catalytic triad and no known hydrolytic activity, display well-identified cell adhesion properties. The availability of compl...

  3. Characterization of catalytic efficiency parameters of brain cholinesterases in tropical fish.

    Science.gov (United States)

    de Assis, Caio Rodrigo Dias; Linhares, Amanda Guedes; Oliveira, Vagne Melo; França, Renata Cristina Penha; Santos, Juliana Ferreira; Marcuschi, Marina; Carvalho, Elba Verônica Matoso Maciel; Bezerra, Ranilson Souza; Carvalho, Luiz Bezerra

    2014-12-01

    Brain cholinesterases from four fish (Arapaima gigas, Colossoma macropomum, Rachycentron canadum and Oreochromis niloticus) were characterized using specific substrates and selective inhibitors. Parameters of catalytic efficiency such as activation energy (AE), k(cat) and k(cat)/k(m) as well as rate enhancements produced by these enzymes were estimated by a method using crude extracts described here. Despite the BChE-like activity, specific substrate kinetic analysis pointed to the existence of only acetylcholinesterase (AChE) in brain of the species studied. Selective inhibition suggests that C. macropomum brain AChE presents atypical activity regarding its behavior in the presence of selective inhibitors. AE data showed that the enzymes increased the rate of reactions up to 10(12) in relation to the uncatalyzed reactions. Zymograms showed the presence of AChE isoforms with molecular weights ranging from 202 to 299 kDa. Values of k(cat) and k(cat)/k(m) were similar to those found in the literature.

  4. HPTLC Fingerprinting and Cholinesterase Inhibitory and Metal-Chelating Capacity of Various Citrus Cultivars and Olea europaea

    Directory of Open Access Journals (Sweden)

    Fatma Sezer Senol

    2016-01-01

    Full Text Available Inhibitory activity of thirty-one ethanol extracts obtained from albedo, flavedo, seed and leaf parts of 17 cultivars of Citrus species from Turkey, the bark and leaves of Olea europaea L. from two locations (Turkey and Cyprus as well as caff eic acid and hesperidin was tested against acetylcholinesterase (AChE and butyrylcholinesterase (BChE, related to the pathogenesis of Alzheimer’s disease, using ELISA microtiter assays at 500 μg/mL. Metal-chelating capacity of the extracts was also determined. BChE inhibitory effect of the Citrus sp. extracts was from (7.7±0.7 to (70.3±1.1 %, whereas they did not show any inhibition against AChE. Cholinesterase inhibitory activity of the leaf and bark ethanol extracts of O. europaea was very weak ((10.2±3.1 to (15.0±2.3 %. The extracts had either no or low metal-chelating capacity at 500 μg/mL. HPTLC fingerprinting of the extracts, which indicated a similar phytochemical pattern, was also done using the standards of caffeic acid and hesperidin with weak cholinesterase inhibition. Among the screened extracts, the albedo extract of C. limon ‘Interdonato’, the flavedo extracts of ‘Kara Limon’ and ‘Cyprus’ cultivars and the seed extract of C. maxima appear to be promising as natural BChE inhibitors.

  5. Alterations of serum cholinesterase in patients with gastric cancer

    Institute of Scientific and Technical Information of China (English)

    Shan-Zhi Gu; Xin-Han Zhao; Ping Quan; Sheng-Bin Li; Bo-Rong Pan

    2005-01-01

    AIM: To understand the correlation of serum cholinesterase (CHE) activity with gastric cancer and to assess their clinical significance.METHODS: The velocity method was adopted to detect the activity of serum CHE in patients with gastric cancer and in patients with non-malignant tumor as controls.RESULTS: The serum CHE activity in the treatment group was significantly lower than that in the control group with a very significant difference between the two groups (83.3:113.1,P = 0.0003). Age was significantly associated with the incidence of gastric caner.CONCLUSION: Serum CHE activity has a close relation with the incidence of gastric cancer.

  6. Automated conductimetric assay of human serum cholinesterase activity.

    Science.gov (United States)

    Duffy, P; Wallach, J M

    1989-01-01

    Serum cholinesterase activity was determined by conductimetry using samples in the microliter range. Butyrylcholine iodide was demonstrated to be a convenient substrate for the conductimetric assay. Validation of the microassay was made by using either purified enzyme or control serum. In the range of 0-60 U/l, a linear relationship was demonstrated. Correlation with a reference spectrophotometric method was obtained with a slope of 1.18. An explanation of this value is proposed, as different hydrolysis rates were obtained with human sera, depending on the substrate used (butyrylthio- or butyryl-choline ester).

  7. Cholinesterase activities and sensitivity to pesticides in different tissues of silver European eel, Anguilla anguilla.

    Science.gov (United States)

    Valbonesi, P; Brunelli, F; Mattioli, M; Rossi, T; Fabbri, E

    2011-11-01

    Cholinesterase (ChE) activities were characterized in silver European eel, Anguilla anguilla, grown in the brackish lagoon of Comacchio (Italy). All specimens were harvested at the "lavoriero", a traditional eel trapping weir that captures eels while leaving internal waters at the onset of reproductive migration. To our knowledge, no investigation on ChE was reported in silver eels. Therefore a first characterization of enzyme activity in muscle, brain, liver and plasma of silver eel was carried out, in the presence of different substrates, selective inhibitors, and four pesticides representative of the carbamate and organophosphate classes. Brain and white skeletal muscle showed similar ChE activities, 5- and 10-fold higher than those detected in liver and plasma, respectively. Km values of 0.31 and 0.30 mM, and Vmax values of 40.28 and 35.47 nmol min(-1) mg protein(-1) were obtained in brain and muscle ChE, respectively. Acetycholinesterase was the predominant ChE form in all tissues, as concluded by comparing the effects of BW 284c51, iso-OMPA and eserine. ChE activities in brain and muscle were significantly inhibited by in vitro treatment with pesticides, with the following order of potency: carbofuran>carbaryl>chlorpyrifos≥diazinon.

  8. A new approach to determining cholinesterase activities in samples of whole blood.

    Science.gov (United States)

    Augustinsson, K B; Eriksson, H; Faijersson, Y

    1978-10-16

    A sensitive method, especially suitable for clinical laboratories, for the routine determination of cholinesterase activities in whole blood is presented. This method is based on the hydrolysis of propionylthiocholine and the spectrophotometric determination of the thiocholine produced by reaction with 4,4'-dithiodipyridine. The reaction product 4-thiopyridone has an absorption maximum at 324 nm, so that measurement in the presence of hemoglobin is possible. Propionylthiocholine is used at the substrate for both plasma butyrylcholinesterase and erythrocyte acetylcholinesterase. These two enzymes, in the relative amounts at which they are present in human blood, split this ester at about the same rate. Consequently, a first determination gives the total activity of which each individual activity is about 50%. A second determination in the presence of a selective inhibitor ("Astra 1397") for plasma butyrylcholinesterase gives the activity of the erythrocyte acetylcholinesterase. The difference between the two values represents the activity of the plasma enzyme. The validity of the method and the reliability of the results were checked with each blood sample in two ways: (1) by determining the activities of whole blood with an earlier gasometric technique which uses blood sample dried on filter paper; and (2) by measuring the activities in separated plasma and erythrocyte hemolysate eith propionylthiocholine as the substrate.

  9. Differential swimming performance of two natricine snakes exposed to a cholinesterase-inhibiting pesticide

    Energy Technology Data Exchange (ETDEWEB)

    Hopkins, W.A. [University of Georgia, Savannah River Ecology Laboratory, Wildlife Ecotoxicology and Physiological Ecology Program, PO Drawer E, Aiken, SC 29802 (United States)]. E-mail: hopkins@srel.edu; Winne, C.T. [University of Georgia, Savannah River Ecology Laboratory, Wildlife Ecotoxicology and Physiological Ecology Program, PO Drawer E, Aiken, SC 29802 (United States); DuRant, S.E. [University of Georgia, Savannah River Ecology Laboratory, Wildlife Ecotoxicology and Physiological Ecology Program, PO Drawer E, Aiken, SC 29802 (United States)

    2005-02-01

    Environmental contaminants have direct effects on organisms at the molecular, cellular, and tissue levels, but the net results of these sub-organismal effects are only consequential to exposed populations if they alter organism-level traits that ultimately influence fitness (e.g., growth, locomotor performance, reproduction, and survival). Here, we explore the possibility that the swimming performance of neonate black swamp snakes (Seminatrix pygaea) and diamondback water snakes (Nerodia rhombifer) may be affected by exposure to carbaryl (2.5 and 5.0 mg/L). The highest concentration of carbaryl caused greater reductions in swim velocity in S. pygaea than in N. rhombifer. Most individuals recovered from the effects of carbaryl on swimming performance within 96 h, but recovery was significantly slower in S. pygaea than in N. rhombifer. We hypothesize that the sensitivity of S. pygaea may arise from its highly permeable integument compared to other natricines. Our findings suggest that performance can serve as an ecologically relevant response to contaminant exposure in reptiles and warrants further study. - Exposure to a cholinesterase inhibitor reduces swimming velocity in snakes.

  10. Toxicity and characterization of cholinesterase-inhibition induced by diisopropyl fluorophosphate in Artemia salina larvae.

    Science.gov (United States)

    Sánchez-Fortún, S; Barahona, M V

    2009-03-01

    The acute toxicity of diisopropyl fluorophosphate (DFP) on three age classes of Artemia salina was evaluated. An increase in toxicity of this organophosphorous (OP) compound was found following longer development of A. salina larvae. The effects of pretreatment with the non-selective muscarinic antagonist atropine, the two reversible acetylcholinesterase inhibitors physostigmine and pyridostigmine, and the cholinesterase-reactivating oxime 2-pyridine aldoxime methoiodide (2-PAM), as individual and combined pretreatments, on DFP-induced lethality in 24h Artemia were also investigated. The lethal action of DFP was not prevented by pretreatment of 24h Artemia with atropine, physostigmine, and pyridostigmine, while 2-PAM proved effective against intoxication with this OP compound. The inhibitory effects of combinations of atropine (10(-5)M) plus 2-PAM or physostigmine were greater than those elicited by either drug alone, with the maximum protection afforded being 100%. Pretreatment with 2-PAM (10(-6)M) plus physostigmine or pyridostigmine was ineffective. These results suggest that the combinations of atropine plus 2-PAM or physostigmine are effective in the prevention of the lethal effects induced by DFP in A. salina larvae.

  11. Antioxidant and cholinesterases inhibitory activities of Verbascum xanthophoeniceum Griseb. and its phenylethanoid glycosides.

    Science.gov (United States)

    Georgiev, Milen; Alipieva, Kalina; Orhan, Ilkay; Abrashev, Radoslav; Denev, Petko; Angelova, Maria

    2011-09-01

    The members of Verbascum L. (Scrophulariaceae) are known to be rich in phenylethnoid glycosides, and among them Verbascum xanthophoeniceum is an endemic plant species for the Balkan region, Northwestern, and Southern Turkey. A scheme was developed for the isolation of the main active constituents that accumulate in plant aerial parts. The antioxidant activities of total methanol extracts, collected phenylethanoid glycosides fractions and specific active constituents (forsythoside B, verbascoside and leucosceptoside B) were then evaluated in 2,2'-diphenyl-1-picrylhydrazyl (DPPH·), oxygen radical absorbance capacity (ORACFL), hydroxyl radical averting capacity (HORACFL), ferric-reducing antioxidant power (FRAP), and superoxide anion (O2(-)) radical scavenging assays. In vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChe) inhibitory activities of abovementioned extracts, fractions and isolated pure compounds were also examined. Depending on the method used, forsythoside B, verbascoside and leucosceptoside B proved to be effective radical scavengers and cholinesterases inhibitors. On the basis of these findings it can be proposed that in addition to providing a potent source of antimicrobial and anti-inflammatory compounds, Verbascum plants could serve as attractive mines of powerful antioxidants for various purposes.

  12. Characterization of plasma cholinesterase from the White stork (Ciconia ciconia) and its in vitro inhibition by anticholinesterase pesticides.

    Science.gov (United States)

    Oropesa, Ana-Lourdes; Gravato, Carlos; Sánchez, Susana; Soler, Francisco

    2013-11-01

    Blood plasma cholinesterase (ChE) activity is a sensitive biomarker of exposure to organophosphorus (OP) and carbamate (CB) insecticides in vertebrates. Several studies indicate that more than one ChE form may be present in blood of birds. In this study the predominant ChE activity (acetylcholinesterase - AChE- or butyrylcholinesterase - BChE-), the range of ChE activity as well as ChE age-dependent changes in non-exposed individuals of White stork (Ciconia ciconia) have been established. The in vitro sensitivity of ChE to OP and CB insecticides such as paraoxon-methyl, carbofuran and carbaryl was also investigated. Plasma ChE was characterised using three substrates (acetylthiocholine iodide, propionylthiocholine iodide, and S-butyrylthiocholine iodide) and three ChE inhibitors (eserine sulphate, BW284C51 and iso-OMPA). The results indicated that propionylthiocholine was the preferred substrate by plasma cholinesterase followed by acetylcholine and butyrylcholine and the predominant enzymatic activity in plasma of White storks was BChE. Normal plasma BChE activity in White stork was 0.32±0.01μmol/min/ml for adults and 0.28±0.03μmol/min/ml for juveniles. So, the age had no significant effect on the range of BChE activity. The study on the in vitro inhibitory potential of tested anticholinesterase pesticides on plasma ChE activity revealed that paraoxon-methyl is the most potent inhibitor followed by carbofuran and finally by carbaryl. The percentage of in vitro plasma ChE inhibition was observed to be similar between adults and juveniles.

  13. Inhibition and recovery of maternal and fetal cholinesterase enzyme activity following a single cutaneous dose of methyl parathion and diazinon, alone and in combination, in pregnant rats.

    Science.gov (United States)

    Abu-Qare, A W; Abou-Donia, M B

    2001-01-01

    might be due to competition of diazinon with methyl parathion for cytochrome P-450 enzymes, resulting in formation of the potent cholinesterase inhibitor methyl paraoxon. The faster recovery of fetal cholinesterase enzymes is attributed to the rapid de novo synthesis of cholinesterase fetal tissues compared with the mother.

  14. Evaluation of flow injection analysis for determination of cholinesterase activities in biological material.

    Science.gov (United States)

    Cabal, Jiri; Bajgar, Jiri; Kassa, Jiri

    2010-09-06

    The method for automatic continual monitoring of acetylcholinesterase (AChE) activity in biological material is described. It is based on flexible system of plastic pipes mixing samples of biological material with reagents for enzyme determination; reaction product penetrates through the semipermeable membrane and it is spectrophotometrically determined (Ellman's method). It consists of sampling (either in vitro or in vivo), adding the substrate and flowing to dialyzer; reaction product (thiocholine) is dialyzed and mixed with 5,5'-dithio-bis-2-nitrobenzoic acid (DTNB) transported to flow spectrophotometer. Flowing of all materials is realised using peristaltic pump. The method was validated: time for optimal hydratation of the cellophane membrane; type of the membrane; type of dialyzer; conditions for optimal permeation of reaction components; optimization of substrate and DTNB concentrations (linear dependence); efficacy of peristaltic pump; calibration of analytes after permeation through the membrane; excluding of the blood permeation through the membrane. Some examples of the evaluation of the effects of AChE inhibitors are described. It was demonstrated very good uniformity of peaks representing the enzyme activity (good reproducibility); time dependence of AChE inhibition caused by VX in vitro in the rat blood allowing to determine the half life of inhibition and thus, bimolecular rate constants of inhibition; reactivation of inhibited AChE by some reactivators, and continual monitoring of the activity in the whole blood in vivo in intact and VX-intoxicated rats. The method is simple and not expensive, allowing automatic determination of AChE activity in discrete or continual samples in vitro or in vivo. It will be evaluated for further research of cholinesterase inhibitors.

  15. Cholinesterase activity of lamellated sensory corpuscles in the rat lip

    Directory of Open Access Journals (Sweden)

    II-Sei Watanabe

    1986-12-01

    Full Text Available Non-specific cholinesterase (ChE activity was demonstrated in lamellated sensory corpuscles of the rat lip by light and electron microscopy using Karnovsky and Root's method. ChE activity was present in the interlamellar spaces between neighbouring lamellae as well as in the periaxonal space between axon terminals and their adjacent lamellae. Reaction products of ChE activity were also deposited in some caveolae of the lamellar cell plasma membrane, and in the cisternae of the rough endoplasmic reticulum as well as in the nuclear envelope of lamellar cell bodies. No definite reaction products were detected within the axon terminals. These findings show that the lamellated corpuscles in the rat lip, like other mechanoreceptors, have an intense ChE activity which is mainly associated with lamellar cells. It can be said that ChE histochemistry is useful to detect mechanoreceptors. The functional significance of ChE in mechanoreceptors is discussed.

  16. [Study of the interaction of main potato glycoalkaloids in inhibition of immobilized butyryl cholinesterase].

    Science.gov (United States)

    Arkhypova, V M; Dziadevych, S V; Jaffrezic-Renault, N; Martelet, C; Soldatkin, O P

    2006-01-01

    The interaction of main potato glycoalkaloids alpha-solanine and alpha-chaconine in inhibition of horse serum butyryl cholinesterases immobilized on the pH-sensitive field-effect transistors has been investigated. The method of isobol diagram of Loewe and Muishnek has been used for interpretation of results. It has been shown the alpha-chaconine inhibits the immobilized bytyryl cholinesterases more strongly than alpha-solanine, and their mixture has the addition effect.

  17. International Meeting on Cholinesterases (5th) Held in Madras, India on 24-28 September, 1994.

    Science.gov (United States)

    1994-09-01

    Masson3. 1- Lab. d’entomologie, Universith Paul Sabatier, 118 route de Narbonne, 31062 Toulouse, France; 2- Lab. IMRCP, groupe de Chimie organique ...LABELING STUDIES ON CHOLINESTERASES. Maurice Goeldner. Laboratoire de Chimie Bio- Organique , URA 1386 CNRS, Facult6 de Pharmacie, Universitd Louis...CHOLINESTERASES. Isabelle Schalk, Christine Loeb, Florian Nachon, Laurence Ehret-Sabatier and Maurice Goeldner. Laboratoire de Chimie Bio- Organique - URA

  18. Cholinesterase inhibition modulates visual and attentional brain responses in Alzheimer's disease and health.

    Science.gov (United States)

    Bentley, Paul; Driver, Jon; Dolan, Ray J

    2008-02-01

    Visuo-attentional deficits occur early in Alzheimer's disease (AD) and are considered more responsive to pro-cholinergic therapy than characteristic memory disturbances. We hypothesised that neural responses in AD during visuo-attentional processing would be impaired relative to controls, yet partially susceptible to improvement with the cholinesterase inhibitor physostigmine. We studied 16 mild AD patients and 17 age-matched healthy controls, using fMRI-scanning to enable within-subject placebo-controlled comparisons of effects of physostigmine on stimulus- and attention- related brain activations, plus between-group comparisons for these. Subjects viewed face or building stimuli while performing a shallow judgement (colour of image) or a deep judgement (young/old age of depicted face or building). Behaviourally, AD subjects performed slower than controls in both tasks, while physostigmine benefited the patients for the more demanding age-judgement task. Stimulus-selective (face minus building, and vice versa) BOLD signals in precuneus and posterior parahippocampal cortex were attenuated in patients relative to controls, but increased following physostigmine. By contrast, face-selective responses in fusiform cortex were not impaired in AD and showed decreases following physostigmine for both groups. Task-dependent responses in right parietal and prefrontal cortices were diminished in AD but improved following physostigmine. A similar pattern of group and treatment effects was observed in two extrastriate cortical regions that showed physostigmine-induced enhancement of stimulus-selectivity for the deep versus shallow task. Finally, for the healthy group, physostigmine decreased stimulus and task-dependent effects, partly due to an exaggeration of selectivity during the shallow relative to deep task. The differences in brain activations between groups and treatments were not attributable merely to performance (reaction time) differences. Our results demonstrate

  19. Partial protection from organophosphate-induced cholinesterase inhibition by metyrapone treatment

    Directory of Open Access Journals (Sweden)

    Radosław Świercz

    2013-08-01

    Full Text Available Background: Organophosphates are cholinesterase (ChE inhibitors with worldwide use as insecticides. Stress response, evidenced by a dramatic and relatively long-lasting (several hours rise in the plasma glucocorticoid concentration is an integral element of the organophosphate (OP poisoning symptomatology. In rodents, corticosterone (CORT is the main glucocorticoid. There are several reports suggesting a relationship between the stressor-induced rise in CORT concentraion (the CORT response and the activity of the cerebral and peripheral ChE. Thus, it seems reasonable to presume that, in OP intoxication, the rise in plasma CORT concentration may somehow affect the magnitude of the OP-induced ChE inhibition. Metyrapone (MET [2-methyl-1,2-di(pyridin-3-ylpropan-1-one] blocks CORT synthesis by inhibiting steoid 11β-hydroxylase, thereby preventing the CORT response. Chlorfenvinphos (CVP [2-chloro-1-(2,4-dichlorophenyl ethenyl diethyl phosphate] is an organophosphate insecticide still in use in some countries. Material and Methods: The purose of the present work was to compare the CVP-induced effects - the rise of the plasma CORT concentration and the reduction in ChE activity - in MET-treated and MET-untreated rats. Chlorfenvinphos was administered once at 0.0, 0.5, 1.0 and 3.0 mg/kg i.p. Metyrapone, at 100 mg/kg i.p., was administered five times, at 24-h intervals. The first MET dose was given two hours before CVP. Conclusion: The following was observed in the MET-treated rats: i no rise in plasma CORT concentration after the CVP administration, ii a reduced inhibition and a faster restitution of blood and brain ChE activities. The results suggest that MET treatment may confer significant protection against at least some effects of OP poisoning. The likely mechanism of the protective MET action has been discussed.

  20. Brain cholinesterases: III. Future perspectives of AD research and clinical practice.

    Science.gov (United States)

    Shen, Z-X

    2004-01-01

    Alzheimer's disease (AD) is initially and primarily associated with the degeneration and alteration in the metabolism of cholinesterases (ChEs). The use of ChEs inhibitors to treat Alzheimer's condition, on the basis of the cholinergic hypothesis of the disease, is, therefore, without grounds. Most disturbing is the fact that the currently available anti-ChEs are designed to inhibit normal ChEs in the brain and throughout the body, but not the abnormal ones. Based on the acetylcholinesterase (AChE) deficiency theory, treatment should be designed to protect the cranial ChEs system from alteration and/or to help that system fight against degeneration through restoring its homeostatic action for brain structure and function instead. The overlap in the clinical, biochemical, molecular-cellular, and pathological alterations seen in patients with AD and individuals with many other brain disorders, which has bewildered many investigators, may now be explained by the shared underlying mismetabolism of brain ChEs. The abnormal metabolism of ChEs existing in asymptomatic subjects may indicate that the system is "at risk" and deserves serious attention. Future perspectives of ChEs research in vivo and in vitro in connection with AD and clinical diagnosis, prevention and treatment are proposed. Several potentially useful therapeutic and preventive means and pharmacological agents in this regard are identified and discussed, such as physical and intellectual stimulation, and a class of drugs including vitamin E, R-(-)-deprenyl (deprenyl, selegiline), acetyl L-carnitine, cytidine diphosphocholine (CDP-choline), centrophenoxine, L-phenylalanine, naloxone, galactose, and lithium, that have been proven to be able to stimulate AChE activity. Their working mechanisms may be through directly changing the configuration of AChE molecules and/or correcting micro- and overall environmental biological conditions for ChEs.

  1. [Interest of the cholinesterase assay during organophosphate poisonings].

    Science.gov (United States)

    Jalady, A-M; Dorandeu, F

    2013-12-01

    Cholinesterases are the main targets of organophosphorus compounds. The two enzymes present in the blood (butyrylcholinesterase, BChE; acetylcholinesterase, AChE) are biomarkers of their systemic toxicity. Activity of the plasma BChE is very often determined as it allows a rapid diagnostic of poisoning and is a marker of the persistence of the toxicant in the blood. The activity of the red blood cell AChE gives a better picture of the synaptic inhibition in the nervous system but the assay is less commonly available in routine laboratories. Better biomarker of the exposure, it allows a diagnosis of the severity of the poisoning and helps to assess the efficacy of oxime therapy. Besides the practical aspects of blood collection and sample processing, and the interpretation of the assays, this review stresses the complementarity of both enzyme assays and recalls their crucial interest for the confirmation of poisoning with an organophosphorus in a situation of war or terrorist attack and for the monitoring of occupational exposures.

  2. Behavioral changes and cholinesterase activity of rats acutely treated with propoxur.

    Science.gov (United States)

    Thiesen, F V; Barros, H M; Tannhauser, M; Tannhauser, S L

    1999-01-01

    Early assessment of neurological and behavioral effects is extremely valuable for early identification of intoxications because preventive measures can be taken against more severe or chronic toxic consequences. The time course of the effects of an oral dose of the anticholinesterase agent propoxur (8.3 mg/kg) was determined on behaviors displayed in the open-field and during an active avoidance task by rats and on blood and brain cholinesterase activity. Maximum inhibition of blood cholinesterase was observed within 30 min after administration of propoxur. The half-life of enzyme-activity recovery was estimated to be 208.6 min. Peak brain cholinesterase inhibition was also detected between 5 and 30 min of the pesticide administration, but the half-life for enzyme activity recovery was much shorter, in the range of 85 min. Within this same time interval of the enzyme effects, diminished motor and exploratory activities and decreased performance of animals in the active avoidance task were observed. Likewise, behavioral normalization after propoxur followed a time frame similar to that of brain cholinesterase. These data indicate that behavioral changes that occur during intoxication with low oral doses of propoxur may be dissociated from signs characteristic of cholinergic over-stimulation but accompany brain cholinesterase activity inhibition.

  3. Brain cholinesterase response in the snakehead fish (Channa striata) after field exposure to diazinon.

    Science.gov (United States)

    Nguyen, Van Cong; Nguyen, Thanh Phuong; Bayley, Mark

    2008-10-01

    The snakehead Channa striata is an economically important air-breathing fish species in the Mekong delta of Vietnam. Rice paddies, which are disturbed by the frequent application of agro-chemicals, are among the preferred habitats for this species during the rainy season. Diazinon is one of most commonly used chemicals in rice paddies. In the present study, exposure of adult snakehead fish to a single diazinon application in cages within a rice field resulted in long-term brain cholinesterase inhibition, while the water concentration of this insecticide fell below the detection limit within 3 days. In addition, incubation of brain homogenates with 2-PAM caused reactivation of the cholinesterase diazinon complex to within 80% of the control level. These experiments also showed that chemical ageing of the diazinon cholinesterase binding occurred, which may explain the long-term effects of this pesticide.

  4. Correlation between Cholinesterase and Paraoxonase 1 Activities: Case Series of Pesticide Poisoning Subjects

    Directory of Open Access Journals (Sweden)

    S Austin Richard

    2013-08-01

    Full Text Available Introduction: Acute exposure to pesticide due to suicidal poisoning is the most extensive cause of pesticide exposure, compared with all other causes including agricultural or industrial exposure. Organophosphate (OP and carbamate group of pesticides can inhibit acetylcholinesterase; on the other hand, paraoxonase1 can detoxify organophosphate poisoning by hydrolyzing organophosphate metabolites. Methods: We have compared the serum paraoxonase1 status and cholinesterase activity of subjects who attempted to commit suicide by consuming OP pesticide. Cholinesterase and paraoxonase1 activity were measured spectrophotometrically using butyrylthiocholine and phenyl acetate as substrates, respectively. Results: A positive correlation was found between serum paraoxonase1 activity and cholinesterase activity among pesticide consumed subjects. Conclusion: Our results suggest that subjects with higher paraoxonase1 activity may have a better chance of detoxifying the lethal effect of acute organophosphate poisoning.

  5. Serum Acetyl Cholinesterase as a Biomarker of Arsenic Induced Neurotoxicity in Sprague-Dawley Rats

    Directory of Open Access Journals (Sweden)

    Paul B. Tchounwou

    2005-04-01

    Full Text Available Arsenic is an environmental toxicant, and one of the major mechanisms by which it exerts its toxic effect is through an impairment of cellular respiration by inhibition of various mitochondrial enzymes, and the uncoupling of oxidative phosphorylation. Most toxicity of arsenic results from its ability to interact with sulfhydryl groups of proteins and enzymes, and to substitute phosphorus in a variety of biochemical reactions. Most toxicity of arsenic results from its ability to interact with sulfhydryl groups of proteins and enzymes, and to substitute phosphorus in a variety of biochemical reactions. Recent studies have pointed out that arsenic toxicity is associated with the formation of reactive oxygen species, which may cause severe injury/damage to the nervous system. The main objective of this study was to conduct biochemical analysis to determine the effect of arsenic trioxide on the activity of acetyl cholinesterase; a critical important nervous system enzyme that hydrolyzes the neurotransmitter acetylcholine. Four groups of six male rats each weighing an average 60 + 2 g were used in this study. Arsenic trioxide was intraperitoneally administered to the rats at the doses of 5, 10, 15, 20mg/kg body weight (BW, one dose per 24 hour given for five days. A control group was also made of 6 animals injected with distilled water without chemical. Following anaesthesia, blood specimens were immediately collected using heparinized syringes, and acetyl cholinesterase detection and quantification were performed in serum samples by spectrophotometry. Arsenic trioxide exposure significantly decreased the activity of cholinesterase in the Sprague-Dawley rats. Acetyl cholinesterase activities of 6895 + 822, 5697 + 468, 5069 + 624, 4054 + 980, and 3158 + 648 U/L were recorded for 0, 5, 10, 15, and 20 mg/kg, respectively; indicating a gradual decrease in acetyl cholinesterase activity with increasing doses of arsenic. These findings indicate that acetyl

  6. In-vitro Evaluation and Molecular Docking Studies of Some Schiff Bases as Cholinesterase Inhibitor

    Directory of Open Access Journals (Sweden)

    Saurabh Kumar Sinha

    2015-09-01

    Full Text Available Some new Schiff bases of 4-aminopyridine were synthesized and evaluated for antiamnesic and cognition enhancing activity. In the current study to further understand the mechanism of action of these derivatives we have evaluated in-vitro acetycholinesterase (AChE and butyrylcholinesterase (BChE inhibitory activity. Enzyme kinetics and docking studies were performed for all compounds to observe their nature of inhibition. The IC50 value of synthesized compounds showed maximum activity of compound 4APg compared to standard drug donepezil and rivastigmine whereas its kinetic analysis of enzyme inhibition demonstrated non-competitive inhibition for both enzymes AChE and BChE. The docking study confirmed their consensual interaction with AChE and BChE active sites justifying the experimental outcome.

  7. In-vitro Evaluation and Molecular Docking Studies of Some Schiff Bases as Cholinesterase Inhibitor

    OpenAIRE

    2015-01-01

    Some new Schiff bases of 4-aminopyridine were synthesized and evaluated for antiamnesic and cognition enhancing activity. In the current study to further understand the mechanism of action of these derivatives we have evaluated in-vitro acetycholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity. Enzyme kinetics and docking studies were performed for all compounds to observe their nature of inhibition. The IC50 value of synthesized compounds showed maximum activity of comp...

  8. Molecular Cloning of Human Gene(s) Directing the Synthesis of Nervous System Cholinesterases

    Science.gov (United States)

    1987-09-01

    Report No. 4 If MOLECULAR CLONING OF O HUMAN GENE(S) DIRECTING qTHE SYNTHESIS OF NERVOUS SYSTEM CHOLINESTERASES cc Annual/Final Report 0 N November...62734A I734A875 IAl 451 MOLECULAR CLONING OF HUMAN GEME(S) DIRECTING THE SYNTHESIS OF NERVOUS SYSTEM CHOLINESTERASE 12. PERSONAL AUTHOR(S) Hermona Soreq...important roles in regulating the pace and mode of function of particular types of synapses. For example, molecular cloning of the nicotinic (44-46) and the

  9. [Change of cholinesterase relative activity under modulated ultra high frequency electromagnetic radiation in experiments in vitro].

    Science.gov (United States)

    Pashovkina, M S; Pashovkin, T N

    2011-01-01

    Changes in the activity of enzyme cholinesterase (ChE) have been experimentally investigated under the influence of amplitude-modulated super-high-frequency electromagnetic radiation (carrier frequency of 2.375 MHz; power flux density of 8 mW/cm2, 20 mW/cm2 and 50 mW/cm2; modulation frequency range 10 to 210 Hz; exposure time 5 min). The appearance of peaks of the cholinesterase increased relative activity, as well as the changes in the direction and intensity of the reaction associated with the modulation frequency and power flux are observed at equal power flux densities and exposure times.

  10. Crystal Structure of the Extracellular Cholinesterase-Like Domain from Neuroligin-2

    Energy Technology Data Exchange (ETDEWEB)

    Koehnke,J.; Jin, X.; Budreck, E.; Posy, S.; Scheiffele, P.; Hnoig, B.; Shapiro, L.

    2008-01-01

    Neuroligins (NLs) are catalytically inactive members of a family of cholinesterase-like transmembrane proteins that mediate cell adhesion at neuronal synapses. Postsynaptic neuroligins engage in Ca2+-dependent transsynaptic interactions via their extracellular cholinesterase domain with presynaptic neurexins (NRXs). These interactions may be regulated by two short splice insertions (termed A and B) in the NL cholinesterase domain. Here, we present the 3.3- Angstroms crystal structure of the ectodomain from NL2 containing splice insertion A (NL2A). The overall structure of NL2A resembles that of cholinesterases, but several structural features are unique to the NL proteins. First, structural elements surrounding the esterase active-site region differ significantly between active esterases and NL2A. On the opposite surface of the NL2A molecule, the positions of the A and B splice insertions identify a candidate NRX interaction site of the NL protein. Finally, sequence comparisons of NL isoforms allow for mapping the location of residues of previously identified mutations in NL3 and NL4 found in patients with autism spectrum disorders. Overall, the NL2 structure promises to provide a valuable model for dissecting NL isoform- and synapse-specific functions.

  11. Regional cholinesterase activity in white-throated sparrow brain is differentially affected by acephate (Orthene?)

    Science.gov (United States)

    Vyas, N.B.; Kuenzel, W.J.; Hill, E.F.; Romo, G.A.; Komaragiri, M.V.S.

    1996-01-01

    Effects of a 14-day dietary exposure to an organophosphorus pesticide, acephate (acetylphosphoramidothioic acid O,S-dimethyl ester), were determined on cholinesterase activity in three regions (basal ganglia, hippocampus, and hypothalamus) of the white-throated sparrow, Zonotrichia albicollis, brain. All three regions experienced depressed cholinesterase activity between 0.5-2 ppm acephate. The regions exhibited cholinesterase recovery at 2-16 ppm acephate; however, cholinesterase activity dropped and showed no recovery at higher dietary levels (>16 ppm acephate). Evidence indicates that the recovery is initiated by the magnitude of depression, not the duration. In general, as acephate concentration increased, differences in ChE activity among brain regions decreased. Three terms are introduced to describe ChE response to acephate exposure: (1) ChE resistance threshold, (2) ChE compensation threshold, and (3) ChE depression threshold. It is hypothesized that adverse effects to birds in the field may occur at pesticide exposure levels customarily considered negligible.

  12. Design and Synthesis of Bifunctional Oxime Reactivators of OP- inhibited Cholinesterase

    Science.gov (United States)

    2013-08-01

    military and civilian personnel. Reactivators of OP inhibited cholinesterases can serve as OP agent antidotes but can be limited by their poor...assisted bifunctional catalytic mechanism 46 O N O N OH 11 REPORTABLE OUTCOMES: None CONCLUSION: We have successfully evaluated the synthetic

  13. RBC acetyl cholinesterase: A poor man′s early diagnostic biomarker for familial alzheimer′s and Parkinson′s disease dementia

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    Himmatrao Saluba Bawaskar

    2015-01-01

    Full Text Available Objective: Analysis of red blood cell acetyl cholinesterase (AChE in a familial Alzheimer′s diseases (AD Parkinson′s disease dementia (PDD and their first generation. Setting: General hospital, Mahad district, Raigad. Patients and Methods: Clinically diagnosed patients of AD and PDD and their asymptomatic relatives. Their blood was collected in EDTA tube and transferred to laboratory at Mumbai. Result: Median red blood cell (RBC cholinesterase levels amongst PDD, their first generation asymptomatic relatives, familial AD, asymptomatic relatives of AD, healthy controls, farmers exposed to pesticides (positive control and other neurological condition without dementia (hypertension with TIA 1, sub-dural hematoma 2, hypothyroid 1, non-familial unilateral parkinsonism without dementia 3, writers cramps 2, hyponitremia 1 and cerebral palsy with non-fluent aphasia 1. Median values of RBC AChE were 19086.78 U/L, 15666.05 U/L, 9013.11 U/L, 7806.19 U/L, 14334.57 U/L, 9785.05 U/L and 13162.60 U/L, respectively. As compared to controls, RBC AChE levels were statistically significant among PDD (P = 0.004 and significantly lowered among familial AD patients (P = 0.010, relatives of patients (P = 0.010. Interpretations: Below the normal RBC AChE level is a potential biomarker in asymptomatic relatives of familial AD patients. RBC AChE is raised than normal level in patients suffering from PDD, where AChE inhibitors are helpful. However, RBC AChE level below the normal where AChE inhibitor may not be effective.

  14. [Ligands of cholinesterases of ephedrine and pseudoephedrine structure].

    Science.gov (United States)

    Basova, N E; Kormilitsin, B N; Perchenok, A Yu; Rozengatt, E V; Saakov, V S; Suvorov, A A

    2013-01-01

    The paper is a review of literature data on interaction of the mammalian erythrocyte acetylcholinesterase and blood serum butyrylcholinesterase with a group of isomer complex ester derivatives (acetates, propionates, butyrates, valerates, and isobutyrates) of bases and iodomethylates of ephedrine and its enantiomer pseudoephedrine. For 20 alkaloid monoesters, parameters of enzymatic hydrolysis are determined and their certain specificity toward acetylcholinesterase is revealed, whereas 5 diesters of iodomethylates of pseudoephedrine were hydrolyzed only by butyrylcholinesterase. The studied 20 aklaloid diesters and 10 trimethylammonium derivatives turned out to be non-competitive reversible inhibitors of acetylcholinesterase and competitive inhibitors of butyrylcholinesterase. The performed for the first time isomer and enantiomer analysis "structure-efficiency" has shown that in most cases it is possible to state the greater comlementarity of the catalytical surface of enzymes for ligands of the pseudoephedrine structure, such differentiation being realized more often at the reversible inhibition of enzymes. pseudoephedrine.

  15. PREDICTING OUTCOME AND SEVERITY IN ACUTE ORGANOPHOSPHOROUS POISONING WITH CLINICAL SCORING AND SERUM CHOLINESTERASE LEVELS

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    Basavaraj R

    2014-11-01

    Full Text Available BACKGROUND AND OBJECTIVES: Organophosphorus compound poisoning is the most common medico toxic emergency in India the increase in pesticide use in agriculture has paralleled the increase in the use of these products for deliberate self-warm. Respiratory failure is the most common complication of OP poisoning leading to death. Early recognition and prompt ventilator support may improve survival. Owing to limited availability of resources, all OP poisoning patients are not managed in ICUs in Indian setup. It is therefore important that clinical features and criteria to predict the need for ventilator support be identified at initial examination. Hence this study was undertaken to assess the severity of organophosphorus compound poisoning both clinically by using Peradeniya scoring and by estimating serum choline esterase levels. METHODS: Cross sectional study was done at basaveswar teaching and general hospital attached to MR Medical College. Cases with history of exposure to organophosphorus compound within previous 24 hours were chosen after applying inclusion and exclusion criteria. Patients were evaluated for Peradeniya OP poisoning scale and serum cholinesterase levels for assessment of severity of poisoning. Serum cholinesterase levels and Peradeniya OP poisoning scale were studied to predict the need for ventilator support. The results were analyzed using Chi-square test. STATISTICAL ANALYSIS: It was done using pearson’s chi square test. RESULTS: In this study requirement of ventilator support was seen in 36% of patients. Mortality in our study was 18%. Only 15.6% of patients with mild grade of poisoning according to Peradeniya OP poisoning scale required ventilator support, whereas 84.4% did not require ventilator support. Most of patients with moderate (70.6% and severe poisoning (100% according to Peradeniya OP poisoning scale required ventilator support. 93.7% of patients with serum cholinesterase levels more than 50% did not require

  16. The use of cholinergic biomarker, cholinesterase activity of blue mussel Mytilus edulis to detect the effects of organophosphorous pesticides

    OpenAIRE

    Yaqin, Khusnul

    2007-01-01

    The aim of the study was to investigate the effects of organophosphorous pesticide on the cholinesterase activity of different organs of Mytilus edulis. The mussels were exposed to serial dilutions of the pesticides (0, 50, 100, 200, 500, and 1000 ??g/l) for 96 h. A significant inhibition of the cholinesterase activity from gill occurred at the lowest concentration, which indicated that gill was the most sensitive organ. The moderate sensitive organs were foot and mantle, which we...

  17. Pesticide use and cholinesterase inhibition in small-scale agricultural workers in southern Brazil

    Directory of Open Access Journals (Sweden)

    Samuel Botião Nerilo

    2014-12-01

    Full Text Available A controlled cross-sectional study of family growers of fruit and vegetables was conducted between October 2009 and October 2010 to characterize the use of pesticides, establish the socio-demographic profile, and analyze cholinesterase activity in small-scale agricultural workers in Southern Brazil. Data was collected for 173 workers and 179 controls. A structured questionnaire was applied collecting socio-demographic information and determining knowledge and work practices in relation to pesticide use. The benchmarks for total cholinesterase (ChEs and butyrylcholinesterase (BuChE were obtained from the average enzymatic activity of the occupationally unexposed group (control. The mean age of the exposed population was 40.0 ± 11.2 years. The symptoms differed significantly (p30% of ChEs activity, whereas no workers showed high inhibition (>50% of BuChE. Potential factors involved include gender, education, pesticide orientation, exposure, and hygiene measures.

  18. Serum and Plasma Cholinesterase Activity in the Cape Griffon Vulture (Gyps coprotheres).

    Science.gov (United States)

    Naidoo, Vinny; Wolter, Kerri

    2016-04-28

    Vulture (Accipitridae) poisonings are a concern in South Africa, with hundreds of birds dying annually. Although some of these poisonings are accidental, there has been an increase in the number of intentional baiting of poached rhinoceros (Rhinocerotidae) and elephant (Elephantidae) carcasses to kill vultures that alert officials to poaching sites by circling overhead. The primary chemicals implicated are the organophosphorous and carbamate compounds. Although most poisoning events can be identified by dead vultures surrounding the scavenged carcass, weak birds are occasionally found and brought to rehabilitation centers for treatment. The treating veterinarian needs to make an informed decision on the cause of illness or poisoning prior to treatment. We established the reference interval for serum and plasma cholinesterase activity in the Cape Griffon Vulture ( Gyps coprotheres ) as 591.58-1,528.26 U/L, providing a clinical assay for determining potential exposure to cholinesterase-depressing pesticides. Both manual and automated samplers were used with the butyrylthiocholine method. Species reference intervals for both serum and plasma cholinesterase showed good correlation and manual and automated measurements yielded similar results.

  19. Determination of cholinesterase levels of the employees working at the pharmaceutical sector and the patients suspected of being poisoned

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    Serdar Alp Suba��ı

    2013-03-01

    Full Text Available OBJECTIVE: The purpose of this work is measure tests using butyrylthiocholine as a substract and get the spectrofotometric results for dispersion level of Cholinesterase in people who is working in the pharmaceutical and agriculture sector, were chronicly affected bypesticide or patiences who are suspected to be poisoned by pesticide, who applied for the Consumer Safety Health Effects Research Laboratories RSHMB biological material lab, Ankara during the period 2008-2010.METHODS: The blood samples were analyzed by the biological materials laboratory. The plasmas Cholinesterase levels were measured with the kits Cholinesterase, butyrylthiocholine kinetic, Spınreact between 01.01.2008 - 17.07.2010; after 17.07.2010 Cholinesterase, butyrylthiocholine substrate, (Quimica clinica aplıcada S.A. The plazmas were seperated from the blood samples and preoperate on them with the spectrofotometric methods under the room temperature of 405nm and Cholinesterase, levels measured by quantitative analysed methodRESULTS: Evidence: In this research 1136 people whose Cholinesterase levels tested; applied to our center because of pestisit toxication. 367 (32,3 % were the ones who works for the pharmaceutical sector and intended to be under control, 769 (67,7% were the ones prediagnoised as poisoned. It has been detected that 222 (28,9% of them were in safe serum Cholinesterase measurement range. 119 (53,6 % of these people were women and majority of them 56 (25,2 % is in 10-19 age group. 347 (94,6 % people who is working either in the pharmaceutical or agriculture sector were in normal range and just 20 (5,4 % of them were in the toxicty range. The intoxicated workers were in the age group of 30-39.CONCLUSION: The Cholinesterase level of the persons, who sprayed or werepoisoned by insecticide containing organophosphate, is of utmost importance.In our research 547 patiente (71,1 % and 347 workers (94,6% were in normal range of cholinesterase level. This results

  20. Synthesis and cholinesterase inhibition of cativic acid derivatives.

    Science.gov (United States)

    Alza, Natalia P; Richmond, Victoria; Baier, Carlos J; Freire, Eleonora; Baggio, Ricardo; Murray, Ana Paula

    2014-08-01

    Alzheimer's disease (AD) is a neurodegenerative disorder associated with memory impairment and cognitive deficit. Most of the drugs currently available for the treatment of AD are acetylcholinesterase (AChE) inhibitors. In a preliminary study, significant AChE inhibition was observed for the ethanolic extract of Grindelia ventanensis (IC₅₀=0.79 mg/mL). This result prompted us to isolate the active constituent, a normal labdane diterpenoid identified as 17-hydroxycativic acid (1), through a bioassay guided fractionation. Taking into account that 1 showed moderate inhibition of AChE (IC₅₀=21.1 μM), selectivity over butyrylcholinesterase (BChE) (IC₅₀=171.1 μM) and that it was easily obtained from the plant extract in a very good yield (0.15% w/w), we decided to prepare semisynthetic derivatives of this natural diterpenoid through simple structural modifications. A set of twenty new cativic acid derivatives (3-6) was prepared from 1 through transformations on the carboxylic group at C-15, introducing a C2-C6 linker and a tertiary amine group. They were tested for their inhibitory activity against AChE and BChE and some structure-activity relationships were outlined. The most active derivative was compound 3c, with an IC₅₀ value of 3.2 μM for AChE. Enzyme kinetic studies and docking modeling revealed that this inhibitor targeted both the catalytic active site and the peripheral anionic site of this enzyme. Furthermore, 3c showed significant inhibition of AChE activity in SH-SY5Y human neuroblastoma cells, and was non-cytotoxic.

  1. Acetylcholine muscarinic receptors and response to anti-cholinesterase therapy in patients with Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Brown, Derek [Department of Psychiatry, Stobhill Hospital, Glasgow (United Kingdom); Chisholm, Jennifer A.; Patterson, Jim; Wyper, David [Department of Clinical Physics, Southern General Hospital, Glasgow, G51 4TF (United Kingdom); Owens, Jonathan; Pimlott, Sally [Department of Clinical Physics, Western Infirmary, Glasgow (United Kingdom)

    2003-02-01

    An acetylcholine deficit remains the most consistent neurotransmitter abnormality found in Alzheimer's disease and various therapeutic agents have been targeted at this. In this study we investigated the action of Donepezil, a cholinesterase inhibitor that has few side-effects. In particular we set out to investigate whether muscarinic acetylcholine receptor (mAChR) availability influences the response to this therapy. We used the novel single-photon emission tomography (SPET) tracer (R,R)[{sup 123}I]I-quinuclidinyl benzilate (R,R[{sup 123}I]I-QNB), which has high affinity for the M1 subtype of mAChR. Regional cerebral perfusion was also assessed using technetium-99m hexamethylpropylene amine oxime. We investigated 20 patients on Donepezil treatment and ten age-matched controls. The results showed a reduction in (R,R)[{sup 123}I]I-QNB binding in the caudal anterior cingulate in patients compared with controls and relatively high binding in the putamen and rostral anterior cingulate, suggesting a relative sparing of mAChR in these regions. The main finding of the study was that mAChR availability as assessed by (R,R)[{sup 123}I]I-QNB binding did not distinguish responders from non-responders. Interestingly, we found that the extent of cognitive improvement showed no positive correlation with (R,R)[{sup 123}I]I-QNB binding in any brain region but was inversely related to binding in the insular cortex. This suggests that, within the advised cognitive performance band for use of Donepezil, response is greater in those patients with evidence of a more marked cholinergic deficit. A larger study should investigate this. (orig.)

  2. Characterisation of cholinesterases and evaluation of the inhibitory potential of chlorpyrifos and dichlorvos to Artemia salina and Artemia parthenogenetica.

    Science.gov (United States)

    Varó, I; Navarro, J C; Amat, F; Guilhermino, L

    2002-08-01

    In this study, the acute toxicity of the organophosphorous pesticides dichlorvos and chlorpyrifos to two different species of Artemia (A. salina and A. parthenogenetica) was evaluated. In addition, the in vivo effect of these two pesticides on cholinesterase (ChE) activity of both A. salina and A. parthenogenetica was also determined. The characterisation of the ChE, using different substrates and specific inhibitors, and the normal range of activity in non-exposed individuals were previously investigated for both species. The results obtained indicate that the ChE of A. salina is different from that of A. parthenogenetica and that both enzymes cannot be classified neither as acetylcholinesterase nor as butyrylcholinesterase since they show intermediary characteristics between the two vertebrate forms. The range of normal ChE activity was 2.65+/-0.15 U/mg protein for A. salina, and 3.69+/-0.17 U/mg protein for A. parthenogenetica. Significant in vivo effects of both pesticides on Artemia ChE activity were found, at concentrations between 5.38 and 9.30 mg/l for dichlorvos and between 1.85 and 3.19 mg/l for chlorpyrifos. Both Artemia species are resistant to these pesticides and they are able to survive with more than 80% ChE inhibition. However, A. parthenogenetica is more resistant than A. salina, with about a 95% reduction in its ChE activity respect to the control for nauplii exposed to the median lethal concentrations (LC50), without lethal effects after 24 h of exposure.

  3. An unexpected plasma cholinesterase activity rebound after challenge with a high dose of the nerve agent VX.

    Science.gov (United States)

    Dorandeu, F; Foquin, A; Briot, R; Delacour, C; Denis, J; Alonso, A; Froment, M T; Renault, F; Lallement, G; Masson, P

    2008-06-27

    Organophosphorus chemical warfare agents (nerve agents) are to be feared in military operations as well as in terrorist attacks. Among them, VX (O-ethyl-S-[2-(diisopropylamino)ethyl] methylphosphonothioate) is a low volatility liquid that represents a percutaneous as well as an inhalation hazard if aerosolized. It is a potent irreversible cholinesterase (ChE) inhibitor that causes severe signs and symptoms, including respiratory dysfunction that stems from different mechanisms. VX-induced pulmonary oedema was previously reported in dogs but mechanisms involved are not well understood, and its clinical significance remains to be assessed. An experimental model was thus developed to study VX-induced cardiovascular changes and pulmonary oedema in isoflurane-anaesthetized swine. In the course of this study, we observed a fast and unexpected rebound of plasma ChE activity following inhibition provoked by the intravenous injection of 6 and 12 microg kg(-1) of VX. In whole blood ChE activity, the rebound could stay unnoticed. Further investigations showed that the rebound of plasma esterase activity was neither related to spontaneous reactivation of ChE nor to VX-induced increase in paraoxonase/carboxylesterase activities. A bias in Ellman assay, haemoconcentration or severe liver cytolysis were also ruled out. All in all, these results suggest that the rebound was likely due to the release of butyrylcholinesterase into the blood stream from ChE producing organs. Nature of the organ(s) and mechanisms involved in enzyme release will need further investigations as it may represent a mechanism of defence, i.e. VX scavenging, that could advantageously be exploited.

  4. Cholinesterase-inhibiting and genotoxic effects of acute carbofuran intoxication in man: a case report.

    Science.gov (United States)

    Zeljezic, Davor; Vrdoljak, Ana Lucic; Kopjar, Nevenka; Radic, Bozica; Milkovic Kraus, Sanja

    2008-10-01

    Carbofuran belongs to the group of N-methylcarbamate insecticides used for the control of soil-dwelling and foliar-feeding insects in various crops; its consumption totals approximately 20,000 tonnes per year. Although the neurological effects on human beings have been well documented, little is known on its impact on the genome. A 38-year-old, healthy male worker employed in a carbofuran production facility accidentally inhaled the dust of the active ingredient carbofuran. Thirty minutes later, he experienced weakness, fatigue, perspiration, breathing difficulties, cephalalgia, disorientation, abdominal pain and vomiting. Blood samples were taken to measure cholinesterase activity, and to perform the alkaline comet assay and micronucleus assay combined with pancentromeric probes. Analyses were repeated 72 hr after intoxication and compared with the results obtained from regular monitoring conducted 10 days prior to the accident. Cholinesterase activity showed the highest correlation with the number of apoptotic cells, comet assay tail length, and number of long-tailed nuclei, suggesting that these are the genomic end-points primarily affected by carbofuran intake. Only a weak correlation was detected for the total number of micronuclei, centromere-containing micronuclei and nuclear buds. Since those end-points increased significantly 72 hr after the accident, they could be considered as late biomarkers of the effects of carbofuran intoxication. The results of this report suggest that, in the interests of higher standards in risk assessment and health hazard protection, periodical medical examination of carbamate-exposed populations should include genotoxicity testing in addition to the assessment of cholinesterase activity.

  5. Cholinesterase Activity in Health Workers Involved in Handling and Spraying of Organophosphorous Insecticides

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    Himanshu Madaan

    2011-04-01

    Full Text Available Background: Recent era of agricultural boon is partially the result of extensive use of insecticides and pesticides. But these compounds also have potential to significantly alter the ecosystem and can cause acute poisonings as well as long term detrimental health effects in humans. These compounds can cause toxicity through all routes of exposure. They exert their effect mainly by the inhibition of Acetylcholinesterase (AC hE, which functions by removing acetylcholine (AC h from its postsynaptic receptors. Aims and Objectives: Human exposure to Organophosphorous (OP pesticides can develop lowered cholinesterase levels. The aim of the present study was to estimate the plasma levels of AC hE in personnel involved in handling of these compounds, during the period of active spraying operations. Methodology: The present study was conducted on 38 subjects working as Multipurpose Health Workers (MPHW GROUP-1 and Field Workers (FW GROUP-2 involved in the actual spraying of the insecticides, in District Rohtak, Haryana, India to see the effect of exposure to OP insecticides. Plasma cholinesterase activity was measured by a kinetic method based on hydrolysis of butrylthiocholine. The data was statistically analyzed using SPSS statistical package (SPSS version 5.0. Results and interpretation: The mean cholinesterase activity in group-2 was lower by 27.76% than that in group-1 and this difference was statistically significant (p < 0.05. The workers involved in actual spraying of the insecticides had a more marked reduction in the levels of Plasma AC hE, compared to the workers involved only in the handling of the insecticides indicating that this group is at a bigger risk.

  6. Cholinesterase inhibition of birds inhabiting wheat fields treated with methyl parathion and toxaphene

    Science.gov (United States)

    Niethammer, K.R.; Baskett, T.S.

    1983-01-01

    Red-winged blackbirds (Agelaius phoeniceus) and dickcissels (Spiza americana) inhabiting wheat fields treated with 0.67 kg AI/ha methyl parathion and 1.35 kg AI/ha toxaphene showed brain cholinesterase (ChE) inhibition compared with birds inhabiting untreated fields. Maximum inhibition occurred about five days after insecticide application. ChE activities again approached normal 10 days after treatment. ChE inhibition for dickcissels and red-winged blackbirds differed significantly (p<0.05); maximum inhibition for the former species was 74%, and for the latter, 40%. These differences could not be explained by the diets of the two species, as they were similar.

  7. Radiometric assay of red cell and plasma cholinesterase in pesticide appliers from Minnesota.

    Science.gov (United States)

    Potter, W T; Garry, V F; Kelly, J T; Tarone, R; Griffith, J; Nelson, R L

    1993-03-01

    In this study we demonstrate the uses of radiometric assay to detect anticholinesterases in a human population (N = 80) exposed to a broad spectrum of pesticides. The assay is nondilutional. Therefore, anticholinesterase (AChE) agents with low binding affinity can be detected. Our initial results show statistically significant exposure-related decreases in either red cell (AChE) or plasma cholinesterase activity ((butyrl)cholinesterase; BuChE) occurred not only among pesticide appliers who use organophosphates, but also among appliers of the fumigant phosphine. These data extend earlier observations made in laboratory animals exposed to this fumigant. Significant exposure-related decreases in AChE activity were seen in herbicide appliers and appear to be associated with exposure to the herbicide 2-methoxy-3,6-dichlorobenzoic acid. There was no evidence of exposure-related decreases in BuChE activity in herbicide appliers. Our in vivo data, coupled with preliminary in vitro studies of phosphine (50% AChE inhibition, 10 ppm) and 2-methoxy-3,6-chlorobenzoic acid (50% AChE and BuChE inhibition, 70 ppm), suggest that the radiometric assay may be used to detect a broader spectrum of biologically active anticholinesterase agents.

  8. Use of cholinesterase activity in monitoring organophosphate pesticide exposure of cattle produced in tropical areas.

    Science.gov (United States)

    Pardío, V T; Ibarra, N; Rodríguez, M A; Waliszewski, K N

    2001-12-01

    The use of cholinesterase activity as a biochemical method for monitoring organophosphate pesticide exposure in cattle is described herein. Determination of cholinesterase activity of whole blood, erythrocyte, and plasma was carried out according to the Ellman modified kinetic method. The mean baseline acetylcholinesterase activities of 9.549 +/- 3.619 IU/mL in whole blood, 9.444 +/- 3.006 IU/mL in erythrocytes, and 0.149 +/- 0.063 IU/mL in plasma were estimated for steers from the control group. Results of multivariate analysis showed that the general responses between the control and experimental groups (in vivo, monitoring and case studies) treated with Coumaphos and Fenthion were statistically different, and the general responses of these experimental groups were statistically different over time as well. Among the fractions that were analyzed, the erythrocyte acetylcholinesterase activity could be adequate for the diagnosis of exposure or acute poisoning in cattle as it showed a good within-run and between-run precision with CVs <10% better than those in plasma.

  9. 7-Methoxytacrine-p-Anisidine Hybrids as Novel Dual Binding Site Acetylcholinesterase Inhibitors for Alzheimer’s Disease Treatment

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    Jan Korabecny

    2015-12-01

    Full Text Available Alzheimer’s disease (AD is a debilitating progressive neurodegenerative disorder that ultimately leads to the patient’s death. Despite the fact that novel pharmacological approaches endeavoring to block the neurodegenerative process are still emerging, none of them have reached use in clinical practice yet. Thus, palliative treatment represented by acetylcholinesterase inhibitors (AChEIs and memantine are still the only therapeutics used. Following the multi-target directed ligands (MTDLs strategy, herein we describe the synthesis, biological evaluation and docking studies for novel 7-methoxytacrine-p-anisidine hybrids designed to purposely target both cholinesterases and the amyloid cascade. Indeed, the novel derivatives proved to be effective non-specific cholinesterase inhibitors showing non-competitive AChE inhibition patterns. This compounds’ behavior was confirmed in the subsequent molecular modeling studies.

  10. TIME COURSE OF CHOLINESTERASE INHIBITION IN ADULT RATS TREATED ACUTELY WITH CARBARYL CARBOFURAN, FORMETANATE, METHOMYL, METHIOCARB, OXAMYL ON PROPOXUR.

    Science.gov (United States)

    To compare the toxicity of seven N-methyl carbamates, time course profiles for brain and red blood cell (RBC) cholinesterase (ChE) inhibition were established for each. Adult, male, Long Evans rats (n=4-5 dose group) were dosed orally with either carbaryl (30 mg/kg in corn oil); ...

  11. INHIBITION OF BRAIN CHOLINESTERASE AND THE PHOTIC AFTER DISCHARGE OF FLASH EVOKED POTENTIALS PRODUCED BY CARBARYL IN LONG EVANS RATS.

    Science.gov (United States)

    Carbaryl is a widely used N-methyl carbamate pesticide that acts by inhibiting cholinesterases (ChE), which may lead to cholinergic toxicity. Flash evoked potentials (FEPs) are a neurophysiological response often used to detect central nervous system (CNS) changes following expos...

  12. New Acetylcholinesterase Inhibitors for Alzheimer's Disease

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    Mona Mehta

    2012-01-01

    Full Text Available Acetylcholinesterase (AChE remains a highly viable target for the symptomatic improvement in Alzheimer's disease (AD because cholinergic deficit is a consistent and early finding in AD. The treatment approach of inhibiting peripheral AchE for myasthenia gravis had effectively proven that AchE inhibition was a reachable therapeutic target. Subsequently tacrine, donepezil, rivastigmine, and galantamine were developed and approved for the symptomatic treatment of AD. Since then, multiple cholinesterase inhibitors (ChEI continue to be developed. These include newer ChEIs, naturally derived ChEIs, hybrids, and synthetic analogues. In this paper, we summarize the different types of ChEIs in development and their respective mechanisms of actions. This pharmacological approach continues to be active with many promising compounds.

  13. Cholinesterase as inflammatory markers in a experimental infection by Trypanosoma evansi in rabbits

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    Márcio M. Costa

    2012-12-01

    Full Text Available The aim of this study is to evaluate the role of cholinesterases as an inflammatory marker in acute and chronic infection by Trypanosoma evansi in rabbits experimentally infected. Twelve adult female New Zealand rabbits were used and divided into two groups with 6 animals each: control group (rabbits 1-6 and infected group (rabbits 7-12. Infected group received intraperitoneally 0.5 mL of blood from a rat containing 108 parasites per animal. Blood samples used for cholinesterases evaluation were collected on days 0, 2, 7, 12, 27, 42, 57, 87, 102 and 118 days post-inoculation (PI. Increased activity (P0.05 was observed in the encephalic structures. The increased activities of AChE and BChE probably have a pro-inflammatory purpose, attempting to reduce the concentration of acetylcholine, a neurotransmitter which has an anti-inflammatory property. Therefore, cholinesterase may be inflammatory markers in infection with T. evansi in rabbits.O objetivo do presente estudo é avaliar o papel das colinesterases como marcadores inflamatórios nas fases aguda e crônica da infecção por T. evansi em coelhos infectados experimentalmente. Foram utilizados 12 coelhos adultos, fêmeas, da raça Nova Zelândia, divididos em dois grupos: um grupo controle, com seis animais (coelhos 1-6, e um grupo infectado, com seis animais (coelhos 7-12. Os animais pertencentes ao grupo infectados receberam, pela via intraperitoneal, 0,5 mL de sangue de rato contendo 108 tripanossomas por animal. Amostras do sangue utilizado para avaliação das colinesterases foram coletadas nos dias 0, 2, 7, 12, 27, 42, 57, 87, 102 e 118 pós-inoculação (PI. Aumento (P0,05 foi observada nas estruturas encefálicas. O aumento de atividade da AChE e BChE provavelmente tenha finalidade pró-inflamatória, a fim de reduzir as concentrações de acetilcolina, neurotransmissor que apresenta propriedade anti-inflamatória. Portanto, as colinesterases podem ser marcadores inflamatórios na infec

  14. Cholinesterase activity in the tissues of bivalves Noah's ark shell (Arca noae) and warty venus (Venus verrucosa): characterisation and in vitro sensitivity to organophosphorous pesticide trichlorfon.

    Science.gov (United States)

    Perić, Lorena; Ribarić, Luka; Nerlović, Vedrana

    2013-08-01

    Cholinesterase (ChE, EC 3.1.1.7) activity was investigated in gills and adductor muscle of two bivalve species: Arca noae and Venus verrucosa. The properties of ChEs were investigated using acetylcholine iodide (ASCh), butyrylcholine iodide (BSCh) and propionylcholine iodide (PrSCh) as substrates and eserine, BW254c51 and iso-OMPA as specific inhibitors. The highest level of ChE activity in crude tissue extracts was detected with PrSCh followed by ASCh, while values obtained with BSCh were apparently low, except in A. noae adductor muscle. The enzyme activity in A. noae gills and V. verrucosa gills and adductor muscle was significantly inhibited by BW254c51, but not with iso-OMPA. ChE activity in adductor muscle of A. noae was significantly reduced by both diagnostic inhibitors. The effect of organophosphorous pesticide trichlorfon on ChE activity was investigated in vitro in both species as well as in the gills of mussels Mytilus galloprovincialis. The highest sensitivity of ChE to trichlorfon was observed in A. noae gills and adductor muscle (IC50 1.6×10(-7)M and 1.1×10(-7)M, respectively), followed by M. galloprovincialis gills (IC50 1.0×10(-6)M) and V. verrucosa gills and adductor muscle (IC50 1.7×10(-5)M and 0.9×10(-5)M, respectively). The results of this study suggest the potential of ChE activity measurement in the tissues of A. noae as effective biomarker of OP exposure in marine environment.

  15. Effects of repeated exposure of diazinon on cholinesterase activity and growth in snakehead fish (Channa striata).

    Science.gov (United States)

    Cong, Nguyen Van; Phuong, Nguyen Thanh; Bayley, Mark

    2009-03-01

    The organophosphate insecticide diazinon is widely used in the Mekong river delta and often applied several times per rice crop. In the present study, juvenile snakehead fish Channa striata, which is a commercially important inhabitant of rice fields, were exposed twice to 4-day pulses of 0.016, 0.079 or 0.35mg/L of diazinon, separated by a 2 week interval to imitate the exposure conditions in the field. After the 4-day exposures to these environmentally realistic concentrations, the fish were moved to clean water for recovery. During this experiment, which lasted a total of 2 months, the individual growth rates and brain cholinesterase levels were measured. We show not only that diazinon caused long term inhibition of brain ChE activity, which was still significantly depressed at the termination of the experiment, but also that the highest of these realistic concentrations caused a significant 30% growth inhibition.

  16. Bisquaternary oximes as reactivators of tabun-inhibited human brain cholinesterases: an in vitro study.

    Science.gov (United States)

    Kuca, Kamil; Jun, Daniel; Cabal, Jiri; Musilova, Lucie

    2007-07-01

    Intoxications caused by tabun nerve agent are generally very hard to treat by convential acetylcholinesterase (AChE) reactivators. Due to this, new AChE reactivators are still developed. In this study, we have tested three new promising bisquaternary AChE reactivators: K027, K033 and K048. These reactivators were previously tested on rat brain homogenate. To mimic reality, we studied the potency of these new oximes to reactivate tabun-inhibited human brain cholinesterases. As is evident from the results, reactivator K048 (reactivation 40%) surpassed all reactivators tested in this study [including the most promising ones, namely trimedoxime (37%) and obidoxime (33%)]. Moreover, if compared to our previous results from rat brain studies, species differences were demonstrated.

  17. Cholinesterase-inhibitory diterpenoids and chemical constituents from aerial parts of Caryopteris mongolica.

    Science.gov (United States)

    Murata, Toshihiro; Selenge, Erdenechimeg; Oikawa, Saki; Ageishi, Keita; Batkhuu, Javzan; Sasaki, Kenroh; Yoshizaki, Fumihiko

    2015-10-01

    A diterpenoid diglucoside (12,19-di-O-β-D-glucopyranosyl-11-hydroxyabieta-8,11,13-triene-19-one), isoscutellarein 7-O-[β-D-xylopyranosyl-(1→2)]-β-D-glucopyranoside, isoscutellarein 7-O-[α-L-rhamnopyranosyl-(1→2)]-β-D-glucopyranoside, hypolaetin 7-O-[6″-O-(p-E-coumaroyl)]-β-D-glucopyranoside, hypolaetin 7-O-[6″-O-(E-caffeoyl)]-β-D-glucopyranoside, and 15 known compounds were isolated from aerial parts of the Mongolian medicinal plant Caryopteris mongolica. The cholinesterase-inhibitory activities of the constituents were estimated. The abietane diterpenoids (12-O-demethylcryptojaponol and 6α-hydroxydemethylcryptojaponol) showed potent inhibitory activity against acetylcholinesterase from human erythrocytes and electric eel, and against butyrylcholinesterase from horse serum.

  18. Cholinesterase inhibitory activity and chemical constituents of Stenochlaena palustris fronds at two different stages of maturity

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    Nelson Jeng-Yeou Chear

    2016-04-01

    Full Text Available Stenochlaena palustris fronds are popular as a vegetable in Southeast Asia. The objectives of this study were to evaluate the anticholinesterase properties and phytochemical profiles of the young and mature fronds of this plant. Both types of fronds were found to have selective inhibitory effect against butyrylcholinesterase compared with acetylcholinesterase. However, different sets of compounds were responsible for their activity. In young fronds, an antibutyrylcholinesterase effect was observed in the hexane extract, which was comprised of a variety of aliphatic hydrocarbons, fatty acids, and phytosterols. In the mature fronds, inhibitory activity was observed in the methanol extract, which contained a series of kaempferol glycosides. Our results provided novel information concerning the ability of S. palustris to inhibit cholinesterase and its phytochemical profile. Further research to investigate the potential use of this plant against Alzheimer's disease is warranted, however, young and mature fronds should be distinguished due to their phytochemical differences.

  19. Diazinon concentrations and blood cholinesterase activities in rats exposed to diazinon.

    Science.gov (United States)

    Tomokuni, K; Hasegawa, T

    1985-04-01

    The tissue distribution of diazinon and the inhibition of blood cholinesterase (ChE) activity were investigated in male rats which received a single intraperitoneal (i.p.) dose of diazinon (100 mg/kg body wt) in olive oil. Diazinon concentration in the blood reached a maximum 1-2 h after dosing. Comparing the distribution of diazinon among liver, kidney and brain in treated rats, the diazinon residue was much greater in the kidney than in other organs, being 500 times that in the liver and 11 times that in the brain at 8 h after dosing. Erythrocyte and plasma ChE activities were inhibited rapidly, but ChE inhibition was greater in the erythrocytes than in plasma.

  20. Action of the herbicide butachlor on cholinesterases in the freshwater snail Pila globosa (Swainson).

    Science.gov (United States)

    Rajyalakshmi, T; Srinivas, T; Swamy, K V; Prasad, N S; Mohan, P M

    1996-11-01

    Butachlor action on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activates in central nervous tissue of the snail Pila globosa was assayed following the method of ELLMAN et al1, in vitro by adding butachlor directly (10-100 mu moles), to tissue homogenates and in in vivo by exposing the snails to sub-lethal concentration (26.6 ppm) and taking out the tissue for experimentation at different intervals (3, 6, 12, 24 and 48 h) of exposure. The enzyme activities decreased in a dose-dependent manner in vitro, and up to 12-24 h in vivo after which they showed recovery towards the control. The inhibition of cholinesterases by butachlor in vitro indicates a direct action of the herbicide on these enzymes. Presumably butachlor exercises its neurotoxic effects through cholinergic impairment in a way similar to that of organophosphates and carbamates.

  1. Diagnosis of anticholinesterase poisoning in birds: Effects of environmental temperature and underfeeding on cholinesterase activity

    Science.gov (United States)

    Rattner, B.A.

    1982-01-01

    Brain cholinesterase (ChE) activity has been used extensively to monitor exposure to organophosphorus (OP) and carbamate (CB) insecticides in wild birds. A series of factorial experiments was conducted to assess the extent to which noncontaminant-related environmental conditions might affect brain ChE activity and thereby confound the diagnosis of OP and CB intoxication. Underfeeding (restricting intake to 50% of control for 21 d or fasting for 1-3 d) or exposure to elevated temperature (36 + 1?C for 1 d) caused only slight reductions (10-17%) in brain AChE activity in adult male Japanese quail (Coturnix coturnix japonica). This degree of 'reduction' in brain AChE activity is considerably less than the 50% 'inhibition' criterion employed in the diagnosis of insecticide-induced mortality, but nevertheless approaches the 20% 'inhibition' level used as a conservative estimate of sublethal exposure to a known insecticide application.

  2. Temperature: a prolonged confounding factor on cholinesterase activity in the tropical reef fish Acanthochromis polyacanthus.

    Science.gov (United States)

    Botté, Emmanuelle S; Smith-Keune, Carolyn; Jerry, Dean R

    2013-09-15

    Cholinesterase activity usually decreases in fish exposed to anticholinesterase compounds such as organophosphate and carbamate pesticides. Here we show that tropical reef fish Acanthochromis polyacanthus (or spiny damsel) also exhibits a decrease in ChE activity when exposed to elevated temperature from 28°C to 32°C or 34°C after 4 days. We further demonstrate that the decline persists even after 7 days of recovery at control temperature. This is the first report of a drop in ChE activity in fish as temperature increases. Our results strongly suggest the need for long-term monitoring of water temperature in the field prior to sampling A. polyacanthus for toxicology studies, as temperature is a prolonged and confounding factor for ChE activity in this species.

  3. Sex and storage affect cholinesterase activity in blood plasma of Japanese quail

    Science.gov (United States)

    Hill, E.F.

    1989-01-01

    Freezing at -25?C had confounding effects on cholinesterase (ChE) activity in blood plasma from breeding female quail, but did not affect ChE activity in plasma from males. Plasma ChE activity of control females increased consistently during 28 days of storage while both carbamate- and cidrotophos-inhibited ChE decreased. Refrigeration of plasma at 4?C for 2 days had little effect of ChE activity. Plasma ChE activity was averaged about 34% higher in breeding males than in females. Extreme caution should be exercised in use of blood plasma for evaluation of anti ChE exposure in free-living birds.

  4. Cholinesterase inhibition and behavioral toxicity of carbofuran on Oreochromis niloticus early life stages.

    Science.gov (United States)

    Pessoa, P C; Luchmann, K H; Ribeiro, A B; Veras, M M; Correa, J R M B; Nogueira, A J; Bainy, A C D; Carvalho, P S M

    2011-10-01

    Nile tilapia Oreochromis niloticus at 9 days post-hatch were exposed in semi-static experiments to the carbamate insecticide carbofuran, which is applied in agricultural systems in Brazil. Although the molecular mechanism of carbofuran toxicity is well known, a detailed understanding of the ecological mechanisms through which carbofuran effects can propagate towards higher levels of biological organization in fish is incomplete. Mortality rates were quantified for larvae exposed for 96 h to 8.3, 40.6, 69.9, 140, 297 and 397 μg/L carbofuran, and the LC(50) 96 h was 214.7 μg/L. In addition, the biochemical biomarker cholinesterase inhibition and behavioral biomarkers related to vision, swimming, prey capture and predator avoidance were quantified in individual larvae, as well as their growth in weight. The behavioral parameters were quantified by analysis of digitally recorded videos of individual larvae within appropriate experimental setups. The activity of the enzyme cholinesterase decreased after exposure to carbofuran with a lowest observed effects concentration (LOEC) of 69.9 μg/L. Visual acuity deficits were detected after carbofuran exposure with a LOEC of 40.6 μg/L. Swimming speed decreased with carbofuran exposure, with a LOEC of 397.6 μg/L. The number of attacks to prey (Daphnia magna nauplii) decreased in larvae exposed to carbofuran, with a LOEC of 397.6 μg/L. Growth in weight was significantly reduced in a dose dependent manner, and all carbofuran groups exhibited a statistically significant decrease in growth when compared to controls (pcarbofuran, and the LOEC was 69.9 μg/L. These results show that exposure of sensitive early life stages of tilapia O. niloticus to sublethal concentrations of carbofuran can affect fundamental aspects of fish larval ecology that are relevant to recruitment of fish populations, and that can be better understood by the application of behavioral biomarkers.

  5. Salvia leriifolia Benth (Lamiaceae) extract demonstrates in vitro antioxidant properties and cholinesterase inhibitory activity.

    Science.gov (United States)

    Loizzo, Monica R; Tundis, Rosa; Conforti, Filomena; Menichini, Federica; Bonesi, Marco; Nadjafi, Farsad; Frega, Natale Giuseppe; Menichini, Francesco

    2010-12-01

    The object of the present study was to investigate the in vitro antioxidant properties and cholinesterase inhibitory activity of Salvia leriifolia Benth extracts and fractions. The functional role of herbs and spices and their constituents is a hot topic in food-related plant research. Salvia species have been used since ancient times in folk medicine for cognitive brain function and have been subjected to extensive research. Thus, we hypothesize that S leriifolia, because of its functional properties, would be a good candidate to use as a nutraceutical product for improving memory in the elderly or patients affected by Alzheimer disease (ad). To test this hypothesis, we examined the cholinesterase inhibitory activity using the modified colorimetric Ellman's method against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The n-hexane exhibited the highest activity, with inhibitory concentration 50% (IC(50)) values of 0.59 and 0.21 mg/mL, for AChE and BChE, respectively. This extract was fractionated, and 9 of these fractions (A-I) were obtained and tested. Fraction G, characterized by the presence of sesquiterpenes as major components, was the most active against AChE (IC(50) = 0.05 mg/mL). Because oxidative stress is a critical event in the pathogenesis of AD, we decided to screen the antioxidant activity (AA) using 2,2-diphenyl-1-picrylhydrazyl test, β-carotene bleaching test, and bovine brain peroxidation (thiobarbituric acid) assay. The ethyl acetate extract showed the highest activity, with IC(50) values of 2 and 33 μg/mL on β-carotene bleaching test and thiobarbituric acid test, respectively. These results suggest potential health benefits of S leriifolia extracts. However, this finding requires additional investigation in vivo.

  6. Cholinesterase reactivators: the fate and effects in the organism poisoned with organophosphates/nerve agents.

    Science.gov (United States)

    Bajgar, J; Kuca, K; Jun, D; Bartosova, L; Fusek, J

    2007-12-01

    Understanding the mechanism of action of organophosphates (OP)/nerve agents -- irreversible acetylcholinesterase (AChE, EC 3.1.1.7) inhibition at the cholinergic synapses followed by metabolic dysbalance of the organism -- two therapeutic principles for antidotal treatment are derived. The main drugs are anticholinergics that antagonize the effects of accumulated acetylcholine at the cholinergic synapses and cholinesterase reactivators (oximes) reactivating inhibited AChE. Anticonvulsants such as diazepam are also used to treat convulsions. Though there are experimental data on a good therapeutic effects of reactivators, some attempts to underestimate the role of reactivators as effective antidotes against OP poisoning have been made. Some arguments on the necessity of their administration following OP poisoning are discussed. Their distribution patterns and some metabolic and pharmacological effects are described with the aim to resolve the question on their effective use, possible repeated administration in the treatment of OP poisoning, their peripheral and central effects including questions on their penetration through the blood brain barrier as well as a possibility to achieve their effective concentration for AChE reactivation in the brain. Reactivation of cholinesterases in the peripheral and central nervous system is described and it is underlined its importance for the survival or death of the organism poisoned with OP. Metabolization and some other effects of oximes (not connected with AChE reactivation) are discussed (e.g. forming of the phosphonylated oxime, parasympatholytic action, hepatotoxicity, behavioral changes etc.). An universality of oximes able to reactivate AChE inhibited by all OP is questioned and therefore, needs of development of new oximes is underlined.

  7. Hepatic cholinesterase of laying hens naturally infected by Salmonella Gallinarum (fowl typhoid).

    Science.gov (United States)

    Da Silva, Aleksandro S; Boiago, Marcel M; Bottari, Nathieli B; do Carmo, Guilherme M; Alves, Mariana Sauzen; Boscato, Carla; Morsch, Vera M; Schetinger, Maria Rosa C; Casagrande, Renata A; Stefani, Lenita M

    2016-09-01

    Salmonella is a facultative intracellular pathogen that may cause foodborne gastroenteritis in humans and animals consisting of over 2000 serovars. The serovar Salmonella Gallinarum is an important worldwide pathogen of poultry. However, little is known on the mechanisms of pathogenesis of Salmonella in chickens. The aim of this study was to evaluate cholinesterase and myeloperoxidase activities in hepatic tissue of laying hens naturally infected by S. Gallinarum. Twenty positive liver samples for S. Gallinarum were collected, in addition to seven liver samples from healthy uninfected laying hens (control group). The right liver lobe was homogenized for analysis of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and myeloperoxidase (MPO), and the left lobe was divided into two fragments, one for histopathology and the other for Salmonella isolation. The results showed changes in AChE and BchE activity in the liver of infected laying hens compared to the control group (P liver samples. Infected animals showed increased MPO activity compared to healthy animals (P cells, macrophages,heterophils in the liver of infected hens. These findings suggest that the inflammatory process was attenuated providing a pro-inflammatory action of both enzyme analyzed in order to reduce the free ACh, a molecule which has an anti-inflammatory action. Therefore, our results lead to the hypothesis that cholinesterase plays an important role on the modulation of immune response against S. Gallinarum with an inflammatory effect, contributing to the response against this bacterium. This study should contribute to a better understanding on the pathogenic mechanisms involved in laying hens infected by S. Gallinarum.

  8. In vitro cholinesterase inhibitory and antioxidant effect of selected coniferous tree species

    Institute of Scientific and Technical Information of China (English)

    Fatma Sezer Senol; Ilkay Erdogan Orhan; Osman Ustun

    2015-01-01

    Objective: To explore cholinesterase inhibitory and antioxidant effect of six coniferous trees (Abies bornmulleriana, Picea pungens, Juniperus communis, Cedrus libani, Taxus baccata, and Cupressus sempervirens var. horizantalis). Methods: Acetone (Ace), ethyl acetate (EtOAc), and ethanol (EtOH) extracts prepared from the needles and shoots of the six coniferous trees were screened for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity at 100 μg/mL. Antioxidant activity of the extracts was tested using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and N,N-dimethyl-p-phenylendiamine (DMPD) radical scavenging, metal-chelation capacity, ferric-(FRAP) and phosphomolibdenum-reducing antioxidant power (PRAP) assays. All of the assays were performed in ELISA microplate reader. Total phenol and flavonoid amounts in the extracts were determined spectrophotometrically. Results: Among thirty-six extracts in total, the shoot-Ace extract of Cupressus sempervirens var. horizantalis exerted the highest inhibition against AChE [(54.84±2.51)%], while the needle-Ace extract of Cedrus libani was the most effective in inhibiting BChE [(67.54±0.30)%]. The highest DPPH radical scavenging effect, FRAP and PRAP was observed in the shoot-Ace and EtOAc extracts from Taxus baccata, whereas all the extracts showed a variable degree of scavenging effect against DPMD radical. The shoot-EtOAc extract of Cedrus libani had the highest metal-chelation capacity [(58.04±0.70)%]. The shoot extracts of Taxus baccata were determined to have the richest total phenol content, which may contribute to its marked antioxidant activity. Conclusions: The conifer species screened in this study may contain cholinesterase-inhibiting and antioxidant properties, which might be useful against Alzheimer’s disease.

  9. Ionic liquid mediated synthesis and molecular docking study of novel aromatic embedded Schiff bases as potent cholinesterase inhibitors.

    Science.gov (United States)

    Abd Razik, Basma M; Osman, Hasnah; Basiri, Alireza; Salhin, Abdussalam; Kia, Yalda; Ezzat, Mohammed Oday; Murugaiyah, Vikneswaran

    2014-12-01

    Novel aromatic embedded Schiff bases have been synthesized in ionic liquid [bmim]Br and evaluated in vitro for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes inhibitory activities. Among the newly synthesized compounds, 5f, 5h and 7j displayed higher AChE enzyme inhibitory activities than standard drug, galanthamine, with IC50 values of 1.88, 2.05 and 2.03μM, respectively. Interestingly, all the compounds except for compound 5c displayed higher BChE inhibitories than standard with IC50 values ranging from 3.49 to 19.86μM. Molecular docking analysis for 5f and 7j possessing the most potent AChE and BChE inhibitory activities, disclosed their binding interaction templates to the active site of AChE and BChE enzymes, respectively.

  10. The Use of Pesticides Against Blood Cholinesterase Level (The Analytical Study on Farmers in Torpedo Village, Sabbang Sub District, Luwu Utara District

    Directory of Open Access Journals (Sweden)

    H. Hamsir Ahmad

    2016-05-01

    Full Text Available Blood Cholinesterase was a enzymes form of biological catalyst in the body's tissues role to keep the muscles, glands and nerve cells to work in an organized and harmonious. Blood Cholinesterase is an indicator of subclinical pesticide poisoning and it can be determined by examining blood Cholinesterase activity into someone. The purpose of this study was known the relationship use of pesticide on levels of blood Cholinesterase on a rice farmer in the village torpedo Sabbang sub district, Luwu Utara district. This type of research is analytic survey research with cross sectional study to determine the relationship use of pesticide on levels of blood Cholinesterase on a farmer in the village of torpedo Sabbang sub district, Luwu Utara. The number of samples in this study were 73 samples. The results showed that length use of pesticides by respondents have longer use than shorter use, but from the results of statistical tests Ho refused meaning there was no significant relationship between length use of pesticides with high levels of farmers blood Cholinesterase, P> 0.005. There was no significant relationship between how pesticides mixing with high levels of farmers blood Cholinesterase, based on the statistical test Ho rejected P> 0.005. There were still some farmers do not use PPE at the time of contact with the pesticide, but from the results of statistical tests Ho refused meaning there was no significant relationship between the use of PPE with high levels of farmers blood Cholinesterase, P> 0.005. Suggestions in the study was expected that health care workers to provide education on the dangers of pesticides on health. It was expected that farmers in the gathering / dispensing pesticides in order to follow the rules of the use of pesticides. It was expected to farmers to use personal protective equipment (PPE at the time of contact with the pesticide.

  11. A Facile Ionic Liquid Promoted Synthesis, Cholinesterase Inhibitory Activity and Molecular Modeling Study of Novel Highly Functionalized Spiropyrrolidines

    Directory of Open Access Journals (Sweden)

    Abdulrahman I. Almansour

    2015-01-01

    Full Text Available A series of novel dimethoxyindanone embedded spiropyrrolidines were synthesized in ionic liquid, [bmim]Br and were evaluated for their inhibitory activities towards cholinesterases. Among the spiropyrrolidines, compound 4f exhibited the most potent activity with an IC50 value of 1.57 µM against acethylcholinesterase (AChE. Molecular docking simulation for the most active compound was employed with the aim of disclosing its binding mechanism to the active site of AChE receptor.

  12. PON1 status does not influence cholinesterase activity in Egyptian agricultural workers exposed to chlorpyrifos

    Energy Technology Data Exchange (ETDEWEB)

    Ellison, Corie A., E-mail: cellison@buffalo.edu [Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14214 (United States); Crane, Alice L., E-mail: alcrane@buffalo.edu [Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14214 (United States); Bonner, Matthew R., E-mail: mrbonner@buffalo.edu [Department of Social and Preventive Medicine, State University of New York at Buffalo, Buffalo, NY 14214 (United States); Knaak, James B., E-mail: jbknaak@aol.com [Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14214 (United States); Browne, Richard W., E-mail: rwbrowne@buffalo.edu [Department of Biotechnical and Clinical Laboratory Sciences, State University of New York at Buffalo, Buffalo, NY 14214 (United States); Lein, Pamela J., E-mail: pjlein@ucdavis.edu [Department of Molecular Biosciences, University of California School of Veterinary Medicine, Davis, CA 95618 (United States); Olson, James R., E-mail: jolson@buffalo.edu [Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14214 (United States); Department of Social and Preventive Medicine, State University of New York at Buffalo, Buffalo, NY 14214 (United States)

    2012-12-15

    Animal studies have shown that paraoxonase 1 (PON1) genotype can influence susceptibility to the organophosphorus pesticide chlorpyrifos (CPF). However, Monte Carlo analysis suggests that PON1 genotype may not affect CPF-related toxicity at low exposure conditions in humans. The current study sought to determine the influence of PON1 genotype on the activity of blood cholinesterase as well as the effect of CPF exposure on serum PON1 in workers occupationally exposed to CPF. Saliva, blood and urine were collected from agricultural workers (n = 120) from Egypt's Menoufia Governorate to determine PON1 genotype, blood cholinesterase activity, serum PON1 activity towards chlorpyrifos-oxon (CPOase) and paraoxon (POase), and urinary levels of the CPF metabolite 3,5,6-trichloro-2-pyridinol (TCPy). The PON1 55 (P ≤ 0.05) but not the PON1 192 genotype had a significant effect on CPOase activity. However, both the PON1 55 (P ≤ 0.05) and PON1 192 (P ≤ 0.001) genotypes had a significant effect on POase activity. Workers had significantly inhibited AChE and BuChE after CPF application; however, neither CPOase activity nor POase activity was associated with ChE depression when adjusted for CPF exposure (as determined by urinary TCPy levels) and stratified by PON1 genotype. CPOase and POase activity were also generally unaffected by CPF exposure although there were alterations in activity within specific genotype groups. Together, these results suggest that workers retained the capacity to detoxify chlorpyrifos-oxon under the exposure conditions experienced by this study population regardless of PON1 genotype and activity and that effects of CPF exposure on PON1 activity are minimal. -- Highlights: ► CPF exposure resulted in an increase in TCPy and decreases in BuChE and AChE. ► CPOase activity decreased in subjects with the PON1 55LM and PON1 55 MM genotypes. ► Neither PON1 genotype nor CPOase activity had an effect on BuChE or AChE inhibition.

  13. The Effect of Diazinon on Cholinesterase Activity in Plasma and Erythrocytes of Male and Female Rats and the Protective Role of Vitamin E

    Directory of Open Access Journals (Sweden)

    F. Rahimi Anbarkeh

    2015-01-01

    Full Text Available Introduction & Objective: Diazinon (DZN is an organophosphate insecticide that one of the mechanisms of toxicity is the inhibition of cholinesterase. The aim of the present study was to evaluate the effects of diazinon on cholinesterase activity in blood serum and erythrocytes of male and female rats and to assess the protective role of vitamin E. Materials & Methods: In this experimental study, 60 adult wistar rats including 30 male and 30 female rats were selected and divided into 5 groups (n = 6: control group (without any intervention, sham group (received only pure olive oil daily, experimental group 1 (DZN daily, 60 mg/kg, experimental group 2 (received DZN+ vitamin E daily, with the same dose and experimental group 3(received vitamin E daily 200 mg/kg. Diazinon and solvent were injected intraperitoneally and vitamin E was given by gavage. After 2 weeks 3 ml blood was taken from the heart tissue, and titrimetric and Ellman’s method respectively were used for serum and erythrocyte cholinesterases activity assay. Results: In both genders, due to administration of diazinon, we observed significant reduction in serum and erythrocytes cholinesterase activity. The use of vitamin E increased serum and erythrocytes cholinesterase activity in experimental group 2 of female rats but inhibition in erythrocyte and serum cholinesterase activity was not recovered in experimental group 2 of male rats. Conclusion: According to a further reduction of these enzymes activity in female rats with the use of diazinon, it can be concluded that female rats are more sensitive than male rats and it seems that vitamin E as an antioxidants has a protective effect on cholinesterase activity and reduces the toxicity of DZN. (Sci J Hamadan Univ Med Sci 2015; 21 (4:294-303

  14. The relationship between total cholinesterase activity and mortality in four butterfly species

    Science.gov (United States)

    Bargar, Timothy A.

    2012-01-01

    The relationship between total cholinesterase activity (TChE) and mortality in four butterfly species (great southern white [Ascia monuste], common buckeye [Junonia coenia], painted lady [Vanessa cardui], and julia butterflies [Dryas julia]) was investigated. Acute contact toxicity studies were conducted to evaluate the response (median lethal dose [LD50] and TChE) of the four species following exposure to the organophosphate insecticide naled. The LD50 for these butterflies ranged from 2.3 to 7.6 μg/g. The average level of TChE inhibition associated with significant mortality ranged from 26 to 67%, depending on the species. The lower bounds of normal TChE activity (2 standard deviations less than the average TChE for reference butterflies) ranged from 8.4 to 12.3 μM/min/g. As a percentage of the average reference TChE activity for the respective species, the lower bounds were similar to the inhibition levels associated with significant mortality, indicating there was little difference between the dose resulting in significant TChE inhibition and that resulting in mortality.

  15. Evidence for inhibition of cholinesterases in insect and mammalian nervous systems by the insect repellent deet

    Directory of Open Access Journals (Sweden)

    Dimitrov Mitko

    2009-08-01

    Full Text Available Abstract Background N,N-Diethyl-3-methylbenzamide (deet remains the gold standard for insect repellents. About 200 million people use it every year and over 8 billion doses have been applied over the past 50 years. Despite the widespread and increased interest in the use of deet in public health programmes, controversies remain concerning both the identification of its target sites at the olfactory system and its mechanism of toxicity in insects, mammals and humans. Here, we investigated the molecular target site for deet and the consequences of its interactions with carbamate insecticides on the cholinergic system. Results By using toxicological, biochemical and electrophysiological techniques, we show that deet is not simply a behaviour-modifying chemical but that it also inhibits cholinesterase activity, in both insect and mammalian neuronal preparations. Deet is commonly used in combination with insecticides and we show that deet has the capacity to strengthen the toxicity of carbamates, a class of insecticides known to block acetylcholinesterase. Conclusion These findings question the safety of deet, particularly in combination with other chemicals, and they highlight the importance of a multidisciplinary approach to the development of safer insect repellents for use in public health.

  16. The effects of chlorpyrifos on cholinesterase activity and foraging behavior in the dragonfly, Anax junius (Odonata)

    Science.gov (United States)

    Brewer, S.K.; Atchison, G.J.

    1999-01-01

    We examined head capsule cholinesterase (ChE) and foraging behavior in nymphs of the dragonfly, Anax junius, exposed for 24 h to 0.2, 0.6 and 1.0 ??g l-1 of the organophosphorus (OP) insecticide, chlorpyrifos [O,O-diethyl O-(3,5,6-trichloro-2-pyridyl) phosphorothioate]. The invertebrate community is an important component of the structure and function of wetland ecosystems, yet the potential effects of insecticides on wetland ecosystems are largely unknown. Our objectives were to determine if exposure to environmentally realistic concentrations of chlorpyrifos affected foraging behavior and ChE activity in head capsules of dragonfly nymphs. Nymphs were exposed to different concentrations of chlorpyrifos and different prey densities in a factorial design. ChE activities and foraging behaviors of treated nymphs were not statistically different (p ??? 0.05) from control groups. Prey density effects exerted a greater effect on dragonfly foraging than toxicant exposures. Nymphs offered higher prey densities exhibited more foraging behaviors but also missed their prey more often. High variability in ChE activities within the control group and across treated groups precluded determination of relationships between ChE and foraging behaviors. It appears that A. junius is relatively tolerant of chlorpyrifos, although the concentrations we tested have been shown in other work to adversely affect the prey base; therefore the introduction of this insecticide may have indirect adverse affects on top invertebrate predators such as Odonata.

  17. Novel brain-penetrating oximes for reactivation of cholinesterase inhibited by sarin and VX surrogates.

    Science.gov (United States)

    Chambers, Janice E; Meek, Edward C; Chambers, Howard W

    2016-06-01

    Current oxime reactivators for organophosphate-inhibited cholinesterase (ChE) do not effectively cross the blood-brain barrier and therefore cannot restore brain ChE activity in vivo. Our laboratories have studied highly relevant sarin and VX surrogates, which differ from their respective nerve agents only in the leaving group and thereby leave ChE phosphylated with the same chemical moiety as sarin and VX. Our laboratories have developed novel substituted phenoxyalkyl pyridinium oximes that lead to reduced ChE inhibition in the brains of rats challenged with a high sublethal dosage of the sarin surrogate, whereas 2-PAM did not, using a paradigm designed to demonstrate brain penetration. In addition, treatment of rats with these novel oximes is associated with attenuation of seizure-like behavior compared to rats treated with 2-PAM, providing additional evidence that the oximes penetrate the blood-brain barrier. Further, some of the oximes provided 24-h survival superior to 2-PAM, and shortened the duration of seizure-like behavior when rats were challenged with lethal dosages of the sarin and VX surrogates, providing additional support for the conclusion that these oximes penetrate the brain.

  18. Quinoxaline derivatives: novel and selective butyrylcholinesterase inhibitors.

    Science.gov (United States)

    Zeb, Aurang; Hameed, Abdul; Khan, Latifullah; Khan, Imran; Dalvandi, Kourosh; Choudhary, M Iqbal; Basha, Fatima Z

    2014-01-01

    Alzheimer's disease (AD) is a progressive brain disorder which occurs due to lower levels of acetylcholine (ACh) neurotransmitters, and results in a gradual decline in memory and other cognitive processes. Acetycholinesterase (AChE) and butyrylcholinesterase (BChE) are considered to be primary regulators of the ACh levels in the brain. Evidence shows that AChE activity decreases in AD, while activity of BChE does not change or even elevate in advanced AD, which suggests a key involvement of BChE in ACh hydrolysis during AD symptoms. Therefore, inhibiting the activity of BChE may be an effective way to control AD associated disorders. In this regard, a series of quinoxaline derivatives 1-17 was synthesized and biologically evaluated against cholinesterases (AChE and BChE) and as well as against α- chymotrypsin and urease. The compounds 1-17 were found to be selective inhibitors for BChE, as no activity was found against other enzymes. Among the series, compounds 6 (IC50 = 7.7 ± 1.0 µM) and 7 (IC50 = 9.7 ± 0.9 µM) were found to be the most active inhibitors against BChE. Their IC50 values are comparable to the standard, galantamine (IC50 = 6.6 ± 0.38 µM). Their considerable BChE inhibitory activity makes them selective candidates for the development of BChE inhibitors. Structure-activity relationship (SAR) of this new class of selective BChE inhibitors has been discussed.

  19. Studies on combined effects of organophosphates or carbamates and morsodren in birds. II. Plasma and cholinesterase in quail fed morsodren and orally dosed with parathion or carbofuran

    Science.gov (United States)

    Dieter, M.P.; Ludke, J.L.

    1978-01-01

    The degree of interaction between mercury and cholinesterase inhibiting pesticides was determined by comparing enzyme responses to sublethal dosages of parathion or carbofuran in quail fed 0.05, 0.5, or 5.0 ppm morsodren for 18 weeks. A statistically significant interaction was defined as greater brain cholinesterase inhibition in morsodren-fed than in clean-fed birds following pesticide dosage. The tissue residues of mercury that accumulated before significant mercury-parathion interactions occurred were higher than levels that might be expected in natural populations, but significant mercury-carbofuran interactions occurred in birds that had only accumulated 1.0 ppm liver mercury. The results indicate that indiscriminate usage of cholinesterase inhibiting pesticides are dangerous, since natural populations of fish-eating birds oftentimes contain this magnitude of mercury.

  20. Cholinesterase-like domains in enzymes and structural proteins: functional and evolutionary relationships and identification of a catalytically essential aspartic acid.

    Science.gov (United States)

    Krejci, E; Duval, N; Chatonnet, A; Vincens, P; Massoulié, J

    1991-01-01

    Primary sequences of cholinesterases and related proteins have been systematically compared. The cholinesterase-like domain of these proteins, about 500 amino acids, may fulfill a catalytic and a structural function. We identified an aspartic acid residue that is conserved among esterases and lipases (Asp-397 in Torpedo acetylcholinesterase) but that had not been considered to be involved in the catalytic mechanism. Site-directed mutagenesis demonstrated that this residue is necessary for activity. Analysis of evolutionary relationships shows that the noncatalytic members of the family do not constitute a separate subgroup, suggesting that loss of catalytic activity occurred independently on several occasions, probably from bifunctional molecules. Cholinesterases may thus be involved in cell-cell interactions in addition to the hydrolysis of acetylcholine. This would explain their specific expression in well-defined territories during embryogenesis before the formation of cholinergic synapses and their presence in noncholinergic tissues. Images PMID:1862088

  1. Hormetic response of cholinesterase from Daphnia magna in chronic exposure to triazophos and chlorpyrifos

    Institute of Scientific and Technical Information of China (English)

    Shaonan Li; Yajun Tan

    2011-01-01

    In vivo activity of cholinesterase (ChE) in Daphnia magna was measured at different time points during 21-day exposure to triazophos and chlorpyrifos ranging from 0.05 to 2.50 μg/L and 0.01 to 2.00 μg/L, respectively.For exposure to triazophos, ChE was induced up to 176.5% at 1.5 μg/L and day 10 when measured by acetylthiocholine (ATCh), whereas it was induced up to 174.2% at 0.5 μg/L and day 10 when measured by butyrylthiocholine (BTCh).For exposure to chlorpyrifos, ChE was induced up to 134.0% and 160.5% when measured by ATCh and BTCh, respectivly, with both maximal inductions detected at 0.l μg/L and day 8.Obvious induction in terms of ChE activity was also detected in daphnia removed from exposures 24 hr after their birth and kept in a recovery culture for 21 days.Results indicated that the enzyme displayed symptoms of hormesis, a characteristic featured by conversion from low-dose stimulation to high-dose inhibition.In spite of that, no promotion in terms of reproduction rate and body size was detected at any tested concentrations regardless of whether the daphnia were collected at end of the 21-day exposure or at end of a 21-day recovery culture.This suggested that induction of ChE caused by anticholinesterases had nothing to do with the prosperity of the daphnia population.

  2. Review of UV spectroscopic, chromatographic, and electrophoretic methods for the cholinesterase reactivating antidote pralidoxime (2-PAM).

    Science.gov (United States)

    John, Harald; Blum, Marc-Michael

    2012-01-01

    Pralidoxime (2-PAM) belongs to the class of monopyridinium oximes with reactivating potency on cholinesterases inhibited by phosphylating organophosphorus compounds (OPC), for example, pesticides and nerve agents. 2-PAM represents an established antidote for the therapy of anticholinesterase poisoning since the late 1950s. Quite high therapeutic concentrations in human plasma (about 13 µg/ml) lead to concentrations in urine being about 100 times higher allowing the use of less sensitive analytical techniques that were used especially in the early years after 2-PAM was introduced. In this time (mid-1950s until the end of the 1970s) 2-PAM was most often analyzed by either paper chromatography or simple UV spectroscopic techniques omitting any sample separation step. These methods were displaced completely after the establishment of column liquid chromatography in the early 1980s. Since then, diverse techniques including cation exchange, size-exclusion, reversed-phase, and ligand-exchange chromatography have been introduced. Today, the most popular method for 2-PAM quantification is ion pair chromatography often combined with UV detection representing more than 50% of all column chromatographic procedures published. Furthermore, electrophoretic approaches by paper and capillary zone electrophoresis have been successfully used but are seldom applied. This review provides a commentary and exhaustive summary of analytical techniques applied to detect 2-PAM in pharmaceutical formulations and biological samples to characterize stability and pharmacokinetics as well as decomposition and biotransformation products. Separation techniques as well as diverse detectors are discussed in appropriate detail allowing comparison of individual preferences and limitations. In addition, novel data on mass spectrometric fragmentation of 2-PAM are provided.

  3. Aging of cholinesterases phosphylated by tabun proceeds through O-dealkylation.

    Science.gov (United States)

    Carletti, Eugénie; Li, He; Li, Bin; Ekström, Fredrik; Nicolet, Yvain; Loiodice, Mélanie; Gillon, Emilie; Froment, Marie T; Lockridge, Oksana; Schopfer, Lawrence M; Masson, Patrick; Nachon, Florian

    2008-11-26

    Human butyrylcholinesterase (hBChE) hydrolyzes or scavenges a wide range of toxic esters, including heroin, cocaine, carbamate pesticides, organophosphorus pesticides, and nerve agents. Organophosphates (OPs) exert their acute toxicity through inhibition of acetylcholinesterase (AChE) by phosphorylation of the catalytic serine. Phosphylated cholinesterase (ChE) can undergo a spontaneous, time-dependent process called "aging", during which the OP-ChE conjugate is dealkylated. This leads to irreversible inhibition of the enzyme. The inhibition of ChEs by tabun and the subsequent aging reaction are of particular interest, because tabun-ChE conjugates display an extraordinary resistance toward most current oxime reactivators. We investigated the structural basis of oxime resistance for phosphoramidated ChE conjugates by determining the crystal structures of the non-aged and aged forms of hBChE inhibited by tabun, and by updating the refinement of non-aged and aged tabun-inhibited mouse AChE (mAChE). Structures for non-aged and aged tabun-hBChE were refined to 2.3 and 2.1 A, respectively. The refined structures of aged ChE conjugates clearly show that the aging reaction proceeds through O-dealkylation of the P(R) enantiomer of tabun. After dealkylation, the negatively charged oxygen forms a strong salt bridge with protonated His438N epsilon2 that prevents reactivation. Mass spectrometric analysis of the aged tabun-inhibited hBChE showed that both the dimethylamine and ethoxy side chains were missing from the phosphorus. Loss of the ethoxy is consistent with the crystallography results. Loss of the dimethylamine is consistent with acid-catalyzed deamidation during the preparation of the aged adduct for mass spectrometry. The reported 3D data will help in the design of new oximes capable of reactivating tabun-ChE conjugates.

  4. Relation between dynamics, activity and thermal stability within the cholinesterase family.

    Science.gov (United States)

    Trovaslet, Marie; Trapp, Marcus; Weik, Martin; Nachon, Florian; Masson, Patrick; Tehei, Moeava; Peters, Judith

    2013-03-25

    Incoherent neutron scattering is one of the most powerful tools for studying dynamics in biological matter. Using the cold neutron backscattering spectrometer IN16 at the Institut Laue Langevin (ILL, Grenoble, France), temperature dependence of cholinesterases' dynamics (human butyrylcholinesterase from plasma: hBChE; recombinant human acetylcholinesterase: hAChE and recombinant mouse acetylcholinesterase: mAChE) was examined using elastic incoherent neutron scattering (EINS). The dynamics was characterized by the averaged atomic mean square displacement (MSD), associated with the sample flexibility at a given temperature. We found MSD values of hAChE above the dynamical transition temperature (around 200K) larger than for mAChE and hBChE, implying that hAChE is more flexible than the other ChEs. Activation energies for thermodynamical transition were extracted through the frequency window model (FWM) (Becker et al. 2004) [1] and turned out to increase from hBChE to mAChE and finally to hAChE, inversely to the MSDs relations. Between 280 and 316K, catalytic studies of these enzymes were carried out using thiocholine esters: at the same temperature, the hAChE activity was systematically higher than the mAChE or hBChE ones. Our results thus suggest a strong correlation between dynamics and activity within the ChE family. We also studied and compared the ChEs thermal inactivation kinetics. Here, no direct correlation with the dynamics was observed, thus suggesting that relations between enzyme dynamics and catalytic stability are more complex. Finally, the possible relation between flexibility and protein ability to grow in crystals is discussed.

  5. The role of serum cholinesterase activity and S100B protein in the evaluation of organophosphate poisoning.

    Science.gov (United States)

    Yardan, T; Baydin, A; Acar, E; Ulger, F; Aygun, D; Duzgun, A; Nar, R

    2013-10-01

    The aim of this study was to investigate the role of serum cholinesterase (SChE) activity and S100B protein in the evaluation of patients with acute organophosphate (OP) poisoning. Patients with acute OP poisoning admitted to the emergency department were included in this cross-sectional study. Twenty healthy volunteers served as controls. The SChE activity and serum S100B were determined on admission. Patients were divided into two groups (low severity and high severity). Thirty-six patients diagnosed with acute OP poisoning were enrolled. Serum S100B concentrations were higher in patients than in the control group (p poisoning.

  6. Cholinesterase inhibitory activity and structure elucidation of a new phytol derivative and a new cinnamic acid ester from Pycnanthus angolensis

    Directory of Open Access Journals (Sweden)

    Taiwo O. Elufioye

    Full Text Available ABSTRACT The leaves of Pycnanthus angolensis (Welw. Warb., Myristicaceae, are used as memory enhancer and anti-ageing in Nigerian ethnomedicine. This study aimed at evaluating the cholinesterase inhibitory property as well as isolates the bioactive compounds from the plant. The acetylcholinesterase and butyrylcholinesterase inhibitory potentials of extracts, fractions, and isolated compounds were evaluated by colorimetric and TLC bioautographic assay techniques. The extract inhibited both enzymes with activity increasing with purification, ethyl acetate fraction being most active fraction at 65.66 ± 1.06% and 49.38 ± 1.66% against acetylcholinesterase and butyrylcholinesterase, respectively while the supernatant had 77.44 ± 1.18 inhibition against acetylcholinesterase. Two new bioactive compounds, (2E, 18E-3,7,11,15,18-pentamethylhenicosa-2,18-dien-1-ol (named eluptol and [12-(4-hydroxy-3-methyl-oxo-cyclopenta-1,3-dien-1yl-11-methyl-dodecyl](E-3-(3,4-dimethylphenylprop-2-enoate (named omifoate A were isolated from the plant with IC50 of 22.26 µg/ml (AChE, 34.61 µg/ml (BuChE and 6.51 µg/ml (AChE, 9.07 µg/ml (BuChE respectively. The results showed that the plant has cholinesterase inhibitory activity which might be responsible for its memory enhancing action, thus justifying its inclusion in traditional memory enhancing preparations

  7. CSF monoamine metabolites, cholinesterases and lactate in the adult hydrocephalus syndrome (normal pressure hydrocephalus) related to CSF hydrodynamic parameters.

    Science.gov (United States)

    Malm, J; Kristensen, B; Ekstedt, J; Adolfsson, R; Wester, P

    1991-03-01

    Monoamine metabolites, cholinesterases and lactic acid in lumbar cerebrospinal fluid (CSF) were investigated on patients with the adult hydrocephalus syndrome (idiopathic normal pressure syndrome; AHS, n = 15), Alzheimer's disease (AD, n = 14), multi-infarct dementia (MID, n = 13) and controls (n = 21). Patients had clinical and CSF hydrodynamic investigations. Monoamine concentrations were determined by reversed-phase liquid chromatography, cholinesterases and lactate were determined photometrically. In the AHS patients, CSF monoamine concentrations were not significantly different compared with controls, AD or MID patients. AHS and AD patients showed a similar reduction of CSF acetylcholinesterase activity compared with controls. Positive correlations were found in concentrations of CSF homovanillic acid, CSF 5-hydroxyindoleacetic acid and CSF lactic acid versus CSF outflow conductance (that is, resistance against CSF outflow) in the AHS patients. A similar pattern was observed in a subgroup of MID patients characterised by dilated ventricles and disturbed CSF hydrodynamics. These data suggest that a low CSF outflow conductance may facilitate the clearance of acidic substances from the arachnoid space at the probenecid sensitive active transport site. Alternative explanations would be that a pathologically low CSF outflow conductance is accompanied by an inverse caudorostral flow of CSF or a compromised trans-ependymal diffusion.

  8. Phytochemical profile of a blend of black chokeberry and lemon juice with cholinesterase inhibitory effect and antioxidant potential.

    Science.gov (United States)

    Gironés-Vilaplana, Amadeo; Valentão, Patrícia; Andrade, Paula B; Ferreres, Federico; Moreno, Diego A; García-Viguera, Cristina

    2012-10-15

    In this study, black chokeberry concentrate was added (5% w/v) to lemon juice, since previous reports suggested potential health benefits of this blend. The phytochemical composition, antioxidant capacity (scavenging of DPPH, superoxide and hydroxyl radicals, and hypochlorous acid), and inhibitory activity against cholinesterase of the new blend were determined and compared with those of lemon juice and chokeberry in citric acid (5%). The chokeberry concentrate, rich in cyanidin-glycosides, quercetin derivatives, and 3-O-caffeoylquinic acid, and lemon juice, possessing flavones, flavanones, quercetin derivates, and hydroxycinnamic acids, were characterised. The new drink showed a higher antioxidant effect than the chokeberry or lemon controls for all the tested methods, except for hypochlorous acid, in which lemon juice displayed higher activity. Both the lemon juice and chokeberry controls inhibited acetylcholinesterase and butyrylcholinesterase, and this effect was increased in the new mixtures. The results of the different radical scavenging assays indicate that the lemon-black chokeberry (5% w/v) mixture was more antioxidative than the respective controls separately. Moreover, their inhibition of cholinesterase is of interest regarding neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, or senile dementia.

  9. Cholinesterase activity as a biomarker of pesticide exposure in Allolobophora chlorotica earthworms living in apple orchards under different management strategies.

    Science.gov (United States)

    Denoyelle, Renaud; Rault, Magali; Mazzia, Christophe; Mascle, Odile; Capowiez, Yvan

    2007-12-01

    The present study used cholinesterase (ChE) activity in earthworms as a biomarker of pesticide exposure at 17 apple orchards using different pest protection strategies (organic, integrated pest management [IPM], conventional, and abandoned) located within a 300-km(2) subregion near Avignon in southeastern France). The most common earthworm species in the 17 orchards was Allolobophora chlorotica. We examined inherent variability in ChE activity that might be attributable to soil characteristics and found that differences in soil structure or type did not significantly influence ChE activity. Furthermore, there was no relation between ChE specific activity and earthworm weight, and thus activity does not require correction for weight. Ten earthworms were collected in two successive months (April and May 2003) from each of the 17 orchards. Compared to the activity in worms from the control abandoned orchards, ChE activity was significantly decreased in earthworms from half the IPM and conventional orchards in April and all these orchards in May. Notably, ChE activity was also lower in earthworms from three organic orchards during May. No relation was observed between ChE decrease and the number of treatments (total or only organophosphorous and carbamate pesticides). Cholinesterase activity in earthworms from abandoned orchards varied between the two collecting periods, illustrating the difficulty in obtaining reference values for the use of ChE as a biomarker in field studies.

  10. Pharmacokinetics and effects on serum cholinesterase activities of organophosphorus pesticides acephate and chlorpyrifos in chimeric mice transplanted with human hepatocytes.

    Science.gov (United States)

    Suemizu, Hiroshi; Sota, Shigeto; Kuronuma, Miyuki; Shimizu, Makiko; Yamazaki, Hiroshi

    2014-11-01

    Organophosphorus pesticides acephate and chlorpyrifos in foods have potential to impact human health. The aim of the current study was to investigate the pharmacokinetics of acephate and chlorpyrifos orally administered at lowest-observed-adverse-effect-level doses in chimeric mice transplanted with human hepatocytes. Absorbed acephate and its metabolite methamidophos were detected in serum from wild type mice and chimeric mice orally administered 150mg/kg. Approximately 70% inhibition of cholinesterase was evident in plasma of chimeric mice with humanized liver (which have higher serum cholinesterase activities than wild type mice) 1day after oral administrations of acephate. Adjusted animal biomonitoring equivalents from chimeric mice studies were scaled to human biomonitoring equivalents using known species allometric scaling factors and in vitro metabolic clearance data with a simple physiologically based pharmacokinetic (PBPK) model. Estimated plasma concentrations of acephate and chlorpyrifos in humans were consistent with reported concentrations. Acephate cleared similarly in humans and chimeric mice but accidental/incidental overdose levels of chlorpyrifos cleared (dependent on liver metabolism) more slowly from plasma in humans than it did in mice. The data presented here illustrate how chimeric mice transplanted with human hepatocytes in combination with a simple PBPK model can assist evaluations of toxicological potential of organophosphorus pesticides.

  11. Comparison of cholinesterase activities in the excretion-secretion products of Trichinella pseudospiralis and Trichinella spiralis muscle larvae

    Directory of Open Access Journals (Sweden)

    Ros-Moreno R.M.

    2002-06-01

    Full Text Available The presence of cholinesterases (ChE is reported in T. pseudospiralis excretion-secretion products (ESP by spectrophotometry method, using acetylthiocholine (ATCI and butyrilthiocholine (BTCI as substrates. By inhibition assays, we found that T. pseudospiralis release both acetyl- and butiryl-cholinesterases (AchE and BchE, respectively. The sedimentation coefficientes of these enzymes were determined by sucrose density gradient. We studied the in vivo ChE secretion by immunoblot assays using AchE from Electrophorus (electric eel and sera from normal or infected mice with T. pseudospiralis or T. spiralis. The presence of anti-AchE antibodies was only demonstrated in the sera from T. pseudospiralis infected mice. Moreover the in vivo secretion was corroborated by the high difference determinate between the ChE activity of the immuno complexes from T. pseudospiralis infected sera and the immunocomplexes from T. spiralis infected sera as well as normal sera. Finally, we analyzed the effect of the organophosphate NeguvónR (metrifonate on the ChE activity from the J. pseudospiralis ESP. The drug inhibits in part this activity. Moreover NeguvónR (metrifonate showed a high activity against the T. pseudospiralis viability.

  12. DEPRESSION OF THE PHOTIC AFTER DISCHARGE OF FLASH EVOKED POTENTIALS BY PHYSOSTIGMINE, CARBARYL AND PROPOXUR AND THE RELATIONSHIP TO INHIBITION OF BRAIN CHOLINESTERASE

    Science.gov (United States)

    The effects of N-methyl carbamate pesticides on the photic after discharge (PhAD) of flash evoked potentials (FEPs) and the relationship between inhibition of brain cholinesterase (ChE) activity and the PhAD were evaluated. FEPs were recorded in Long Evans rats treated with physo...

  13. [The high-pressure chemistry, barophysiological chemistry, comparative enzymology of cholinesterase the 100th anniversary from the birth of A. P. Brestkin].

    Science.gov (United States)

    Rozengart, E V

    2012-01-01

    There are exposed the main landmarks of the scientific biography of Professor Aleksandr Pavlovich Brestkin, connected with his investigations in the field of chemistry of high pressures, physiological chemistry of caisson disease, kinetics of esterase catalysis, and in comparative enzymology of cholinesterases.

  14. Differential acetyl cholinesterase inhibition by volatile oils from two specimens of Marlierea racemosa (Myrtaceae) collected from different areas of the Atlantic Rain Forest.

    Science.gov (United States)

    Souza, Amanda; Silva, Michelle C; Cardoso-Lopes, Elaine M; Cordeiro, Inês; Sobral, Marcos E G; Young, Maria Cláudia M; Moreno, Paulo R H

    2009-08-01

    The volatile oil composition and anti-acetyl cholinesterase activity were analyzed in two specimens of Marlierea racemosa growing in different areas of the Atlantic Rain Forest (Cananéia and Caraguatatuba, SP, Brazil). Component identifications were performed by GC/MS and their acetyl cholinesterase inhibitory activity was measured through colorimetric analysis. The major constituent in both specimens was spathulenol (25.1% in Cananéia and 31.9% in Caraguatatuba). However, the first one also presented monoterpenes (41.2%), while in the Carguatatuba plants, this class was not detected. The oils from the plants collected in Cananéia were able to inhibit the acetyl cholinesterase activity by up to 75%, but for oils from the other locality the maximal inhibition achieved was 35%. These results suggested that the monoterpenes are more effective in the inhibition of acetyl cholinesterase activity than sesquiterpenes as these compounds are present in higher amounts in the M. racemosa plants collected in Cananéia.

  15. BRAIN CHOLINESTERASE INHIBITION PRODUCED BY PROPOXUR AND DEPRESSION OF THE PHOTIC AFTER DISCHARGE OF FLASH EVOKED POTENTIALS IN LONG EVANS RATS.

    Science.gov (United States)

    Propoxur is a widely used N-methyl carbamate pesticide that acts by inhibiting cholinesterases (ChE), which may lead to cholinergic toxicity. Flash evoked potentials (FEPs) are a neurophysiological response following stimulation of the visual system with flashes of light. They ar...

  16. Cholinesterase Inhibition and Depression of the Photic After Discharge of Flash Evoked Potentials Following Acute or Repeated Exposures to a Mixture of Carbaryl and Propoxur

    Science.gov (United States)

    While information exists regarding inhibition of cholinesterase (ChE) activity, little is known about neurophysiological changes produced by a mixture of N-methyl carbamate pesticides. Previously, we reported that acute treatment with propoxur or carbaryl decreased the duration o...

  17. The Determination of the Whole Blood Cholinesterase Activities of Tree Shrews%树鼩全血胆碱酯酶活性测定分析

    Institute of Scientific and Technical Information of China (English)

    木云珍; 曹慧芳; 周肇晏; 杨彤; 王婧; 李波

    2012-01-01

    目的 测定分析树鼩全血胆碱酯酶活性.方法 采用WS/T66-1996全血胆碱酯酶活性的羟胺-三氯化铁分光光度法测定10只树鼩和10只小鼠全血胆碱酯酶活性.结果 树鼩的全血胆碱酯酶活性个体差异比小鼠小,树鼩全血胆碱酯酶活性(μmol/mL全血,37℃,30min)绝对值为94.15±4.65,大于小鼠的平均值78.22±8.77,差异具有统计学意义(P<0.05).结论 树鼩在全血胆碱酯酶活性相关研究方面是较好的实验动物.%Objective To determine and analyse the whole blood cholinesterase activities of Tree Shrews. Method The whole blood cholinesterase activities of 10 rats and 10 Tree Shrews were determinted by WS/T66-1996 hydroxylamine hydrochloride- ferric chloride Spectrophotometer. Results The tree shrew's whole blood cholinesterase activity (μmol/mL, 37℃, 30 min) was 94.15± 4.65 , which was higher than mouse's whole blood cholinesterase activity (78.22± 8.77), the difference was statistically significant (P<0.01). Conclusion Tree shrews are excellent experimental animals for the related research on the whole blood cholinesterase activities.

  18. Colinesterasas eritrocitaria y plasmática en trabajadores con enfermedades crónicas controladas y en usuarios de medicamentos Erythrocytic and plasmatic cholinesterases in workers with chronic controlled diseases and in users of medicines

    Directory of Open Access Journals (Sweden)

    Jaime Carmona Fonseca

    2006-01-01

    nunca hubo diferencia significativa. Tampoco hubo diferencias importan-tes cuando se procedió a comparar los valores enzimáticos entre personas con una enfermedad específica y quienes no la tenían, excepto en el caso de «anemia». CONCLUSIONES: los niveles de colinesterasas eritrocitaria y plasmática son similares entre trabajadores sanos o con enfermedades crónicas controladas, con o sin drogas. PROBLEM: Physiological values of cholinesterase are known in healthy population, but limited information on them is available in individuals with chronic, controlled diseases, either with or without medication. OBJECTIVES: To measure erythrocytic and plasmatic cholinesterase levels in active workers who met the following conditions: to be feeling well and active at their jobs at the time of the study; to suffer from some disease that was under control either with or without medication; not to have been exposed to pesticides based on cholinesterase inhibitors. METHODOLOGY: A survey was carried out among workers affiliated to the Social Security Institute in Antioquia, Colombia, to identify those suffering from some disease and who had it under control. Acetylcholinesterase and butyrylcholinesterase levels were determined using two techniques for the former and three for the latter. Surveyed workers belonged to two different parts of Antioquia, namely: the Aburra Valley and the Near East region. The study sample was made up by 827 persons, 19% of which informed to be suffering from some disease. RESULTS: Prevalence of disease in the Aburra Valley workers was 30% and in those from the Near East region, 9% (p = 0.0000000. The list of their diseases included 13 different ones, the most frequent of which were: hypertension (29%, “liver disease” (16%, anemia (10%, and arthritis (10%. Out of the 827 people, 127 (15% were under some kind of medication at the moment of the study; of them, 85% were being treated with only one drug. Eight per cent were diseased and under

  19. Predictive value of serum cholinesterase for the prognosis of aged patients with systemic inflammatory response syndrome

    Institute of Scientific and Technical Information of China (English)

    JIN Qi-hui; HE Xiao-jun; LI Tian-lang; CHEN Huai-hong

    2011-01-01

    Background Some studies found that cholinesterase (ChE) can be an independent risk factor for patients with multiple organ dysfunction syndrome.To assess aged patients with systemic inflammatory response syndrome (SIRS) early and predict their prognosis,the predictive value of ChE for the prognosis of aged patients with SIRS was analyzed.Methods From September 2009 to September 2010,all aged patients with SIRS in the ICU of the Second Affiliated Hospital of Zhejiang University School of Medicine were retrospectively analyzed if they met inclusion criteria:patients aged >65 years and met American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference criteria for SIRS.Serum ChE,albumin,D-dimer,lactic acid and C-reactive protein (CRP) were measured,and the Acute Physiology and Chronic Health Evaluation (APACHE) Ⅱ and Glasgow Coma Scale (GCS) scores were evaluated within the first 24 hours in the ICU.Fisher's exact test was used for comparison of the primary disease between the deceased group and surviving group.For comparison of study variables between the two groups,the Student's t test or Mann-Whitney U test was used.Multivariate significance was tested with binary Logistic regression analysis.Results The clinical data of 124 aged patients with SIRS were collected and analyzed.Sixty-six patients (46 male,20female,mean age (78.70±8.08) years) who died were included in the deceased group and 58 patients (34 male,24female,mean age (76.02±6.57) years) who survived were included in the surviving group.There were no significant differences in age,gender,APACHE Ⅱ score and GCS score between the deceased group and surviving group (all P>0.05),but there were significant differences in lactic acid (P=0.011),D-dimer (P=0.011),albumin (P=0.007),CRP (P=0.008),and ChE (P <0.0001).The correlation analysis showed that the APACHE Ⅱ score and CRP were not correlated with ChE (both P <0.05).D-dimer and albumin were correlated with Ch

  20. Ferulic acid-carbazole hybrid compounds: Combination of cholinesterase inhibition, antioxidant and neuroprotection as multifunctional anti-Alzheimer agents.

    Science.gov (United States)

    Fang, Lei; Chen, Mohao; Liu, Zhikun; Fang, Xubin; Gou, Shaohua; Chen, Li

    2016-02-15

    In order to search for novel multifunctional anti-Alzheimer agents, a series of ferulic acid-carbazole hybrid compounds were designed and synthesized. Ellman's assay revealed that the hybrid compounds showed moderate to potent inhibitory activity against the cholinesterases. Particularly, the AChE inhibition potency of compound 5k (IC50 1.9μM) was even 5-fold higher than that of galantamine. In addition, the target compounds showed pronounced antioxidant ability and neuroprotective property, especially against the ROS-induced toxicity. Notably, the neuroprotective effect of 5k was obviously superior to that of the mixture of ferulic acid and carbazole, indicating the therapeutic effect of the hybrid compound is better than the combination administration of the corresponding mixture.

  1. Identifying motor and sensory myelinated axons in rabbit peripheral nerves by histochemical staining for carbonic anhydrase and cholinesterase activities

    Science.gov (United States)

    Riley, Danny A.; Sanger, James R.; Matloub, Hani S.; Yousif, N. John; Bain, James L. W.

    1988-01-01

    Carbonic anhydrase (CA) and cholinesterase (CE) histochemical staining of rabbit spinal nerve roots and dorsal root ganglia demonstrated that among the reactive myeliated axons, with minor exceptions, sensory axons were CA positive and CE negative whereas motor axons were CA negative and CE positive. The high specificity was achieved by adjusting reaction conditions to stain subpopulations of myelinated axons selectively while leaving 50 percent or so unstained. Fixation with glutaraldehyde appeared necessary for achieving selectivity. Following sciatic nerve transection, the reciprocal staining pattern persisted in damaged axons and their regenerating processes which formed neuromas within the proximal nerve stump. Within the neuromas, CA-stained sensory processes were elaborated earlier and in greater numbers than CE-stained regenerating motor processes. The present results indicate that histochemical axon typing can be exploited to reveal heterogeneous responses of motor and sensory axons to injury.

  2. Reactivation of human brain homogenate cholinesterases inhibited by Tabun using newly developed oximes K117 and K127.

    Science.gov (United States)

    Kuca, Kamil; Cabal, Jiri; Jung, Yung Sik; Musilek, Kamil; Soukup, Ondrej; Jun, Daniel; Pohanka, Miroslav; Musilova, Lucie; Karasová, Jana; Novotný, Ladislav; Hrabinova, Martina

    2009-09-01

    Newly developed acetylcholinesterase reactivators K117 [1,5-bis(4-hydroxyiminomethylpyridinium)-3-oxapentane dichloride] and K127 [(1-(4-hydroxyiminomethylpyridinium)-5-(4-carbamoylpyridinium)-3-oxapentane dibromide)] were tested for their potency to reactivate tabun-inhibited human brain cholinesterases. Pralidoxime and trimedoxime were chosen as standard reference reactivators. Human tissue was used, as that was closer on the real treatment of human beings. As a result, oxime K127 was found as the best tested reactivator according to the constant k(r), characterizing the overall reactivation process. On the contrary, the maximal reactivation ability expressed as percentage of reactivation was the best for trimedoxime. This differences were caused as a result of using the enzyme from different species. Due to this, experiments on human tissue should be conducted after in vitro and in vivo tests on animals to eliminate such important failures of promising oximes.

  3. 2-Benzoyl-6-benzylidenecyclohexanone analogs as potent dual inhibitors of acetylcholinesterase and butyrylcholinesterase.

    Science.gov (United States)

    Leong, Sze Wei; Abas, Faridah; Lam, Kok Wai; Shaari, Khozirah; Lajis, Nordin H

    2016-08-15

    In the present study, a series of 2-benzoyl-6-benzylidenecyclohexanone analogs have been synthesized and evaluated for their anti-cholinesterase activity. Among the forty-one analogs, four compounds (38, 39, 40 and 41) have been identified as lead compounds due to their highest inhibition on both AChE and BChE activities. Compounds 39 and 40 in particular exhibited highest inhibition on both AChE and BChE with IC50 values of 1.6μM and 0.6μM, respectively. Further structure-activity relationship study suggested that presence of a long-chain heterocyclic in one of the rings played a critical role in the dual enzymes' inhibition. The Lineweaver-Burk plots and docking results suggest that both compounds could simultaneously bind to the PAS and CAS regions of the enzyme. ADMET analysis further confirmed the therapeutic potential of both compounds based upon their high BBB-penetrating. Thus, 2-benzoyl-6-benzylidenecyclohexanone containing long-chain heterocyclic amine analogs represent a new class of cholinesterase inhibitor, which deserve further investigation for their development into therapeutic agents for cognitive diseases such as Alzheimer.

  4. Chronic exposure to cigarette smoke during gestation results in altered cholinesterase enzyme activity and behavioral deficits in adult rat offspring: potential relevance to schizophrenia.

    Science.gov (United States)

    Zugno, Alexandra I; Fraga, Daiane B; De Luca, Renata D; Ghedim, Fernando V; Deroza, Pedro F; Cipriano, Andreza L; Oliveira, Mariana B; Heylmann, Alexandra S A; Budni, Josiane; Souza, Renan P; Quevedo, João

    2013-06-01

    Prenatal cigarette smoke exposure (PCSE) has been associated with physiological and developmental changes that may be related to an increased risk for childhood and adult neuropsychiatric diseases. The present study investigated locomotor activity and cholinesterase enzyme activity in rats, following PCSE and/or ketamine treatment in adulthood. Pregnant female Wistar rats were exposed to 12 commercially filtered cigarettes per day for a period of 28 days. We evaluated motor activity and cholinesterase activity in the brain and serum of adult male offspring that were administered acute subanesthetic doses of ketamine (5, 15 and 25 mg/kg), which serves as an animal model of schizophrenia. To determine locomotor activity, we used the open field test. Cholinesterase activity was assessed by hydrolysis monitored spectrophotometrically. Our results show that both PCSE and ketamine treatment in the adult offspring induced increase of locomotor activity. Additionally, it was observed increase of acetylcholinesterase and butyrylcholinesterase activity in the brain and serum, respectively. We demonstrated that animals exposed to cigarettes in the prenatal period had increased the risk for psychotic symptoms in adulthood. This also occurs in a dose-dependent manner. These changes provoke molecular events that are not completely understood and may result in abnormal behavioral responses found in neuropsychiatric disorders, such as schizophrenia.

  5. Plasma cholinesterase inhibition in the clay-colored robin (Turdus grayi) exposed to diazinon in maradol papaya crops in Yucatan, Mexico

    Science.gov (United States)

    Cobos, V.M.; Mora, M.A.; Escalona, G.

    2006-01-01

    The use of organophosphorous pesticides in agriculture can result in intoxication of birds foraging in sprayed crops. Effects on birds resulting from pesticide intoxication are varied and include behavioral and reproductive effects, including death. One widely used insecticide in Maradol papaya crops is diazinon which has been associated with various incidents of intoxication and death of wild birds. The objective of this study was to evaluate the impact of diazinon application to papaya crops on plasma cholinesterase activity of the clay-colored robin (Turdus grayi). We captured clay-colored robins foraging in a papaya crop the following day after the field had been sprayed with diazinon at a dose of 1.5 kg/ha during March and May, respectively. We took a blood sample from the brachialis vein of the birds captured and measured plasma enzymatic activity. The plasma samples from birds used as controls were taken during the same time period and were analyzed in a similar way. Enzymatic activity of males was greater than that of females (53,52%) and mean cholinesterase inhibition was 49.43%. Cholinesterase inhibition was greater during May than in March probably due to more continuous exposure and ingestion of the insecticide through food and possible absorption through the skin. This degree of enzymatic inhibition is possibly affecting the behavior of the clay-colored robin and could result in death in severe cases.

  6. Monitoring exposure of northern cardinals, Cardinalis cardinalis, to cholinesterase-inhibiting pesticides: enzyme activity, reactivations, and indicators of environmental stress.

    Science.gov (United States)

    Maul, Jonathan D; Farris, Jerry L

    2005-07-01

    Northern cardinals (Cardinalis cardinalis) frequently use agricultural field edges in northeast Arkansas, USA, and may be at risk of exposure to cholinesterase (ChE)-inhibiting pesticides. We monitored northern cardinal exposure to ChE-inhibiting pesticides by comparing plasma total ChE (TChE) activity to reference-derived benchmarks and TChE reactivations. Total ChE and acetylcholinesterase (AChE) were measured for 128 plasma samples from 104 northern cardinals from nine study sites. Of birds sampled from sites treated with ChE-inhibiting pesticides, 4.3% of the samples had TChE activities below the diagnostic threshold (2 standard deviations [SD] below the reference mean) and 8.7% of the samples had TChE reactivations. No difference was found in TChE (p = 0.553) and AChE (p = 0.288) activity between treated and reference sites; however, activity varied among treated sites (p = 0.003). These data do not suggest uniform exposure to individuals, but rather exposure was variable and likely influenced by mitigating factors at individual and site scales. Furthermore, monitoring of TChE reactivation appeared to be a more sensitive indicator of exposure than the diagnostic threshold. Fluctuating asymmetry (FA) was greater at agricultural sites than reference sites (p = 0.016), supporting the hypothesis that FA may be useful for assessing a combination of habitat- and contaminant-related environmental stress.

  7. The Use of Selected Biomarkers, Phagocytic and Cholinesterase Activity to Detect the Effects of Dimethoate on Marine Mussel (Mytilus edulis

    Directory of Open Access Journals (Sweden)

    KHUSNUL YAQIN

    2008-03-01

    Full Text Available Effects of organophosphorous pesticide, dimethoate on blue mussels, Mytilus edulis using selected biomarkers have been studied. Mussels were exposed to serial dilutions of dimethoate, 7.88, 15.75, 31.35, and 63.00 µg/l including positive and negative controls for 14 days. The suppression effects of dimethoate on phagocytic activity significantly occurred at two lowest concentrations of dimethoate (7.88 and 15.75 µg/l, but stimulation effects significantly emerged at the following highest concentrations (31.35 and 63.00 µg/l. The declining tendency of the cholinesterase (ChE activity (23% lower than the control appeared when mussels exposed to 7.88 and 15.75 µg/l dimethoate. Moreover, the significant inhibition of the ChE activity occurred at 31.35 µg/l dimethoate exposure. This study suggested that the phagocytic and the ChE activity are useful biomarkers for assessing the affects of organophosporous pesticide, dimethoate on neuro-immune system of blue mussels, M. edulis.

  8. Assessment of antioxidant, anti-inflammatory, anti-cholinesterase and cytotoxic activities of pomegranate (Punica granatum) leaves.

    Science.gov (United States)

    Bekir, Jalila; Mars, Mohamed; Souchard, Jean Pierre; Bouajila, Jalloul

    2013-05-01

    This study evaluated antioxidant, anti-inflammatory, anti-cholinesterase and cytotoxic activities of extracts with different polarities (hexane, dichloromethane, ethyl acetate, ethanol and methanol) obtained from Punica granatum leaves. Total phenolics (8.8-127.3mg gallic acid equivalent/g dry weight), flavonoids (1.2-76.9mg quercetin equivalent/g dry weight), tannins (63.7-260.8mg catechin equivalent/kg dry weight) and anthocyanins (0.41-3.73mg cyanidin-3-glucoside equivalent/g dry weight) of different extracts were evaluated. The methanolic extract presented a good IC50 by DPPH and ABTS assays (5.62 and 1.31mg/l respectively). The strongest 5-lipoxygenase (5-LOX), acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition activities were obtained for the ethanol extract (IC50 values of 6.20, 14.83 and 2.65mg/l, respectively) and the best cytotoxic activity against MCF-7 cells was obtained for the methanol extract (IC50=31mg/l). These important biological activities showed that P. granatum leaves could be a potential source of the active molecules intended for applications in pharmaceutical industry, but only after additional in vivo experiments.

  9. Naturally Occurring Genetic Variants of Human Acetylcholinesterase and Butyrylcholinesterase and Their Potential Impact on the Risk of Toxicity from Cholinesterase Inhibitors

    Science.gov (United States)

    2016-01-01

    Acetylcholinesterase (AChE) is the physiologically important target for organophosphorus toxicants (OP) including nerve agents and pesticides. Butyrylcholinesterase (BChE) in blood serves as a bioscavenger that protects AChE in nerve synapses from inhibition by OP. Mass spectrometry methods can detect exposure to OP by measuring adducts on the active site serine of plasma BChE. Genetic variants of human AChE and BChE do exist, but loss of function mutations have been identified only in the BCHE gene. The most common AChE variant, His353Asn (H322N), also known as the Yt blood group antigen, has normal AChE activity. The most common BChE variant, Ala567Thr (A539T) or the K-variant in honor of Werner Kalow, has 33% reduced plasma BChE activity. The genetic variant most frequently associated with prolonged response to muscle relaxants, Asp98Gly (D70G) or atypical BChE, has reduced activity and reduced enzyme concentration. Early studies in young, healthy males, performed at a time when it was legal to test nerve agents in humans, showed that individuals responded differently to the same low dose of sarin with toxic symptoms ranging in severity from minimal to moderate. Additionally, animal studies indicated that BChE protects from toxicants that have a higher reactivity with AChE than with BChE (e.g., nerve agents) but not from toxicants that have a higher reactivity with BChE than with AChE (e.g., OP pesticides). As a corollary, we hypothesize that individuals with genetic variants of BChE may be at increased risk of toxicity from nerve agents but not from OP pesticides. PMID:27551784

  10. [Dementia with Lewy bodies; 2 patients with exacerbation due to an atypical antipsychotic, but with a favorable response to the cholinesterase inhibitor rivastigmine

    NARCIS (Netherlands)

    Scheepmaker, A.J.T.M.; Horstink, M.W.I.M.; Hoefnagels, W.H.L.; Strijks, F.E.

    2003-01-01

    In two patients, men aged 80 and 75 years with cognitive deterioration, hallucinations and parkinsonism, the clinical diagnosis 'dementia with Lewy bodies' was established. Treatment with an atypical antipsychotic, risperidone and olanzapine respectively, resulted in an exacerbation of the parkinson

  11. Proton pump inhibitors

    Science.gov (United States)

    Proton pump inhibitors (PPIs) are medicines that work by reducing the amount of stomach acid made by ... Proton pump inhibitors are used to: Relieve symptoms of acid reflux, or gastroesophageal reflux disease (GERD). This ...

  12. Integrated Lateral Flow Test Strip with Electrochemical Sensor for Quantification of Phosphorylated Cholinesterase: Biomarker of Exposure to Organophosphorus Agents

    Energy Technology Data Exchange (ETDEWEB)

    Du, Dan; Wang, Jun; Wang, Limin; Lu, Donglai; Lin, Yuehe

    2012-02-08

    An integrated lateral flow test strip with electrochemical sensor (LFTSES) device with rapid, selective and sensitive response for quantification of exposure to organophosphorus (OP) pesticides and nerve agents has been developed. The principle of this approach is based on parallel measurements of post-exposure and baseline acetylcholinesterase (AChE) enzyme activity, where reactivation of the phosphorylated AChE is exploited to enable measurement of total amount of AChE (including inhibited and active) which is used as a baseline for calculation of AChE inhibition. Quantitative measurement of phosphorylated adduct (OP-AChE) was realized by subtracting the active AChE from the total amount of AChE. The proposed LFTSES device integrates immunochromatographic test strip technology with electrochemical measurement using a disposable screen printed electrode which is located under the test zone. It shows linear response between AChE enzyme activity and enzyme concentration from 0.05 to 10 nM, with detection limit of 0.02 nM. Based on this reactivation approach, the LFTSES device has been successfully applied for in vitro red blood cells inhibition studies using chlorpyrifos oxon as a model OP agent. This approach not only eliminates the difficulty in screening of low-dose OP exposure because of individual variation of normal AChE values, but also avoids the problem in overlapping substrate specificity with cholinesterases and avoids potential interference from other electroactive species in biological samples. It is baseline free and thus provides a rapid, sensitive, selective and inexpensive tool for in-field and point-of-care assessment of exposures to OP pesticides and nerve agents.

  13. Altered quantities and in vivo activities of cholinesterase from Daphnia magna in sub-lethal exposure to organophosphorus insecticides.

    Science.gov (United States)

    Liu, Hongcui; Yuan, Bingqiang; Li, Shaonan

    2012-06-01

    For investigating relationship between activity of cholinesterase (ChE) and ambient concentration of anticholinesterases, Daphnia magna had been exposed for 21 day to sub-lethal concentrations, i.e. 1/6 EC(50), 1/36 EC(50), and 1/216 EC(50), of either triazophos or chlorpyrifos. Samples were taken at different points of time for measuring total activity and immunoreactive content of ChE and actual concentrations of the anticholinesterases. A type of antigen formerly developed by immunizing mice with purified ChE was utilized in this study to establish an indirect non-competitive ELISA for measuring immunoreactive content of ChE in Daphnia. Studies showed that for apparent activity, i.e. activity that was scaled with total protein, the insecticides caused 5.2-6.9 percent inhibition and 17.0-17.7 percent inductions during the 21 d exposure, whereas for inherent activity, i.e. activity that was scaled with immunoreactive protein, no induction was detected during the exposure. Accompanied by up to 65.9 percent and 68.0 percent promotion in terms of the immunoreactive content, up to 42.8 percent and 44.6 percent inhibition in terms of the inherent activity was indicated, respectively, for triazophos and chlopyrifos. Judged by measured concentrations, the inherent activity recovered faster than the rate of dissipation of the anticholinesterases. Result of the study suggested that the inherent activity was more sensitive than the apparent one in predicting sub-lethal and/or long-term stress of anticholinesterases. It also suggested that apart from promotion in terms of content of the ChE, the Daphnia developed capacities to block bio-concentration of anticholinesterases, and these capacities would make it liable to underestimate ambient concentration of anticholinesterases along with the time of exposure.

  14. Efficacy of novel phenoxyalkyl pyridinium oximes as brain-penetrating reactivators of cholinesterase inhibited by surrogates of sarin and VX.

    Science.gov (United States)

    Chambers, Janice E; Chambers, Howard W; Funck, Kristen E; Meek, Edward C; Pringle, Ronald B; Ross, Matthew K

    2016-11-25

    Pyridinium oximes are strong nucleophiles and many are effective reactivators of organophosphate-inhibited cholinesterase (ChE). However, the current oxime reactivators are ineffective at crossing the blood-brain barrier and reactivating brain ChE in the intact organism. Our laboratories have developed a series of substituted phenoxyalkyl pyridinium oximes (US patent 9,227,937 B2) with the goal of identifying reactivators effective in crossing the blood-brain barrier. The first 35 of the series were found to have similar in vitro efficacy as reactivators of ChE inhibited by a sarin surrogate (phthalimidyl isopropyl methylphosphonate, PIMP) or a VX surrogate (nitrophenyl ethyl methylphosphonate, NEMP) in bovine brain preparations as previously observed in rat brain preparations. A number of these novel oximes have shown the ability to decrease the level of ChE inhibition in the brains of rats treated with a high sublethal dosage of either a sarin surrogate (nitrophenyl isopropyl methylphosphonate, NIMP) or the VX surrogate NEMP. Levels of reactivation at 2 h after oxime administration were up to 35% while the currently approved therapeutic, 2-PAM, yielded no reduction in brain ChE inhibition. In addition, there was evidence of attenuation of seizure-like behavior with several of the more effective novel oximes, but not 2-PAM. Therefore these novel oximes have demonstrated an ability to reactivate inhibited ChE in brain preparations from two species and in vivo data support their ability to enter the brain and provide a therapeutic action. These novel oximes have the potential to be developed into improved antidotes for nerve agent therapy.

  15. PATTERN AND SEVERITY OF DIASTOLIC DYSFUNCTION IN ORGANOPHOSPHORUS COMPOUND POISONING PATIENTS IN RELATION TO PLASMA CHOLINESTERASE (PC h E LEVEL IN RURAL POPULATION IN SOUTH INDIA

    Directory of Open Access Journals (Sweden)

    Prashant S

    2015-07-01

    Full Text Available BACKGROUND : Organophosphorus (OP poisoning is a major public health problem in developing world. OP pesticides inhibit carboxylic esterase enzymes including plasma cholinesterase (PChE. Clinical manifestations following OP poisoning can be associated with the extent of decrease of PChE. This study was designed to investigate the relevance of diastolic function of the heart, severity of diastolic dysfunction and the reversibility of dysfunction in organophosphoru s compound poisoning patients in relation to plasma cholinesterase (PChE levels with the treatment. MATERIALS AND METHODS : 76 patients admitted with organophosphorus compound poisoning were evaluated for diastolic dysfunction by echocardiography. Clinical features and the nature of compound involved were recorded. Severity of diastolic dysfunction was assessed. Cholinesterase levels were assessed. Initially there was worsening of diastolic function. As the treatment progressed, there was improvement in the pattern of diastolic dysfunction with the corresponding improvement in cholinesterase level and clinical improvement. This was a cross - sectional study which was conducted from 1st January 2014 to February 2015. RESULTS : In total, mean age of patients were 31.2 (range : 19 - 46 years. Majority of patients were females (68.4%, and agricultural workers (75%. Main clinical findings at the time of admission were congested conjunctiva (83%, pin point pupil (89%, lacrimation (78%, vomiting (69%, non - reactive pupil (85%, respiratory distress (65% and abdominal pain (45%. Mean (SD PChE at 6 hours post - exposure was 3242.6 IU/L. At presentation, cyanosis, muscle weakness, convulsion, respiratory distress and fasciculation were related to cases with >75%reducti on of PChE, while, constricted and nonreactive pupil, lacrimation and congested conjunctivae were related to cases with 50 - 75% reduction and abdominal pain, dryness of conjunctiva, vomiting and diarrhea were related to <50

  16. Effect of a mixture of pyridostigmine and atropine on forced expiratory volume (FEV1), and serum cholinesterase activity in normal subjects

    DEFF Research Database (Denmark)

    Feldt-Rasmussen, B F; Gefke, Kaj; Mosbech, H

    1985-01-01

    Pyridostigmine 0.143 mg kg-1 (maximum 10 mg) and atropine 0.0143 mg kg-1 (maximum 1 mg) were administered i.v. to six healthy male volunteers. Peripheral venous blood samples were drawn for measurement of serum cholinesterase activity. Maximum inhibition of the enzyme was found 5 min after...... injection with a decrease to 27 +/- 5% (mean +/- SEM) of the original activity. Forced expiratory volume in the first 1s (FEV1) was measured at fixed time intervals for 90 min. No decrease in FEV1 was observed; on the contrary, there was a small increase. We conclude that atropine effectively antagonizes...

  17. One-pot synthesis of tetrazole-1,2,5,6-tetrahydronicotinonitriles and cholinesterase inhibition: Probing the plausible reaction mechanism via computational studies.

    Science.gov (United States)

    Hameed, Abdul; Zehra, Syeda Tazeen; Abbas, Saba; Nisa, Riffat Un; Mahmood, Tariq; Ayub, Khurshid; Al-Rashida, Mariya; Bajorath, Jürgen; Khan, Khalid Mohammed; Iqbal, Jamshed

    2016-04-01

    In the present study, one-pot synthesis of 1H-tetrazole linked 1,2,5,6-tetrahydronicotinonitriles under solvent-free conditions have been carried out in the presence of tetra-n-butyl ammonium fluoride trihydrated (TBAF) as catalyst and solvent. Computational studies have been conducted to elaborate two plausible mechanistic pathways of this one-pot reaction. Moreover, the synthesized compounds were screened for cholinesterases (acetylcholinesterase and butyrylcholinesterase) inhibition which are consider to be major malefactors of Alzheimer's disease (AD) to find lead compounds for further research in AD therapy.

  18. Brain choline acetyltransferase and muscarinic receptor sites, brain and liver cholinesterases in precocial Acomys cahirinus and altricial rat during post-natal development.

    Science.gov (United States)

    Michalek, H; Pintor, A; Fortuna, S; Bisso, G M

    1988-01-01

    Brain choline acetyltransferase, acetylcholinesterase with its molecular forms, and muscarinic receptor sites, as well as liver total cholinesterases were evaluated during the first postnatal month in pups of a precocial (Acomys cahirinus) and altricial (rat) murid species. At birth the levels of brain cholinergic markers were higher in the Acomys than in the rat, but in adulthood the differences were smaller or even reversed. The postnatal increase up in the markers to weaning was considerably more pronounced in the rat. However, substantial variations in the patterns of development of the three cholinergic markers within and between species were observed. Liver cholinesterases were considerably higher in Acomys than in rats at all ages investigated. These and literature data are discussed in relation to postnatal, post-conception and post-organogenesis age of pups belonging to the two species. The variability of the ontogenetic patterns between the enzymes suggests that there is some biological control of individual rates of maturation and that it is necessary to be careful in broadly interpreting growth patterns across organs within the same species and across species.

  19. Impact of repeated nicotine and alcohol coexposure on in vitro and in vivo chlorpyrifos dosimetry and cholinesterase inhibition.

    Science.gov (United States)

    Lee, S; Poet, T S; Smith, J N; Hjerpe, A L; Gunawan, R; Timchalk, C

    2011-01-01

    Chlorpyrifos (CPF) is an organophosphorus insecticide, and neurotoxicity results from inhibition of acetylcholinesterase (AChE) by its metabolite, chlorpyrifos-oxon. Routine consumption of alcohol and tobacco modifies metabolic and physiological processes impacting the metabolism and pharmacokinetics of other xenobiotics, including pesticides. This study evaluated the influence of repeated ethanol and nicotine coexposure on in vivo CPF dosimetry and cholinesterase (ChE) response (ChE- includes AChE and/or butyrylcholinesterase (BuChE)). Hepatic microsomes were prepared from groups of naive, ethanol-only (1 g/kg/d, 7 d, po), and ethanol + nicotine (1 mg/kg/d 7 d, sc)-treated rats, and the in vitro metabolism of CPF was evaluated. For in vivo studies, rats were treated with saline or ethanol (1 g/kg/d, po) + nicotine (1 mg/kg/d, sc) in addition to CPF (1 or 5 mg/kg/d, po) for 7 d. The major CPF metabolite, 3,5,6-trichloro-2-pyridinol (TCPy), in blood and urine and the plasma ChE and brain acetylcholinesterase (AChE) activities were measured in rats. There were differences in pharmacokinetics, with higher TCPy peak concentrations and increased blood TCPy AUC in ethanol + nicotine groups compared to CPF only (approximately 1.8- and 3.8-fold at 1 and 5 mg CPF doses, respectively). Brain AChE activities after ethanol + nicotine treatments showed significantly less inhibition following repeated 5 mg CPF/kg dosing compared to CPF only (96 ± 13 and 66 ± 7% of naive at 4 h post last CPF dosing, respectively). Although brain AChE activity was minimal inhibited for the 1-mg CPF/kg/d groups, the ethanol + nicotine pretreatment resulted in a similar trend (i.e., slightly less inhibition). No marked differences were observed in plasma ChE activities due to the alcohol + nicotine treatments. In vitro, CPF metabolism was not markedly affected by repeated ethanol or both ethanol + nicotine exposures. Compared with a previous study of nicotine and CPF exposure, there were no

  20. Time course of cholinesterase inhibition in adult rats treated acutely with carbaryl, carbofuran, formetanate, methomyl, methiocarb, oxamyl or propoxur.

    Science.gov (United States)

    Padilla, S; Marshall, R S; Hunter, D L; Lowit, A

    2007-03-01

    To compare the toxicity of seven N-methyl carbamates, time course profiles for brain and red blood cell (RBC) cholinesterase (ChE) inhibition were established for each. Adult, male, Long Evans rats (n=4-5 dose group) were dosed orally with either carbaryl (30 mg/kg in corn oil); carbofuran (0.5 mg/kg in corn oil); formetanate HCl (10 mg/kg in water); methomyl (3 mg/kg in water); methiocarb (25 mg/kg in corn oil); oxamyl (1 mg/kg in water); or propoxur (20 mg/kg in corn oil). This level of dosing produced at least 40% brain ChE inhibition. Brain and blood were taken from 0.5 to 24 h after dosing for analysis of ChE activity using two different methods: (1) a radiometric method which limits the amount of reactivation of ChE activity, and (2) a spectrophotometric method (Ellman method using traditional, unmodified conditions) which may encourage reactivation. The time of peak ChE inhibition was similar for all seven N-methyl carbamate pesticides: 0.5-1.0 h after dosing. By 24 h, brain and RBC ChE activity in all animals returned to normal. The spectrophotometric method underestimated ChE inhibition. Moreover, there was a strong, direct correlation between brain and RBC ChE activity (radiometric assay) for all seven compounds combined (r(2)=0.73, slope 1.1), while the spectrophotometric analysis of the same samples showed a poor correlation (r(2)=0.09). For formetanate, propoxur, methomyl, and methiocarb, brain and RBC ChE inhibitions were not different over time, but for carbaryl, carbofuran and oxamyl, the RBC ChE was slightly more inhibited than brain ChE. These data indicate (1) the radiometric method is superior for analyses of ChE activity in tissues from carbamate-treated animals (2) that animals treated with these N-methyl carbamate pesticides are affected rapidly, and recover rapidly, and (3) generally, assessment of RBC ChE is an accurate predictor of brain ChE inhibition for these seven pesticides.

  1. Hologram QSAR models of 4-[(diethylamino)methyl]-phenol inhibitors of acetyl/butyrylcholinesterase enzymes as potential anti-Alzheimer agents.

    Science.gov (United States)

    de Souza, Simone Decembrino; de Souza, Alessandra Mendonça Teles; de Sousa, Ana Carolina Corrêa; Sodero, Ana Carolina Rennó; Cabral, Lúcio Mendes; Albuquerque, Magaly Girão; Castro, Helena Carla; Rodrigues, Carlos Rangel

    2012-01-01

    Hologram QSAR models were developed for a series of 36 inhibitors (29 training set and seven test set compounds) of acetyl/butyrylcholinesterase (AChE/BChE) enzymes, an attractive molecular target for Alzheimer's disease (AD) treatment. The HQSAR models (N = 29) exhibited significant cross-validated (AChE, q2 = 0.787; BChE, q2 = 0. 904) and non-cross-validated (AChE, r2 = 0.965; BChE, r2= 0.952) correlation coefficients. The models were used to predict the inhibitory potencies of the test set compounds, and agreement between the experimental and predicted values was verified, exhibiting a powerful predictive capability. Contribution maps show that structural fragments containing aromatic moieties and long side chains increase potency. Both the HQSAR models and the contribution maps should be useful for the further design of novel, structurally related cholinesterase inhibitors.

  2. BRAIN CHOLINESTERASE INHIBITION AND DEPRESSION OF THE PHOTIC AFTER DISCHARGE (PHAD) OF FLASH EVOKED POTENTIALS (FEPS) IN LONG EVANS RATS FOLLOWING ACUTE OR REPEATED EXPOSURES TO A MIXTURE OF CARBARYL AND PROPOXUR.

    Science.gov (United States)

    Carbaryl and propoxur are N-methyl carbamate pesticides (NMCs) which are part of the EPA’s cumulative risk assessments for NMCs. These NMCs inhibit cholinesterase (ChE) activity and may lead to cholinergic disruption of CNS function. We used decreases in the PhAD of FEPs to indic...

  3. Pharmacological treatments of behavioral and psychological symptoms of dementia in Alzheimer's disease: role of acetylcholinesterase inhibitors and memantine.

    Science.gov (United States)

    Desmidt, Thomas; Hommet, Caroline; Camus, Vincent

    2016-09-01

    Behavioral and psychological symptoms of dementia (BPSD) are frequent in Alzheimer's disease (AD). They are associated with disability and suffering for both the patients and their caregivers. Even if BPSD are now well diagnosed and characterized by standardized tools, their treatment remains often challenging in clinical setting because of the frequent and severe side effects of the psychotropic drugs when used in this indication. Evidence-based data confirm that antipsychotics and antidepressants are efficient for the treatment of BPSD but have a poor tolerance profile and their use is problematic. Use of cholinesterase inhibitors and memantine, whom French authorities have questioned the relevance in 2008, also have a significant efficacy on non-cognitive symptoms of AD. Therefore, and although their tolerance profile is considered unsatisfying, they keep an indication in patients with AD and BPSD.

  4. Nonquaternary Cholinesterase Reactivators.

    Science.gov (United States)

    2014-09-26

    C2H5O(e)P(O)OX + H20 - products (15) K BOX __a__ OX + H+ (16) Equations (7) and (8) show the reaction of enzyme (EOH) with EPMP to yield ethyl ...kinetics. The reactivation of ethyl methylphosphonyl-AChE proceeds via the mechanism shown in equation (14): K rr OX + EOP [OX°EOP] - EOP + products (14... ether eluant. The crude product was dissolved in a minimal amount of ether and placed on a silica-gel column. Fractions of 40 mL were collected and

  5. Scutellarin protects against Aβ-induced learning and memory deficits in rats: involvement of nicotinic acetylcholine receptors and cholinesterase

    Institute of Scientific and Technical Information of China (English)

    Li-li GUO; Zhi-zhong GUAN; Yong-lin WANG

    2011-01-01

    increased,but were significantly decreased in the plasma,as compared to the control and the sham operation groups.Scu or piracetam treatment restored the activities in brain and plasma nearly to the levels in the control group.Conclusion:The results suggest that Scu may rescue some of the deleterious effects of Aβ,possibly by stimulating nAChR protein translation and regulating cholinesterase activity.

  6. Toxicity of parathion on embryo and yolk-sac larvae of gilthead seabream (Sparus aurata l.): effects on survival, cholinesterase, and carboxylesterase activity.

    Science.gov (United States)

    Arufe, M Isabel; Arellano, Juana M; Albendín, Gemma; Sarasquete, Carmen

    2010-12-01

    This study was conducted to examine the acute toxicity of the organophosphorus pesticide (OP) parathion on embryos and yolk-sac larvae of gilthead seabream (Sparus aurata), and to investigate the effects of this compound on cholinesterase and carboxylesterase activity of seabream larvae in the phase of endogenous feeding. The 72-h LC50 for yolk-sac larvae (0.523 mg L⁻¹) was about two-fold lower than the 48-h LC50 for embryos (1.005 mg L⁻¹). Parathion significantly inhibited the activity of ChE and CaE activity in yolk sac larvae but there were not significant differences in the sensitivity of both esterases to parathion as inferred by their 72-h IC50 values. Larvae exposed to parathion for 72 h showed a 70% inhibition of the whole body acetylcholinesterase at approximately the LC50.

  7. The tissue distribution of diazinon and the inhibition of blood cholinesterase activities in rats and mice receiving a single intraperitoneal dose of diazinon.

    Science.gov (United States)

    Tomokuni, K; Hasegawa, T; Hirai, Y; Koga, N

    1985-10-01

    The tissue distribution of diazinon and the inhibition of cholinesterase (ChE) activities in plasma, erythrocyte and brain were investigated using male rats and mice which received a single intraperitoneal (i.p.) dose of diazinon (20 or 100 mg/kg body wt) in olive oil. The blood diazinon level was estimated to reach a maximum at 1-2 h after the i.p. administration. It was demonstrated that the diazinon residue levels are the highest in the kidney, when comparing the distribution of diazinon among liver, kidney and brain in the animals after dosing. It was indicated that the ChE inhibition by diazinon exposure is greater in the plasma than in the erythrocytes for male mice, while its inhibition is greater in the erythrocytes for male rats. Brain ChE activity was also inhibited markedly in the mice after dosing.

  8. In vitro reactivation potency of acetylcholinesterase reactivators--K074 and K075--to reactivate tabun-inhibited human brain cholinesterases.

    Science.gov (United States)

    Kuca, Kamil; Cabal, Jiri; Jun, Daniel; Musilek, Kamil

    2007-02-01

    In this work, two oximes for the treatment of tabun-inhibited acetylcholinesterase (AChE; EC 3.1.1.7), K074 (1,4-bis(4-hydroxyiminomethylpyridinium)butane dibromide) and K075 ((E)-1,4-bis(4-hydroxyiminomethylpyridinium)but-2-en dibromide), were tested in vitro as reactivators of AChE. Comparison was made with currently used AChE reactivators (pralidoxime, HI-6, methoxime and obidoxime). Human brain homogenate was taken as an appropriate source of the cholinesterases. As resulted, oxime K074 appears to be the most potent reactivator of tabun-inhibited AChE, with reactivation potency comparable to that of obidoxime. A second AChE reactivator, K075, does not attain as great a reactivation potency as K074, although its maximal reactivation (17%) was achieved at relevant concentrations for humans.

  9. Tabun-inhibited rat tissue and blood cholinesterases and their reactivation with the combination of trimedoxime and HI-6 in vivo.

    Science.gov (United States)

    Bajgar, Jiri; Karasova, Jana Zdarova; Kassa, Jiri; Cabal, Jiri; Fusek, Josef; Blaha, Vaclav; Tesarova, Sandra

    2010-09-06

    Up to now, intensive attempts to synthesize a universal reactivator able to reactivate cholinesterases inhibited by all types of nerve agents/organophosphates were not successful. Therefore, another approach using a combination of two reactivators differently reactivating enzyme was used: in rats poisoned with tabun and treated with combination of atropine (fixed dose) and different doses of trimedoxime and HI-6, changes of acetylcholinesterase activities (blood, diaphragm and different parts of the brain) were studied. An increase of AChE activity was observed following trimedoxime treatment depending on its dose; HI-6 had very low effect. Combination of both oximes showed potentiation of their reactivation efficacy; this potentiation was expressed for peripheral AChE (blood, diaphragm) and some parts of the brain (pontomedullar area, frontal cortex); AChE in the basal ganglia was relatively resistant. These observations suggest that the action of combination of oximes in vivo is different from that observed in vitro.

  10. Interactions of butane, but-2-ene or xylene-like linked bispyridinium para-aldoximes with native and tabun-inhibited human cholinesterases.

    Science.gov (United States)

    Calić, Maja; Bosak, Anita; Kuca, Kamil; Kovarik, Zrinka

    2008-09-25

    Kinetic parameters were evaluated for inhibition of native and reactivation of tabun-inhibited human erythrocyte acetylcholinesterase (AChE, EC 3.1.1.7) and human plasma butyrylcholinesterase (BChE, EC 3.1.1.8) by three bispyridinium para-aldoximes with butane (K074), but-2-ene (K075) or xylene-like linker (K114). Tested aldoximes reversibly inhibited both cholinesterases with the preference for binding to the native AChE. Both cholinesterases showed the highest affinity for K114 (K(i) was 0.01 mM for AChE and 0.06 mM for BChE). The reactivation of tabun-inhibited AChE was efficient by K074 and K075. Their overall reactivation rate constants were around 2000 min(-1)M(-1), which is seven times higher than for the classical bispyridinium para-aldoxime TMB-4. The reactivation of tabun-inhibited AChE assisted by K114 was slow and reached 90% after 20 h. Since the aldoxime binding affinity of tabun-inhibited AChE was similar for all tested aldoximes (and corresponded to their K(i)), the rate of the nucleophilic displacement of the phosphoryl-moiety from the active site serine was the limiting factor for AChE reactivation. On the other hand, none of the aldoximes displayed a significant reactivation of tabun-inhibited BChE. Even after 20 h, the reactivation maximum was 60% for 1 mM K074 and K075, and only 20% for 1 mM K114. However, lower BChE affinities for K074 and K075 compared to AChE suggest that the fast tabun-inhibited AChE reactivation by these compounds would not be obstructed by their interactions with BChE in vivo.

  11. Acetylcholinesterase enzyme inhibitor activity of some novel pyrazinamide condensed 1,2,3,4-tetrahydropyrimidines

    Directory of Open Access Journals (Sweden)

    Karthikeyan Elumalai

    2015-03-01

    Full Text Available A new series of some novel pyrazinamide condensed 1,2,3,4-tetrahydropyrimidines was prepared by reacting of N-(3-oxobutanoylpyrazine-2-carboxamide with urea/thiourea and appropriate aldehyde in the presence of catalytic amount of laboratory made p-toluenesulfonic acid as an efficient catalyst. Confirmation of the chemical structure of the synthesized compounds (4a–l was substantiated by TLC, different spectral data IR, 1H NMR, mass spectra and elemental analysis. The synthesized compounds were evaluated for acetyl and butyl cholinesterase (AChE and BuChE inhibitor activity. The titled compounds exhibited weak, moderate or high AChE and BuChE inhibitor activity. Especially, compound (4l showed the best AChE and BuChE inhibitory activity of all the 1,2,3,4-tetrahydropyrimidine derivatives, with an IC50 value of 0.11 μM and 3.4 μM.

  12. Aging mechanism of butyrylcholinesterase inhibited by an N-methyl analogue of tabun: implications of the trigonal-bipyramidal transition state rearrangement for the phosphylation or reactivation of cholinesterases.

    Science.gov (United States)

    Nachon, Florian; Carletti, Eugenie; Worek, Franz; Masson, Patrick

    2010-09-06

    Cholinesterases are the main target of organophosphorus nerve agents (OPs). Their inhibition results in cholinergic syndrome and death. The enzymes are inhibited by phosphylation of the catalytic serine enzyme, but can be reactivated by oximes to some extent. However, phosphylated cholinesterases undergo a side reaction that progressively prevents their reactivatability. This unimolecular reaction, termed "aging", has been investigated for decades. It was shown that most OP-ChE conjugates aged by O-dealkylation of an alkoxy substituent of the phosphorus atom, a mechanism involving the stabilization of a transient carbocation. In this paper we present structural data supporting a substitution-based mechanism for aging of the huBChE conjugate of an N-mono-methyl analogue of tabun. This mechanism involves an adjacent nucleophilic attack followed by Berry pseudorotation. A similar adjacent attack and subsequent rearrangement of the transition state have been recently proposed for tabun phosphylation of AChE. We suggest that a similar mechanism is also possible for oxime reactivation of phosphylated cholinesterases. This opens new perspectives in terms of reactivator design.

  13. In vitro and in vivo metabolism and inhibitory activities of vasicine, a potent acetylcholinesterase and butyrylcholinesterase inhibitor.

    Directory of Open Access Journals (Sweden)

    Wei Liu

    Full Text Available Vasicine (VAS, a potential natural cholinesterase inhibitor, exhibited promising anticholinesterase activity in preclinical models and has been in development for treatment of Alzheimer's disease. This study systematically investigated the in vitro and in vivo metabolism of VAS in rat using ultra performance liquid chromatography combined with electrospray ionization quadrupole time-of-flight mass spectrometry. A total of 72 metabolites were found based on a detailed analysis of their 1H- NMR and 13C NMR data. Six key metabolites were isolated from rat urine and elucidated as vasicinone, vasicinol, vasicinolone, 1,2,3,9-tetrahydropyrrolo [2,1-b] quinazolin-3-yl hydrogen sulfate, 9-oxo-1,2,3,9-tetrahydropyrrolo [2,1-b] quinazolin-3-yl hydrogen sulfate, and 1,2,3,9-tetrahydropyrrolo [2,1-b] quinazolin-3-β-D-glucuronide. The metabolic pathway of VAS in vivo and in vitro mainly involved monohydroxylation, dihydroxylation, trihydroxylation, oxidation, desaturation, sulfation, and glucuronidation. The main metabolic soft spots in the chemical structure of VAS were the 3-hydroxyl group and the C-9 site. All 72 metabolites were found in the urine sample, and 15, 25, 45, 18, and 11 metabolites were identified from rat feces, plasma, bile, rat liver microsomes, and rat primary hepatocyte incubations, respectively. Results indicated that renal clearance was the major excretion pathway of VAS. The acetylcholinesterase (AChE and butyrylcholinesterase (BChE inhibitory activities of VAS and its main metabolites were also evaluated. The results indicated that although most metabolites maintained potential inhibitory activity against AChE and BChE, but weaker than that of VAS. VAS undergoes metabolic inactivation process in vivo in respect to cholinesterase inhibitory activity.

  14. Identification of Potential Herbal Inhibitor of Acetylcholinesterase Associated Alzheimer’s Disorders Using Molecular Docking and Molecular Dynamics Simulation

    Directory of Open Access Journals (Sweden)

    Chandrabhan Seniya

    2014-01-01

    Full Text Available Cholinesterase inhibitors (ChE-Is are the standard for the therapy of AD associated disorders and are the only class of approved drugs by the Food and Drug Administration (FDA. Additionally, acetylcholinesterase (AChE is the target for many Alzheimer’s dementia drugs which block the function of AChE but have some side effects. Therefore, in this paper, an attempt was made to elucidate cholinesterase inhibition potential of secondary metabolite from Cannabis plant which has negligible or no side effect. Molecular docking of 500 herbal compounds, against AChE, was performed using Autodock 4.2 as per the standard protocols. Molecular dynamics simulations have also been carried out to check stability of binding complex in water for 1000 ps. Our molecular docking and simulation have predicted high binding affinity of secondary metabolite (C28H34N2O6 to AChE. Further, molecular dynamics simulations for 1000 ps suggest that ligand interaction with the residues Asp72, Tyr70-121-334, and Phe288 of AChE, all of which fall under active site/subsite or binding pocket, might be critical for the inhibitory activity of AChE. This approach might be helpful to understand the selectivity of the given drug molecule in the treatment of Alzheimer's disease. The study provides evidence for consideration of C28H34N2O6 as a valuable small ligand molecule in treatment and prevention of AD associated disorders and further in vitro and in vivo investigations may prove its therapeutic potential.

  15. Thrombin inhibitor design.

    Science.gov (United States)

    Sanderson, P E; Naylor-Olsen, A M

    1998-08-01

    Recently, iv formulated direct thrombin inhibitors have been shown to be safe and efficacious alternatives to heparin. These results have fueled the hopes for an orally active compound. Such a compound could be a significant advance over warfarin if it had predictable pharmacokinetics and a duration of action sufficient for once or twice a day dosing. In order to develop an orally active compound which meets these criteria, the deficiencies of the prototype inhibitor efegatran have had to be addressed. First, using a combination of structure based design and empirical structure optimization, more selective compounds have been identified by modifying the P1 group or by incorporating different peptidomimetic P2/P3 scaffolds. Secondly, this optimization has resulted in the development of potent and selective non-covalent inhibitors, thus bypassing the liabilities of the serine trap. Thirdly, oral bioavailability has been achieved while maintaining selectivity and efficacy through the incorporation of progressively less basic P1 groups. The duration of action of these compounds remains to be optimized. Other advances in thrombin inhibitor design have included the development of uncharged P1 groups and the discovery of two non-peptide templates.

  16. ACE inhibitors and proteinuria

    NARCIS (Netherlands)

    Gansevoort, RT; deZeeuw, D; deJong, PE

    1996-01-01

    This review discusses the clinical consequences of urinary protein loss and the effects of inhibitors of the angiotensin converting enzyme (ACE) on this clinical finding. Proteinuria appears to be an important risk factor for renal function deterioration and for cardiovascular mortality. ACE inhibit

  17. Transglutaminase inhibitor from milk

    NARCIS (Netherlands)

    Jong, G.A.H. de; Wijngaards, G.; Koppelman, S.J.

    2003-01-01

    Cross-linking experiments of skimmed bovine milk with bacterial transglutaminase isolated from Streptoverticillium mobaraense showed only some degree of formation of high-molecular-weight casein polymers. Studies on the nature of this phenomenon revealed that bovine milk contains an inhibitor of tra

  18. Inhibitors of histone demethylases

    DEFF Research Database (Denmark)

    Lohse, Brian; Kristensen, Jesper L; Kristensen, Line H;

    2011-01-01

    Methylated lysines are important epigenetic marks. The enzymes involved in demethylation have recently been discovered and found to be involved in cancer development and progression. Despite the relative recent discovery of these enzymes a number of inhibitors have already appeared. Most of the i...

  19. Inhibitors of histone deacetylase

    DEFF Research Database (Denmark)

    2015-01-01

    The present invention relates to compounds of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein X1, X2, X3, X4, X5, W1, W2, W3, and W4 are as described. The present invention relates generally to inhibitors of histone deacetylase and to methods...

  20. Parathion, a cholinesterase-inhibiting plaguicide induces changes in tertiary villi of placenta of women exposed: a scanning electron microscopy study.

    Science.gov (United States)

    Levario-Carrillo, M; Feria-Velasco, A; De Celis, R; Ramos-Martínez, E; Córdova-Fierro, L; Solís, F J

    2001-01-01

    The objective of this work was to describe the anatomy of placentas from women who were at risk of exposure to parathion during their pregnancy, when examined with the light and scanning electron microscopes. Twenty term placentas were analyzed; 10 from women living in an agricultural area, who were at risk of exposure to parathion during their pregnancy, and 10 from women living in an urban area, not expressly exposed to pesticides. Each sample was examined with both light and scanning electron microscopes. Cholinesterase activity was significantly reduced in blood from women of the exposed group. In some placentas of women exposed to parathion, recent microinfarctions, microcalcifications and increased deposition of fibrinoid material were seen, along with a larger proportion of atypical characteristics of villi, such as bullous and balloon-like formations with nonhomogeneous surface, and other areas devoid of microvilli. These observations suggest that in chronic exposure to pesticides, the rate of atypical characteristics of placental villi increases, which could be related to changes in the fetus biology. In this study, one newborn from the exposed group showed intrauterine growth retardation and another one, some signs of hypoxia.

  1. Relationship between serum cholinesterase level and urinary bladder activity in patients with or without overactive bladder and/or neurogenic bladder.

    Science.gov (United States)

    Sugaya, Kimio; Onaga, Tomohiro; Nishijima, Saori; Miyazato, Minoru; Oshiro, Yoshinori; Hokama, Sanehiro; Uchida, Atsushi; Ogawa, Yoshihide

    2007-12-01

    We compared the serum cholinesterase (ChE) level and various parameters between patients with or without overactive bladder (OAB) and/or neurogenic bladder (NB). A total of 258 patients who met the following criteria were enrolled: the presence/absence of OAB and/or NB was documented, laboratory data were available, and liver and renal functions were normal. Patients were divided into the 3 groups: 1) a NB+/OAB+ group who had both NB and OAB, 2) a NB-/OAB+ group who had OAB alone, and 3) an OAB- group who did not have OAB. The relationship between the presence of OAB and various biochemical parameters were examined, as well as the therapeutic outcome in relation to the same biochemical parameters. Forty-three patients had both NB and OAB (NB+/OAB+), 66 patients had OAB without NB (NB-/OAB+), and 149 patients had no OAB (OAB-). Serum ChE, total protein, and albumin levels were lower in the NB-/OAB+ group than the NB+/OAB+ group or the OAB- group. In the NB-/OAB+ group, a higher serum albumin or ChE level was associated with a better therapeutic outcome. These results suggest that a decrease of serum ChE level is related to the occurrence of OAB and the poor response to treatment in OAB patients without NB.

  2. DEVELOPMENT OF REFERENCE RANGES FOR PLASMA TOTAL CHOLINESTERASE AND BRAIN ACETYLCHOLINESTERASE ACTIVITY IN FREE-RANGING CARNABY'S BLACK-COCKATOOS (CALYPTORHYNCHUS LATIROSTRIS).

    Science.gov (United States)

    Vaughan-Higgins, Rebecca; Vitali, Simone; Reiss, Andrea; Besier, Shane; Hollingsworth, Tom; Smith, Gerard

    2016-07-01

    Published avian reference ranges for plasma cholinesterase (ChE) and brain acetylcholinesterase (AChE) are numerous. However, a consistently reported recommendation is the need for species- and laboratory-specific reference ranges because of variables, including assay methods, sample storage conditions, season, and bird sex, age, and physiologic status. We developed normal reference ranges for brain AChE and plasma total ChE (tChE) activity for Carnaby's Black-Cockatoos (Calyptorhynchus latirostris) using a standardized protocol (substrate acetylthiocholine at 25 C). We report reference ranges for brain AChE (19-41 μmol/min per g, mean 21±6.38) and plasma tChE (0.41-0.53 μmol/min per mL, mean 0.47±0.11) (n=15). This information will be of use in the ongoing field investigation of a paresis-paralysis syndrome in the endangered Carnaby's Black-Cockatoos, suspected to be associated with exposure to anticholinesterase compounds and add to the paucity of reference ranges for plasma tChE and brain AChE in Australian psittacine birds.

  3. Benzoylurea Chitin Synthesis Inhibitors.

    Science.gov (United States)

    Sun, Ranfeng; Liu, Chunjuan; Zhang, Hao; Wang, Qingmin

    2015-08-12

    Benzoylurea chitin synthesis inhibitors are widely used in integrated pest management (IPM) and insecticide resistance management (IRM) programs due to their low toxicity to mammals and predatory insects. In the past decades, a large number of benzoylurea derivatives have been synthesized, and 15 benzoylurea chitin synthesis inhibitors have been commercialized. This review focuses on the history of commercial benzolyphenylureas (BPUs), synthetic methods, structure-activity relationships (SAR), action mechanism research, environmental behaviors, and ecotoxicology. Furthermore, their disadvantages of high risk to aquatic invertebrates and crustaceans are pointed out. Finally, we propose that the para-substituents at anilide of benzoylphenylureas should be the functional groups, and bipartite model BPU analogues are discussed in an attempt to provide new insight for future development of BPUs.

  4. Sequencing of aromatase inhibitors

    OpenAIRE

    2005-01-01

    Since the development of the third-generation aromatase inhibitors (AIs), anastrozole, letrozole and exemestane, these agents have been the subject of intensive research to determine their optimal use in advanced breast cancer. Not only have they replaced progestins in second-line therapy and challenged the role of tamoxifen in first-line, but there is also evidence for a lack of cross-resistance between the steroidal and nonsteroidal AIs, meaning that they may be used in sequence to obtain p...

  5. Update on Aromatase Inhibitors

    Directory of Open Access Journals (Sweden)

    Seifert-Klauss V

    2015-01-01

    Full Text Available Aromatase inhibitors (AI block the last phase of estrogen production in many types of tissues which express the enzym aromatase, among them muscle, liver, adrenal, brain and fat. The enzyme catalyzes the last step of the biosynthesis of the estrogens, i. e. the aromatisation of testosterone to estradiol and of androstendion to estrone. Aromatase is localized in the membrane of the endoplasmatic reticulum and is also produced in the placenta and the gonads. Mutations in the gene CYP19A1, which codes for aromatase, can lead either to lack or excess of aromatase. Gene polymorphisms also influence the amount of bioavailable estrogen and bone density.br Indications: AI are approved for the treatment of postmenopausal women with hormone receptor positive breast cancer, both in the adjuvant setting as well as after recurrence and in progressive disease. In premenopausal and in perimenopausal women AI cause an increased sensitivity of the ovaries to follicle stimulating hormone (FSH and can thereby lead to a boosted estrogen answer – this effect is particularly pronounced in early perimenopausal women – so that these situations demand a combination with GnRH-analogue if AI treatment is to be initiated. Alternatively, tamoxifene may be used in premenopausal patients, with or without GnRH analogues. Treatment of premenopausal patients with hormone receptor positive breast cancer with aromatase inhibiting therapy alone constitutes an absolute contraindication. Aromatase inhibitors do not lead to estrogen receptor downregulation or block the receptor such as tamoxifene. An exceptional application is the application in reproductive medicine in women who do not have hormone receptor positive breast cancer: because of the higher sensitivity induced by AI-co-therapy, FSH-doses and -costs for assisted reproduction are reduced, and ovarian hyperstimulation syndrome (OHSS may be avoided. For premenopausal diseases which are said to be positively affected by

  6. Hologram QSAR Models of 4-[(Diethylaminomethyl]-phenol Inhibitors of Acetyl/Butyrylcholinesterase Enzymes as Potential Anti-Alzheimer Agents

    Directory of Open Access Journals (Sweden)

    Carlos Rangel Rodrigues

    2012-08-01

    Full Text Available Hologram QSAR models were developed for a series of 36 inhibitors (29 training set and seven test set compounds of acetyl/butyrylcholinesterase (AChE/BChE enzymes, an attractive molecular target for Alzheimer’s disease (AD treatment. The HQSAR models (N = 29 exhibited significant cross-validated (AChE, q2 = 0.787; BChE, q2 = 0. 904 and non-cross-validated (AChE, r2 = 0.965; BChE, r2 = 0.952 correlation coefficients. The models were used to predict the inhibitory potencies of the test set compounds, and agreement between the experimental and predicted values was verified, exhibiting a powerful predictive capability. Contribution maps show that structural fragments containing aromatic moieties and long side chains increase potency. Both the HQSAR models and the contribution maps should be useful for the further design of novel, structurally related cholinesterase inhibitors.

  7. QSAR, docking, dynamic simulation and quantum mechanics studies to explore the recognition properties of cholinesterase binding sites.

    Science.gov (United States)

    Correa-Basurto, J; Bello, M; Rosales-Hernández, M C; Hernández-Rodríguez, M; Nicolás-Vázquez, I; Rojo-Domínguez, A; Trujillo-Ferrara, J G; Miranda, René; Flores-Sandoval, C A

    2014-02-25

    despite the multiple conformations obtained through MD simulations on both ChEs, the ligand recognition properties were conserved. In fact, the complex formed between ChEs and the best N-aryl compound reproduced the binding mode experimentally reported, where the ligand was coupled into the choline-binding site and stabilized through π-π interactions with Trp82 or Trp86 for BChE and AChE, respectively, suggesting that this compound could be an efficient inhibitor and supporting our model.

  8. It All Starts at the Ends: Multifaceted Involvement of C- and N-Terminally Modified Cholinesterases in Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Amit Berson

    2010-10-01

    Full Text Available In Alzheimer’s disease (AD, premature demise of acetylcholine-producing neurons and the consequent decline of cholinergic transmission associate with the prominent cognitive impairments of affected individuals. However, the enzymatic activities of acetylcholinesterase (AChE and butyrylcholinesterase (BChE are altered rather late in the disease progress. This raised questions regarding the causal involvement of AChE and BChE in AD. Importantly, single nucleotide polymorphisms (SNPs, alternative splicing, and alternate promoter usage generate complex expression of combinatorial cholinesterase (ChE variants, which called for testing the roles of specific variants in AD pathogenesis. We found accelerated amyloid fibril formation in engineered mice with enforced over-expression of the AChE-S splice variant which includes a helical C-terminus. In contrast, the AChE-R variant, which includes a naturally unfolded C-terminus, attenuated the oligomerization of amyloid fibrils and reduced amyloid plaque formation and toxicity. An extended N-terminus generated by an upstream promoter enhanced the damage caused by N-AChE-S, which in cell cultures induced caspases and GSK3 activation, tau hyperphosphorylation, and apoptosis. In the post-mortem AD brain, we found reduced levels of the neuroprotective AChE-R and increased levels of the neurotoxic N-AChE-S, suggesting bimodal contribution to AD progress. Finally, local unwinding of the α-helical C-terminal BChE peptide and loss of function of the pivotal tryptophan at its position 541 impair amyloid fibril attenuation by the common BChE-K variant carrying the A539T substitution, in vitro. Together, our results point to causal yet diverse involvement of the different ChEs in the early stages of AD pathogenesis. Harnessing the neuroprotective variants while reducing the levels of damaging ones may hence underlie the development of novel therapeutics.

  9. In vivo Alterations in Glutathione-Related Processes, Lipid Peroxidation, and Cholinesterase Enzyme Activities in the Liver of Diazinon-Exposed Oreochromis niloticus.

    Science.gov (United States)

    Uner, Nevin; Sevgiler, Yusuf; Durmaz, Hülya; Piner, Petek

    2007-01-01

    ABSTRACT Although its usage is partially banned in developed countries, organophosphate (OP) pesticide diazinon finds extensive agricultural application in our country (Turkey). This study was conducted to evaluate the effects of diazinon on total glutathione (tGSH), GSH-related enzymes, cholinesterase (ChE) enzyme activities, and lipid peroxidation in the liver of Oreochromis niloticus, a freshwater fish, as a model organism. Fish were exposed to 0.1, 1, and 2 mg/L sublethal concentrations of diazinon for 1, 7, 15, and 30 days. Total GSH levels, GSH-related enzyme and ChE-specific activities, and malondialdehyde (MDA) levels were analyzed using spectrophotometric methods. tGSH levels are decreased at 1 day, while they were increased in the long-term period. GSH-related enzyme activities are affected by diazinon exposure, except glutathione reductase (GR; EC 1.6.2.4). Diazinon displayed an oxidative stress-inducing potential and it increased lipid peroxidation. Similar inhibition levels were observed in acetylcholinesterase (AChE; EC 3.1.1.7) and butyrylcholinesterase (BChE; EC 3.1.1.8.) enzyme activities, and these inhibitions were not dose dependent. ChE inhibition-related oxidative stress was observed using its correlation with elevated tGSH levels and increased glutathione S-transferase (GST; EC 2.5.1.18) enzyme activities; that reflects the diazinon-induced oxidative stress in the liver of O. niloticus. According to the results of the present study, tGSH level and GST-specific activity are suitable for reflecting the toxic effects of diazinon in fish.

  10. In vivo evaluation of cholinesterase activity, oxidative stress markers, cyto- and genotoxicity of K048 oxime–a promising antidote against organophosphate poisoning.

    Science.gov (United States)

    Zunec, Suzana; Kopjar, Nevenka; Zeljezić, Davor; Kuca, Kamil; Musilek, Kamil; Lucić Vrdoljak, Ana

    2014-04-01

    K048 is a member of K-oximes, a new oxime class that has recently been confirmed effective against poisoning by the nerve agent tabun and several pesticides. The toxicity profile of the K048 oxime has not been fully characterized and its optimal therapeutic dose has not yet been established. Earlier studies report excellent results with K048 in reactivating tabun-phosphorylated AChE and in the therapy of tabun-poisoned mice. It possesses a low acute toxicity and exerts an acceptable toxicity profile on isolated human peripheral blood lymphocytes in vitro. Intraperitoneal administration of K048 in rats resulted in an LD50 of 238.3 mg/kg. In this in vivo study, we investigated cholinesterase (ChE) activity and oxidative stress marker levels (lipid peroxidation and superoxide dismutase activity) in the plasma of exposed rats after administering the compound at 25% of its LD50. Lymphocyte viability was evaluated using an acridine orange/ethidium bromide in situ fluorescent assay. The levels of primary DNA damage in rat white blood cells were measured using the alkaline comet assay. The compound applied at 25% of its LD50 did not significantly affect ChE activity and lipid peroxidation and did not cause significant changes in the SOD activity in plasma. The cytotoxicity profile of K048 in the tested dose was also acceptable, and it did not possess significant DNA-damaging potential. The obtained results are promising for further evaluations of the K048 oxime, which should include tests on a broader concentration range and longer incubation times.

  11. Development of a Physiologically Based Pharmacokinetic and Pharmacodynamic Model to Determine Dosimetry and Cholinesterase Inhibition for a Binary Mixture of Chlorpyrifos and Diazinon in the Rat

    Energy Technology Data Exchange (ETDEWEB)

    Timchalk, Chuck; Poet, Torka S.

    2008-05-01

    Physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models have been developed and validated for the organophosphorus (OP) insecticides chlorpyrifos (CPF) and diazinon (DZN). Based on similar pharmacokinetic and mode of action properties it is anticipated that these OPs could interact at a number of important metabolic steps including: CYP450 mediated activation/detoxification, and blood/tissue cholinesterase (ChE) binding/inhibition. We developed a binary PBPK/PD model for CPF, DZN and their metabolites based on previously published models for the individual insecticides. The metabolic interactions (CYP450) between CPF and DZN were evaluated in vitro and suggests that CPF is more substantially metabolized to its oxon metabolite than is DZN. These data are consistent with their observed in vivo relative potency (CPF>DZN). Each insecticide inhibited the other’s in vitro metabolism in a concentration-dependent manner. The PBPK model code used to described the metabolism of CPF and DZN was modified to reflect the type of inhibition kinetics (i.e. competitive vs. non-competitive). The binary model was then evaluated against previously published rodent dosimetry and ChE inhibition data for the mixture. The PBPK/PD model simulations of the acute oral exposure to single- (15 mg/kg) vs. binary-mixtures (15+15 mg/kg) of CFP and DZN at this lower dose resulted in no differences in the predicted pharmacokinetics of either the parent OPs or their respective metabolites; whereas, a binary oral dose of CPF+DZN at 60+60 mg/kg did result in observable changes in the DZN pharmacokinetics. Cmax was more reasonably fit by modifying the absorption parameters. It is anticipated that at low environmentally relevant binary doses, most likely to be encountered in occupational or environmental related exposures, that the pharmacokinetics are expected to be linear, and ChE inhibition dose-additive.

  12. Use of enzyme inhibitors to evaluate the conversion pathways of ester and amide prodrugs: a case study example with the prodrug ceftobiprole medocaril.

    Science.gov (United States)

    Eichenbaum, Gary; Skibbe, Jennifer; Parkinson, Andrew; Johnson, Mark D; Baumgardner, Dawn; Ogilvie, Brian; Usuki, Etsuko; Tonelli, Fred; Holsapple, Jeff; Schmitt-Hoffmann, Anne

    2012-03-01

    An approach was developed that uses enzyme inhibitors to support the assessment of the pathways that are responsible for the conversion of intravenously administered ester and amide prodrugs in different biological matrices. The methodology was applied to ceftobiprole medocaril (BAL5788), the prodrug of the cephalosporin antibiotic, ceftobiprole. The prodrug was incubated in plasma, postmitochondrial supernatant fractions from human liver (impaired and nonimpaired), kidney, and intestine as well as erythrocytes, in the presence and absence of different enzyme inhibitors (acetylcholinesterase, pseudocholinesterase, retinyl palmitoyl hydrolase, serine esterases, amidases, and cholinesterase). Hydrolysis was rapid, extensive, and not dependent on the presence of β-nicotinamide-adenine dinucleotide phosphate (reduced form) in all matrices tested, suggesting the involvement of carboxylesterases but not P450 enzymes. Hydrolysis in healthy human plasma was rapid and complete and only partially inhibited in the presence of paraoxonase inhibitors or in liver from hepatic impaired patients, suggesting involvement of nonparaoxonase pathways. The results demonstrate the utility of this approach in confirming the presence of multiple conversion pathways of intravenously administered prodrugs and in the case of BAL5788 demonstrated that this prodrug is unlikely to be affected by genetic polymorphisms, drug interactions, or other environmental factors that might inhibit or induce the enzymes involved in its conversion.

  13. Inhibitors of lysosomal cysteine proteases

    Directory of Open Access Journals (Sweden)

    Lyanna O. L.

    2011-04-01

    Full Text Available The review is devoted to the inhibitors of cysteine proteinases which are believed to be very important in many biochemical processes of living organisms. They participate in the development and progression of numerous diseases that involve abnormal protein turnover. One of the main regulators of these proteinases is their specific inhibitors: cystatins. The aim of this review was to present current knowledge about endogenous inhibitors of lysosomal cysteine proteases and their synthetic analogs.

  14. ACE INHIBITORS: A COMPREHENSIVE REVIEW

    Directory of Open Access Journals (Sweden)

    Pradeep Kumar Arora* and Ashish Chauhan

    2013-02-01

    Full Text Available Hypertension is a chronic increase in blood pressure, characterized as primary and secondary hypertension. The disorder is associated with various risk factors like obesity, diabetes, age, lack of exercise etc. Hypertension is being treated since ancient times by Ayurvedic, Chinese and Unani medicine. Now various allopathic drugs are available which include diuretics, calcium channel blockers, α-blockers, β-blockers, vasodilators, central sympatholytics and ACE-inhibitors. Non-pharmacological treatments include weight reduction, dietary sodium reduction, increased potassium intake and reduction in alcohol consumption. ACE-inhibitors are widely used in the treatment of hypertension by inhibiting the angiotensin converting enzyme responsible for the conversion of angiotensin I to angiotensin II (responsible for vasoconstriction. Various structure activity relationship studies led to the synthesis of ACE-inhibitors, some are under clinical development. This comprehensive review gives various guidelines on classification of hypertension, hypertension therapy including ancient, pharmacological, non-pharmacological therapies, pharmacoeconomics, historical perspectives of ACE, renin, renin angiotensin system (circulating vs local RAS, mechanism of ACE inhibitors, and development of ACE inhibitors. Review also emphasizes on the recent advancements on ACE inhibitors including drugs in clinical trials, computational studies on ACE-inhibitors, peptidomimetics, dual, natural, multi-functional ACE inhibitors, and conformational requirements for ACE-inhibitors.

  15. Acetylcholinesterase Inhibitors: Pharmacology and Toxicology

    OpenAIRE

    Čolović, Mirjana B.; Krstić, Danijela Z; Lazarević-Pašti, Tamara D; Bondžić, Aleksandra M; Vasić, Vesna M

    2013-01-01

    Acetylcholinesterase is involved in the termination of impulse transmission by rapid hydrolysis of the neurotransmitter acetylcholine in numerous cholinergic pathways in the central and peripheral nervous systems. The enzyme inactivation, induced by various inhibitors, leads to acetylcholine accumulation, hyperstimulation of nicotinic and muscarinic receptors, and disrupted neurotransmission. Hence, acetylcholinesterase inhibitors, interacting with the enzyme as their primary target, are appl...

  16. Therapeutic applications of selective and non-selective inhibitors of monoamine oxidase A and B that do not cause significant tyramine potentiation.

    Science.gov (United States)

    Youdim, Moussa B H; Weinstock, Marta

    2004-01-01

    The major side effect with the use of first generation of non selective monoamine oxidase (MAO) inhibitors as neuropsychiatric drugs was what became known as the "cheese reaction". Namely, potentiation of sympathomimetic activity of ingested tyramine present in cheese and other food stuff, resulting from its ability to release noradrenaline, when prevented from metabolism by MAO. The identification of two forms of MAO, termed types A and B and their selective irreversible inhibitors resolved some of this problems. However irreversible MAO-A inhibitors continue to induce a cheese reaction, whereas MAO-B inhibitors at their selective dosage did not and led to introduction of L-deprenyl (selegiline) as an anti-Parkinson drug, since dopamine is equally well metabolized by both enzyme forms. The cheese reaction is a consequence of inhibition of MAO-A, the enzyme responsible for metabolism of noradrenaline and serotonin, located in peripheral adrenergic neurons. The consequence of these findings were the development of reversible MAO-A inhibitors (RIMA), moclobemide and brofaromin, as antidepressants and possible anti-Parkinson activity, with limited tyramine potentiation, since the amine can displace the inhibitor from its binding site on the enzyme. It has always been deemed a greater pharmacological advantage to inhibit both forms of the enzymes to get the full functional activities of the amine neurotransmitters, and without inducing a "cheese reaction". This was not possible until recently, with the development of the novel cholinesterase-brain selective MAO-AB inhibitor, TV3326 (N-propargyl-(3R)-aminoidnan-5-yl-ethyl methylcarbamate hemitartiate), a carbamate derivative of the irreversible MAO-B inhibitor anti-Parkinson drug, rasagiline. This drug is a brain selective MAO-A and B inhibitor, with little inhibition of liver and small intestine enzymes. Pharmacologically it has limited tyramine potentiation, very similar to moclobemide and being a MAO-AB inhibitor it

  17. Proteinaceous alpha-araylase inhibitors

    DEFF Research Database (Denmark)

    Svensson, Birte; Fukuda, Kenji; Nielsen, P.K.;

    2004-01-01

    Proteins that inhibit alpha-amylases have been isolated from plants and microorganisms. These inhibitors can have natural roles in the control of endogenous a-amylase activity or in defence against pathogens and pests; certain inhibitors are reported to be antinutritional factors. The alpha-amylase...... inhibitors belong to seven different protein structural families, most of which also contain evolutionary related proteins without inhibitory activity. Two families include bifunctional inhibitors acting both on alpha-amylases and proteases. High-resolution structures are available of target alpha-amylases...... in complex with inhibitors from five families. These structures indicate major diversity but also some similarity in the structural basis of alpha-amylase inhibition. Mutational analysis of the mechanism of inhibition was performed in a few cases and various protein engineering and biotechnological...

  18. Proteinase inhibitors in Brazilian leguminosae

    Directory of Open Access Journals (Sweden)

    C. A. M. Sampaio

    1991-01-01

    Full Text Available Serine proteinase inhitors, in the seeds of several Leguminosae from the Pantanal region (West Brazil, were studied using bovine trypsin, a digestive enzyme, Factor XIIa and human plasma Kallikrein, two blood clotting factors. The inhibitors were purified from Enterolobium contortisiliquum (Mr=23,000, Torresea cearensis (Mr = 13,000, Bauhinia pentandra (Mr = 20,000 and Bauhinia bauhinioides (Mr = 20,000. E. contortisiliquum inhibitor inactivates all three enzymes, whereas the T. cearensis inhibitor inactivates trypsin and Factor XSSa, but does nor affect plasma kallikrein; both Bauhinia inhibitors, on the other hand, inactivate trypsin and plasma kallikrein but only the Bpentandra inhibitor affects Factor XIIa. Ki values were calculated between 10 [raised to the power of] -7 and 10 [raised to the power of] -8 M.

  19. Dynamic changes of serum cholinesterase activity after severe trauma%严重创伤后血清胆碱酯酶活性的动态变化

    Institute of Scientific and Technical Information of China (English)

    Li BA; Ding-qian WU; An-yu QIAN; Mao ZHANG; Bing XIONG

    2014-01-01

    Objective: The aim of the present study was to examine dynamic changes in serum cholinesterase (ChE) activity during early-stage severe trauma and the clinical significance of these changes. Methods: This prospective, observational study included 81 patients with severe trauma who were treated between October 2011 and April 2013 in the emergency intensive care unit (EICU) of a university-affiliated, tertiary-care, grade A general hospital in China. Serum ChE activity was measured on Days 1, 3, and 7 post-injury. The correlation of dynamic changes in serum ChE activity with trauma severity and prognosis was assessed. Correlations between changes in serum ChE activity after injury and albumin (ALB), prealbumin (PAB), transferrin (TRF), and C-reactive protein (CRP) levels were also analyzed. Results: Serum ChE activity in trauma patients was 42.3%–50.2% lower on Days 1, 3, and 7 compared with the control (P25 subgroup. ChE activity was significantly lower in both the death and the ISS>25 subgroups than in the survival and ISS≤25 subgroups on Days 1, 3, and 7 after injury. Activity was negatively correlated with ISS and acute physiology and chronic health evaluation III (APACHE III) at al time points. When comparing the receiver operating characteristic (ROC) curves for predicting prognosis, the area under the curve (AUC) in the plot of serum ChE was similar to the AUCs in plots of ISS and APACHE III, but significantly smaler than the AUC in the plot of the trauma and injury severity score (TRISS). Serum ChE activity was positively correlated with ALB, PAB, and TRF at al time points post-injury. Activity was not significantly correlated with CRP on Day 1, but was significantly and negatively correlated with CRP on Days 3 and 7. Conclusions: There is a significant decrease in serum ChE activity after severe trauma. Serum ChE may be regarded as a negative acute phase protein (APP) and the dynamic changes in serum ChE may be useful as an auxiliary indicator for

  20. Depression of the photic after discharge of flash evoked potentials by physostigmine, carbaryl and propoxur, and the relationship to inhibition of brain cholinesterase.

    Science.gov (United States)

    Mwanza, Jean-Claude; Finley, Dana; Spivey, Christopher L; Graff, Jaimie E; Herr, David W

    2008-01-01

    The effects of N-methyl carbamate pesticides on the photic after discharge (PhAD) of flash evoked potentials (FEPs) and the relationship between inhibition of brain cholinesterase (ChE) activity and the PhAD were evaluated. FEPs were recorded in Long Evans rats treated with physostigmine (s.c.) 0, 0.05, 0.1, 0.2 or 0.3mg/kg (free base), in an ascorbic acid/saline vehicle, carbaryl (p.o.) 0, 1, 3, 10, 30, 50 or 75 mg/kg, or propoxur (p.o.) 0, 0.3, 3, 10, 20, 30, or 40 mg/kg in a corn oil vehicle. Physostigmine served as positive control based on literature data. Early (e.g. peak N(36)) and late FEP components (peak N(166) and PhAD) are related to the initial retino-geniculate afferent volley and higher cortical processing of visual information, respectively. Compared to controls, the PhAD duration decreased following treatment with 0.1 and 0.3mg/kg physostigmine, 7 5 mg/kg carbaryl or 30 mg/kg propoxur. Lesser changes were noted in FEP amplitudes or peak latencies. Treatment with 0.2 or 0.3 mg/kg physostigmine increased peak N(36) latency. Peak N(166) latency increased only following exposure to 40 mg/kg propoxur. None of the compounds altered peak N(36) or N(166) amplitudes. Hypothermia was observed at doses greater than 0.05 mg/kg physostigmine, at 30 or 50 mg/kg carbaryl, and after treatment with 10, 20 or 40 mg/kg propoxur. Inhibition of brain ChE activity occurred at dosages greater than 0.05 mg/kg physostigmine, 1mg/kg carbaryl, and 0.3 mg/kg propoxur. Linear regression analysis indicated that the decrease in PhAD duration correlated with decrease in brain ChE activity. The results indicate that at 30 min after treatment, inhibition of brain ChE activity did not affect cortical processing of the input from the retino-geniculate volley (evidenced by unaltered peak N(36) amplitude). However, the data suggest that disruption of cortical processing of visual signals related to FEP late components, as indicated by depression of the PhAD, was related to inhibition

  1. 磷化铝中毒抑制大鼠胆碱酯酶及阿托品和氯解磷啶的作用%Cholinesterase inhibition by aluminium phosphide poisoning in rats and effects of atropine and pralidoxime chloride

    Institute of Scientific and Technical Information of China (English)

    Shivani MHrRA; Sharda Shah PESHIN; Shyam Bala LALL

    2001-01-01

    AIM: To investigate the cholinesterase inhibition and effect of atropine and pralidoxime (PAM) treatment on the survival time in the rat model of aluminium phosphide (ALP) poisoning. METHODS: The rats were treated with AlP (10 mg/kg; 5.55×LD50; ig) and the survival time was noted. The effect of atropine (1 mg/kg, ip) and PAM (5 mg/kg, ip) was noted on the above. Atropine and PAM were administered 5 min after AlP. Plasma cholinesterase levels were measured spectrophotometrically in the control and AlP treated rats 30 min after administration. RESULTS: Treaanent with atropine and PAM increased the survival time by 2.5 fold (1.4 h ±0.3 h vs 3.4 h±2.5 h, P<0.01) in9 out of 15 animals and resulted in total survival of the 6 remaining animals. Plasma cholinesterase levels were inhibited by 47%, (438±74) U/L in AlP treated rats as compared tocontrol (840±90) U/L (P<0.01). CONCLUSION: This preliminary study concludes that AlP poisoning causes cholinesterase inhibition and responds to treatment with atropine and PAM.

  2. [ACE inhibitors and the kidney].

    Science.gov (United States)

    Hörl, W H

    1996-01-01

    Treatment with ACE inhibitors results in kidney protection due to reduction of systemic blood pressure, intraglomerular pressure, an antiproliferative effect, reduction of proteinuria and a lipid-lowering effect in proteinuric patients (secondary due to reduction of protein excretion). Elderly patients with diabetes melitus, coronary heart disease or peripheral vascular occlusion are at risk for deterioration of kidney function due to a high frequency of renal artery stenosis in these patients. In patients with renal insufficiency dose reduction of ACE inhibitors is necessary (exception: fosinopril) but more important is the risk for development of hyperkalemia. Patients at risk for renal artery stenosis and patients pretreated with diuretics should receive a low ACE inhibitor dosage initially ("start low - go slow"). For compliance reasons once daily ACE inhibitor dosage is recommended.

  3. Study of the correlation between blood cholinesterases activity, urinary dialkyl phosphates, and the frequency of micronucleated polychromatic erythrocytes in rats exposed to disulfoton

    Directory of Open Access Journals (Sweden)

    Mariane Gonçalves Santos

    2013-03-01

    Full Text Available Organophosphates (OPs are widely used as pesticides, and its urinary metabolites as well as the blood cholinesterases (ChEs activity have been reported as possible biomarkers for the assessment of this pesticide exposure. Moreover, the OPs can induce mutagenesis, and the bone marrow micronucleus test is an efficient way to assess this chromosomal damage. This paper reports a study carried out to verify the correlation among the disulfoton exposure, blood ChEs activity, urinary diethyl thiophosphate (DETP, and diethyl dithiophosphate (DEDTP, as well as micronucleated polychromatic erythrocytes (MNPCEs frequency. Four groups of rats (n=12 were exposed to disulfoton at 0, 2.8, 4.7, and 6.6 mg kg-1 body weight. The blood ChEs activity, urinary DETP and DEDTP concentrations, and MNPCEs frequency were determined. It was observed that the plasmatic and erythrocytary ChEs activity decreased from 2.9% to 0.5% and from 35.9 to 3.3%, respectively, when the disulfoton dose was increased from 0 to 6.6 mg kg-1 (correlation of 0.99. Urinary DETP and DEDTP concentrations, as well as the MNPCEs frequency, increased from 0 to 6.58 µg mL-1, from 0 to 0.04 µg mL-1, and from 0 to 1.4%, respectively, when the disulfoton dose was increased from 0 to 6.58 mg kg-1 body weight.Os organofosforados (OPs são amplamente usados como praguicidas e a atividade da colinesterase sanguínea bem como os metabólitos urinários desses praguicidas têm sido reportados como biomarcadores eficazes para avaliar casos de exposição. Além disso, os OPs podem induzir mutagênese e o teste de micronúcleo de medula óssea é uma boa alternativa para avaliar os danos cromossômicos. Esse artigo reporta um estudo sobre a correlação entre a exposição a dissulfoton, a atividade da colinesterase sanguínea, a excreção urinária de dietil tiofosfato e dietil ditiofosfato e a frequência de micronúcleos em eritrócitos policromáticos. Quatro grupos de ratos (n=12 foram expostos a

  4. In Vitro Comparison of Two Most Promising H-Oximes (HI-6 and HLö-7) and Currently Commercially Available Reactivators Pralidoxime and Obidoxime in Reactivation of Cyclosarin-Inhibited Human Cholinesterases.

    Science.gov (United States)

    Kuca, Kamil; Cabal, Jiri; Jun, Daniel; Koleckar, Vit

    2008-01-01

    ABSTRACT This study describes the evaluation of the in vitro ability of two acetylcholinesterase (EC 3.1.1.7) reactivators, HI-6 and HLö-7, very promising at present, to reactivate human brain cholinesterases inhibited by the nerve agent cyclosarin. The results obtained (percentage of reactivation and appropriate constants characterizing the whole reactivation process) were compared with two currently available reactivators on the market: pralidoxime and obidoxime. It is clear that both promising oximes surpassed the potency of standard reactivators, especially at human relevant concentrations (10(-4) M and lower). Because of the prohibition of such experiments on humans, data obtained in this study could be used as input data for prediction of in vivo action of these drugs in future.

  5. Atividade colinesterásica cerebral e comportamento de ratos após exposição perinatal ao diclorvós Brain cholinesterase activity and the behavior of rats after perinatal exposure to dichlorvos

    Directory of Open Access Journals (Sweden)

    Jaqueline Pérola de Souza

    2006-04-01

    Full Text Available O organofosforado diclorvós impregnado em coleiras plásticas é um recurso utilizado em medicina veterinária que visa ao controle de ectoparasitas de cães e gatos. O objetivo deste trabalho foi avaliar os efeitos do uso de coleiras plásticas impregnadas com diclorvós (8,37% em ratas Wistar durante o período de gestação e lactação, como possível fonte de alterações comportamentais e da atividade colinesterásica cerebral dos filhotes. Na desmama, não houve diferença na atividade colinesterásica cerebral entre as mães tratadas com diclorvós e o grupo controle, bem como entre os respectivos filhotes. O tratamento com diclorvós também não influenciou no comportamento geral dos animais, avaliado no campo aberto, nem no nível de ansiedade testado no labirinto em cruz elevado, ambos aos 35 dias pós-natal.The organophosphate dichlorvos impregnated into plastic collars (8.37% is used in veterinary practice as an alternative for the control of ectoparasites in dogs and cats. The aim of this work was to determine the possible toxic effects of these collars in female Wistar rats during pregnancy and lactation, as a possible cause of alterations in brain cholinesterase activity and behavior of offspring. At weaning, there was no difference in brain cholinesterase activity between control and treated dams, nor between their respective offspring as well. The treatment did not affect the general behavior of the offspring, when evaluated in the open field, nor anxiety in the elevated plus-maze, both evaluated on the 35th postnatal day.

  6. 庫存血液膽碱酯酶水平變化及其在重症有機磷中毒搶救中應用選擇%Alteration of Banked Blood Cholinesterase Level and Its Significance in Emergency Treatment of Acute Organophosphorus Pesticide Poisoning

    Institute of Scientific and Technical Information of China (English)

    鍾沛霖; 王勤鷹; 盛慧球

    2002-01-01

    目的觀察庫血保存天數與血漿膽碱酯酶(CHE)水平變化關係;探討重症有機磷農藥中毒(AOPP)搶救中合理選擇血源.方法輸血前隨機留取保留不同天數的庫血測定血漿CHE值;血液中心採血當日留取正常人血漿、即日測定CHE值作對照組.CHE測定用BM公司膽碱酯酶試劑盒,Roch公司的Cobas-FaraⅡ自動分析儀測定.結果庫血保存天數為第一天的血漿CHE值與正常對照組比較無顯著差異(p>o.05),其他各組均顯著低於對照組(P>0.05).各組與正常對照組相比較其下降百分比約19%-83%.保存天數與CHE值呈負相關(r=-0.7929,P<0.01).曲線回歸Y=-1 823.3Ln(X)+6229.4.結論隨採血後庫血保存天數的增加,血漿CHE值逐漸下降.在重度AOPP搶救中,以使用保留天數為一天以內新鮮血液最為適宜,以免浪費血源,貽( )搶救時機.本報告為強調輸入新鮮血液,保證高活性膽碱酯酶輸入提供實驗依據,並可供臨床參考.%Objective To observe the relationship between the preservation days of banked blood and the alteration level of plasma cholinesterase(CHE) with the aim of making proper selection of banked blood in emergency treatment of acute organophosphorus pesticide poisoning (AOPP). Methods We selected at random the banked blood that has been stored for different length of time before blood transfusion so as to determine the plasma cholinesterase value. The normal plasma cholinesterase value was determined on blood samples in the Blood Center which served as a control group. The cholinesterase value was determined with a kit of the BM Company and the Cobas-Fara Ⅱ automatic analysis of the Roch Company. Results It was found that there was no significant difference of plasma cholinesterase value between the one-day banked blood and the normal control group (P>0.05), but the plasma cholinesterase values of the other experiment groups were all significantly lower than that of the control group(P<0.05). As

  7. Diverse inhibitors of aflatoxin biosynthesis.

    Science.gov (United States)

    Holmes, Robert A; Boston, Rebecca S; Payne, Gary A

    2008-03-01

    Pre-harvest and post-harvest contamination of maize, peanuts, cotton, and tree nuts by members of the genus Aspergillus and subsequent contamination with the mycotoxin aflatoxin pose a widespread food safety problem for which effective and inexpensive control strategies are lacking. Since the discovery of aflatoxin as a potently carcinogenic food contaminant, extensive research has been focused on identifying compounds that inhibit its biosynthesis. Numerous diverse compounds and extracts containing activity inhibitory to aflatoxin biosynthesis have been reported. Only recently, however, have tools been available to investigate the molecular mechanisms by which these inhibitors affect aflatoxin biosynthesis. Many inhibitors are plant-derived and a few may be amenable to pathway engineering for tissue-specific expression in susceptible host plants as a defense against aflatoxin contamination. Other compounds show promise as protectants during crop storage. Finally, inhibitors with different modes of action could be used in comparative transcriptional and metabolomic profiling experiments to identify regulatory networks controlling aflatoxin biosynthesis.

  8. Corrosion inhibitors from expired drugs.

    Science.gov (United States)

    Vaszilcsin, Nicolae; Ordodi, Valentin; Borza, Alexandra

    2012-07-15

    This paper presents a method of expired or unused drugs valorization as corrosion inhibitors for metals in various media. Cyclic voltammograms were drawn on platinum in order to assess the stability of pharmaceutically active substances from drugs at the metal-corrosive environment interface. Tafel slope method was used to determine corrosion rates of steel in the absence and presence of inhibitors. Expired Carbamazepine and Paracetamol tablets were used to obtain corrosion inhibitors. For the former, the corrosion inhibition of carbon steel in 0.1 mol L(-1) sulfuric acid solution was about 90%, whereas for the latter, the corrosion inhibition efficiency of the same material in the 0.25 mol L(-1) acetic acid-0.25 mol L(-1) sodium acetate buffer solution was about 85%.

  9. Cardanol-derived AChE inhibitors: Towards the development of dual binding derivatives for Alzheimer's disease.

    Science.gov (United States)

    Lemes, Laís Flávia Nunes; de Andrade Ramos, Giselle; de Oliveira, Andressa Souza; da Silva, Fernanda Motta R; de Castro Couto, Gina; da Silva Boni, Marina; Guimarães, Marcos Jorge R; Souza, Isis Nem O; Bartolini, Manuela; Andrisano, Vincenza; do Nascimento Nogueira, Patrícia Coelho; Silveira, Edilberto Rocha; Brand, Guilherme D; Soukup, Ondřej; Korábečný, Jan; Romeiro, Nelilma C; Castro, Newton G; Bolognesi, Maria Laura; Romeiro, Luiz Antonio Soares

    2016-01-27

    Cardanol is a phenolic lipid component of cashew nut shell liquid (CNSL), obtained as the byproduct of cashew nut food processing. Being a waste product, it has attracted much attention as a precursor for the production of high-value chemicals, including drugs. On the basis of these findings and in connection with our previous studies on cardanol derivatives as acetylcholinesterase (AChE) inhibitors, we designed a novel series of analogues by including a protonable amino moiety belonging to different systems. Properly addressed docking studies suggested that the proposed structural modifications would allow the new molecules to interact with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE, thus being able to act as dual binding inhibitors. To disclose whether the new molecules showed the desired profile, they were first tested for their cholinesterase inhibitory activity towards EeAChE and eqBuChE. Compound 26, bearing an N-ethyl-N-(2-methoxybenzyl)amine moiety, showed the highest inhibitory activity against EeAChE, with a promising IC50 of 6.6 μM, and a similar inhibition profile of the human isoform (IC50 = 5.7 μM). As another positive feature, most of the derivatives did not show appreciable toxicity against HT-29 cells, up to a concentration of 100 μM, which indicates drug-conform behavior. Also, compound 26 is capable of crossing the blood-brain barrier (BBB), as predicted by a PAMPA-BBB assay. Collectively, the data suggest that the approach to obtain potential anti-Alzheimer drugs from CNSL is worth of further pursuit and development.

  10. The effect of chemical anti-inhibitors on fibrinolytic enzymes and inhibitors

    DEFF Research Database (Denmark)

    Sidelmann, Johannes Jakobsen; Jespersen, J; Kluft, C;

    1997-01-01

    Fibrinolytic enzyme inhibitors hamper the determination of the specific fibrinolytic serine protease activity. Reportedly, chemical anti-inhibitors eliminate the influence of fibrinolytic inhibitors, but it remains unclear to what extent they change the specific activity of fibrinolytic serine pr...

  11. Proton pump inhibitors and gastroenteritis

    NARCIS (Netherlands)

    R.J. Hassing (Robert); A. Verbon (Annelies); H. de Visser (Herman); A. Hofman (Albert); B.H.Ch. Stricker (Bruno)

    2016-01-01

    textabstractAn association between proton pump inhibitor (PPI) therapy and bacterial gastroenteritis has been suggested as well as contradicted. The aim of this study was to examine the association between the use of PPIs and occurrence of bacterial gastroenteritis in the prospective Rotterdam Study

  12. Corrosion Inhibitors for Reinforced Concrete

    OpenAIRE

    ECT Team, Purdue

    2007-01-01

    Steel corrosion in reinforced concrete structures has been a major problem across the U.S. Steel-reinforced concrete structures are continually subject to attack by corrosion brought on by naturally occurring environmental conditions. FerroGard, a corrosion inhibitor, developed by Sika Corporation, penetrates hardened concrete to dramatically reduce corrosion by 65% and extend the structure's service life.

  13. Biocatalysts with enhanced inhibitor tolerance

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Shihui; Linger, Jeffrey; Franden, Mary Ann; Pienkos, Philip T.; Zhang, Min

    2015-12-08

    Disclosed herein are biocatalysts for the production of biofuels, including microorganisms that contain genetic modifications conferring tolerance to growth and fermentation inhibitors found in many cellulosic feedstocks. Methods of converting cellulose-containing materials to fuels and chemicals, as well as methods of fermenting sugars to fuels and chemicals, using these biocatalysts are also disclosed.

  14. Renal targeting of kinase inhibitors

    NARCIS (Netherlands)

    Dolman, M. E. M.; Fretz, M. M.; Segers, Gj. W.; Lacombe, M.; Prakash, J.; Storm, G.; Hennink, W. E.; Kok, R. J.

    2008-01-01

    Activation of proximal tubular cells by fibrotic and inflammatory mediators is an important hallmark of chronic kidney disease. We have developed a novel strategy to intervene in renal fibrosis, by means of locally delivered kinase inhibitors. Such compounds will display enhanced activity within tub

  15. Nicotinamide phosphoribosyltransferase inhibitors, design, preparation and SAR

    DEFF Research Database (Denmark)

    Christensen, Mette Knak; Erichsen, Kamille Dumong; Olesen, Uffe Hogh;

    2013-01-01

    Existing pharmacological inhibitors for nicotinamide phosphoribosyltransferase (NAMPT) are promising therapeutics for treating cancer. Using medicinal and computational chemistry methods, the structure-activity relationship for novel classes of NAMPT inhibitors is described and compounds optimized....... Compounds are designed inspired by the NAMPT inhibitor APO866 and cyanoguanidine inhibitor scaffolds. In comparison with recently published derivatives the new analogues exhibit an equally potent anti-proliferative activity in vitro and comparable activity in vivo. The best performing compounds from...

  16. Allosteric small-molecule kinase inhibitors

    DEFF Research Database (Denmark)

    Wu, Peng; Clausen, Mads Hartvig; Nielsen, Thomas E.

    2015-01-01

    current barriers of kinase inhibitors, including poor selectivity and emergence of drug resistance. In spite of the small number of identified allosteric inhibitors in comparison with that of inhibitors targeting the ATP pocket, encouraging results, such as the FDA-approval of the first small...

  17. Conversion of calcineurin inhibitors with mammalian target of rapamycin inhibitors after kidney transplant.

    Science.gov (United States)

    Nikoueinejad, Hassan; Soleimani, Alireza; Mirshafiey, Abbas; Amirzargar, Aliakbar; Sarrafnejad, Abdolfattah; Kamkar, Ideh; Einollahi, Behzad

    2013-02-01

    One way to overcome chronic allograft nephropathy induced by calcineurin inhibitors in immunosuppression protocols for organ transplants is to replace such inhibitors with mammalian target of rapamycin inhibitors, which are not clinically nephrotoxic because they have better renal function. If patients tolerate replacement, there could be a clear preference for mammalian target of rapamycin inhibitors as a maintenance immunosuppressant after renal transplant. This replacement could be sufficient if it were used for a certain time after calcineurin inhibitors. This review considers the conversion effects of calcineurin inhibitors with mammalian target of rapamycin inhibitors from the view point of kidney function during different periods after a kidney transplant.

  18. Notch Inhibitors for Cancer Treatment

    OpenAIRE

    Espinoza, Ingrid; Miele, Lucio

    2013-01-01

    Notch signaling is an evolutionarily conserved cell signaling pathway involved in cell fate during development, stem cell renewal and differentiation in postnatal tissues. Roles for Notch in carcinogenesis, in the biology of cancer stem cells and tumor angiogenesis have been reported. These features identify Notch as a potential therapeutic target in oncology. Based on the molecular structure of Notch receptor, Notch ligands and Notch activators, a set of Notch pathway inhibitors have been de...

  19. Nelfinavir: fourth protease inhibitor approved.

    Science.gov (United States)

    1997-01-01

    The Food and Drug Administration (FDA) has granted accelerated approval to nelfinavir in both adult and pediatric formulations. Agouron, the manufacturer, used innovative computerized drug design techniques to discover, design, and refine the nelfinavir molecule. Nelfinavir is marketed under the trade name Viracept, and costs $5,000 per year. Early clinical trials find it to be as powerful as the other protease inhibitors, but with a different resistance profile. The drug has relatively few drug indications; however, several compounds have been contraindicated.

  20. Inhibitors of protein kinase C

    Institute of Scientific and Technical Information of China (English)

    LIU Shiying; JIANG Yuyang; CAO Jian; LIU Feng; MA Li; ZHAO Yufen

    2005-01-01

    Protein kinase catalyzes the transfer of the γ-phosphoryl group from ATP to the hydroxyl groups of protein side chains, which plays critical roles in signal transduction pathways by transmitting extracellular signals across the plasma membrane and nuclear membrane to the destination sites in the cytoplasm and the nucleus. Protein kinase C (PKC) is a superfamily of phospholipid-dependent Ser/Thr kinase. There are at least 12 isozymes in PKC family. They are distributed in different tissues and play different roles in physiological processes. On account of their concern with a variety of pathophysiologic states, such as cancer, inflammatory conditions, autoimmune disorder, and cardiac diseases, the inhibitors, which can inhibit the activity of PKC and the interaction of cytokine with receptor, and interfere signal transduction pathway, may be candidates of therapeutic drugs. Therefore, intense efforts have been made to develop specific protein kinase inhibitors as biological tools and therapeutic agents. This article reviews the recent development of some of PKC inhibitors based on their interaction with different conserved domains and different inhibition mechanisms.

  1. Carbonic anhydrase inhibitors drug design.

    Science.gov (United States)

    McKenna, Robert; Supuran, Claudiu T

    2014-01-01

    Inhibition of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) has pharmacologic applications in the field of antiglaucoma, anticonvulsant, antiobesity, and anticancer agents but is also emerging for designing anti-infectives (antifungal and antibacterial agents) with a novel mechanism of action. As a consequence, the drug design of CA inhibitors (CAIs) is a very dynamic field. Sulfonamides and their isosteres (sulfamates/sulfamides) constitute the main class of CAIs which bind to the metal ion in the enzyme active site. Recently the dithiocarbamates, possessing a similar mechanism of action, were reported as a new class of inhibitors. Other families of CAIs possess a distinct mechanism of action: phenols, polyamines, some carboxylates, and sulfocoumarins anchor to the zinc-coordinated water molecule. Coumarins and five/six-membered lactones are prodrug inhibitors, binding in hydrolyzed form at the entrance of the active site cavity. Novel drug design strategies have been reported principally based on the tail approach for obtaining all these types of CAIs, which exploit more external binding regions within the enzyme active site (in addition to coordination to the metal ion), leading thus to isoform-selective compounds. Sugar-based tails as well as click chemistry were the most fruitful developments of the tail approach. Promising compounds that inhibit CAs from bacterial and fungal pathogens, of the dithiocarbamate, phenol and carboxylate types have also been reported.

  2. Substituted androstanes as aromatase inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Levina, Inna S [N.D.Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow (Russian Federation)

    1998-11-30

    The synthesis and structure-activity relationships of inhibitors of steroid aromatase which catalyses the last stage of a multistep biotransformation of cholesterol into estrogens, viz., aromatisation of C{sub 19}-steroids into C{sub 18}-phenolic steroids, are discussed. Compounds of the androstane series which are structurally related to the natural substrate, viz., androst-4-ene-3,17-dione, are the subjects of consideration. The review encompasses problems of synthesis of various substituted androstanes and their aromatase-inhibiting activities and structural requirements for selective specific aromatase inhibitors based on in vitro and in vivo structure-activity studies of compounds synthesised, their biological properties and the results of clinical trials. Special attention is paid to practical applications of aromatase inhibitors in the treatment of hormone-dependent mammary and ovarian tumours as well as benign prostatic tumours. In writing this report, the author has used all the information currently available in the chemical, biochemical, endocrinological and medicinal literature as well as in patents. The bibliography includes 173 references.

  3. Substituted androstanes as aromatase inhibitors

    Science.gov (United States)

    Levina, Inna S.

    1998-11-01

    The synthesis and structure-activity relationships of inhibitors of steroid aromatase which catalyses the last stage of a multistep biotransformation of cholesterol into estrogens, viz., aromatisation of C19-steroids into C18-phenolic steroids, are discussed. Compounds of the androstane series which are structurally related to the natural substrate, viz., androst-4-ene-3,17-dione, are the subjects of consideration. The review encompasses problems of synthesis of various substituted androstanes and their aromatase-inhibiting activities and structural requirements for selective specific aromatase inhibitors based on in vitro and in vivo structure-activity studies of compounds synthesised, their biological properties and the results of clinical trials. Special attention is paid to practical applications of aromatase inhibitors in the treatment of hormone-dependent mammary and ovarian tumours as well as benign prostatic tumours. In writing this report, the author has used all the information currently available in the chemical, biochemical, endocrinological and medicinal literature as well as in patents. The bibliography includes 173 references.

  4. A cyclic peptidic serine protease inhibitor

    DEFF Research Database (Denmark)

    Zhao, Baoyu; Xu, Peng; Jiang, Longguang;

    2014-01-01

    Peptides are attracting increasing interest as protease inhibitors. Here, we demonstrate a new inhibitory mechanism and a new type of exosite interactions for a phage-displayed peptide library-derived competitive inhibitor, mupain-1 (CPAYSRYLDC), of the serine protease murine urokinase...... pocket, its carbonyl group aligning improperly relative to Ser195 and the oxyanion hole, explaining why the peptide is an inhibitor rather than a substrate. Substitution of the P1 Arg with novel unnatural Arg analogues with aliphatic or aromatic ring structures led to an increased affinity, depending...... of this peptidic inhibitor, a concept different from conventional attempts at improving inhibitor affinity by reducing the entropic burden....

  5. Conformation-specific inhibitors of Raf kinases.

    Science.gov (United States)

    Wang, Xiaolun; Schleicher, Kristin

    2013-01-01

    Since the discovery linking B-Raf mutations to human tumors in 2002, significant advances in the development of Raf inhibitors have been made, leading to the recent approval of two Raf inhibitor drugs. This chapter includes a brief introduction to B-Raf as a validated target and focuses on the three different binding modes observed with Raf small-molecule inhibitors. These various binding modes lock the Raf kinase in different conformations that impact the toxicity profiles of the inhibitors. Possible solutions to mitigate the side effects caused by inhibitor-induced dimerization are also discussed.

  6. Inhibitor of Phosphodiestearse-4 improves memory deficits, oxidative stress, neuroinflammation and neuropathological alterations in mouse models of dementia of Alzheimer's Type.

    Science.gov (United States)

    Kumar, Amit; Singh, Nirmal

    2017-04-01

    The study investigates the potential of Rolipram a phosphodiesterase-4 inhibitor in cognitive deficits induced by streptozotocin (STZ, 3mg/kg intracerebroventricularly) and natural ageing in mice. Morris water maze (MWM) test was employed to evaluate learning and memory of the animals. Extent of oxidative stress was measured by estimating the levels of brain glutathione (GSH) and thiobarbituric acid reactive species (TBARS). Brain acetylcholinestrase (AChE) activity was also estimated. The brain activity of myeloperoxidase (MPO) was measured as a marker of inflammation. STZ and ageing results in marked decline in MWM performance of the animals, reflecting impairment of learning and memory. STZ treated mice and aged mice exhibited a marked accentuation of AChE activity, TBARS and MPO activity along with fall in GSH level. Further the stained micrographs of STZ treated mice and aged mice indicate pathological changes, severe neutrophilic infiltration and amyloid deposition. Rolipram treatment significantly attenuated STZ induced and age related memory deficits, biochemical and histopathological alterations. The findings demonstrate the potential of Rolipram in memory dysfunctions which may probably be attributed to its anti-cholinesterase, anti-amyloid, anti-oxidative and anti-inflammatory effects. The study concludes that PDE-4 can be explored as a potential therapeutic target in dementia.

  7. Synthesis of Selective Butyrylcholinesterase Inhibitors Coupled between α-Lipoic Acid and Polyphenols by Using 2-(Piperazin-1-yl)ethanol Linker

    Energy Technology Data Exchange (ETDEWEB)

    Yeun, Go Heun; Lee, Seung Hwan; LIm, Yong Bae; Lee, Hye Sook; Lee, Bong Ho; Park, Jeong Ho [Hanbat National Univ., Daejeon (Korea, Republic of); Won, Mooho [Kangwon National Univ., Chuncheon (Korea, Republic of)

    2013-04-15

    In the previous paper (Bull. Korean Chem. Soc., 2011, 32, 2997), the hybrid molecules between α-lipoic acid (ALA) and polyphenols (PPs) connected with neutral 2-(2-aminoethoxy)ethanol linker (linker-1) showed new biological activity such as butyrylcholinesterase (BuChE) inhibition. In order to increase the binding affinity of the hybrid compounds to cholinesterase (ChE), the neutral 2-(2-aminoethoxy)ethanol (linker 1) was switched to the cationic 2-(piperazin-1-yl)ethanol linker (linker 2). The IC{sub 50} values of the linker-2 hybrid molecules for BuChE inhibition were lower than those of linker-1 hybrid molecules (except 9-2) and they also had the same great selectivity for BuChE over AChE (> 800 fold) as linker-1 hybrid molecules. ALA-acetyl caffeic acid (10-2, ALA-AcCA) was shown as an effective inhibitor of BuChE (IC{sub 50} = 0.44 ± 0.24 μM). A kinetic study using 7-2 showed that it is the same mixed type inhibition as 7-1. Its inhibition constant (Ki) to BuChE is 4.3 ± 0.09 μM.

  8. Brain cholinesterase reactivation as a marker of exposure to anticholinesterase pesticides: a case study in a population of yellow-legged gull Larus michahellis (Naumann, 1840) along the northern coast of Portugal.

    Science.gov (United States)

    Santos, Cátia S A; Monteiro, Marta S; Soares, Amadeu M V M; Loureiro, Susana

    2016-01-01

    Between late 2010 to early 2011, an increased mortality in gulls was observed along the northern coast of Portugal, with individuals exhibiting neurologic disorders consistent with an eventual anticholinesterase pesticide poisoning event. To clarify if this mortality was related to organophosphate (OP) and/or carbamate (CB) poisoning, chemical and spontaneous cholinesterase (ChE) reactivation was tested in the brain of the yellow-legged gull (Larus michahellis). Initial brain ChE activity in L. michahellis was 40.92 ± 5.23 U/mg of protein (average ± SE). Following chemical and spontaneous reactivation, ChE activity increased in average 70.38 ± 48.59% and 131.95 ± 92.64%, respectively. ChE reactivation was found to decrease at increasing concentrations of the oxime pyridine-2-aldoxime methochloride and dilution factor, underscoring the importance of first optimizing the assay conditions prior to its use on bird species. These results suggest that birds analysed could have been exposed to OP and CB pesticide compounds and that in most cases CB exposure appeared to be the main cause of birds poisoning. These results are an important contribution to environmental monitoring as it demonstrates the suitability of L. michaellis as sentinel species of OP and CB pesticides within an urban environment.

  9. Tissue factor pathway inhibitor endocytosis.

    Science.gov (United States)

    Schwartz, A L; Broze, G J

    1997-10-01

    Tissue factor pathway inhibitor (TFPI), a 42 kD protein, provides the physiological inhibition of tissue factor initiated coagulation by inhibition of both factor Xa and factor VIIa/tissue factor. In plasma, most TFPI is lipoprotein bound with an additional "releasable" pool bound to the endothelial cell surface. TFPI clearance is via receptor mediated endocytosis into liver. Heparin sulfate proteoglycans and LRP (low density lipoprotein receptor-related protein), an extremely large (∼600 kD) cell surface protein, primarily mediate this clearance, although additional TFPI binding sites and endocytosis pathways exist. (Trends Cardiovasc Med 1997; 7:234-239). © 1997, Elsevier Science Inc.

  10. Aromatase inhibitors and bone loss.

    Science.gov (United States)

    Perez, Edith A; Weilbaecher, Katherine

    2006-08-01

    The aromatase inhibitors (AIs) anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are significantly more effective than the selective estrogen-receptor modulator (SERM) tamoxifen in preventing recurrence in estrogen receptor-positive early breast cancer. Aromatase inhibitors are likely to replace SERMs as first-line adjuvant therapy for many patients. However, AIs are associated with significantly more osteoporotic fractures and greater bone mineral loss. As antiresorptive agents, oral and intravenous bisphosphonates such as alendronate (Fosamax), risedronate (Actonel), ibandronate (Boniva), pamidronate (Aredia), and zoledronic acid (Zometa) have efficacy in preventing postmenopausal osteoporosis, cancer treatment-related bone loss, or skeletal complications of metastatic disease. Clinical practice guidelines recommend baseline and annual follow-up bone density monitoring for all patients initiating AI therapy. Bisphosphonate therapy should be prescribed for patients with osteoporosis (T score vitamin D intake, weight-bearing exercise, and smoking cessation should be addressed. Adverse events associated with bisphosphonates include gastrointestinal toxicity, renal toxicity, and osteonecrosis of the jaw. These safety concerns should be balanced with the potential of bisphosphonates to minimize or prevent the debilitating effects of AI-associated bone loss in patients with early, hormone receptor-positive breast cancer.

  11. Myeloperoxidase Inhibitors as Potential Drugs.

    Science.gov (United States)

    Lazarević-Pasti, Tamara; Leskovac, Andreja; Vasić, Vesna

    2015-01-01

    Myeloperoxidase (MPO) is an important member of the haem peroxidase - cyclooxygenase superfamily. This enzyme is physiologically expressed in circulating neutrophils, monocytes and some tissue macrophages including microglia. MPO plays an essential role in the antimicrobial and antiviral system of humans. The microbicidal activity of MPO exists due to its capability to oxidize halide and pseudohalide ions (CI(-), Br(-), I(-) and SCN(-)) by H2O2, thereby producing respective hypohalous acids (HOX). During the phagocytosis of pathogens, azurophilic granules release their content together with MPO into phagolysosomes. On the other hand, MPO can be discharged outside the phagocytes. Due to this, tissue damage during inflammation is greatly promoted by MPO-derived oxidants. Regarding its activity, MPO is a key factor in a great number of conditions within the group of cardiovascular diseases, inflammatory diseases, neurodegenerative diseases, kidney diseases and immune-mediated diseases. Therefore, MPO and its downstream inflammatory pathways might be attractive targets for both prognostic and therapeutic intervention in the prophylaxis of all mentioned illnesses. Nowadays, structure and reaction mechanism of MPO are known, which enable rational strategy in the development of specific MPO inhibitors that still preserve MPO activity during host defense from bacteria, but hinder pathophysiologically persistent activation of MPO. Various methods for MPO activity inhibition and unfavorable effects of MPO-derived oxidants remodeling will be discussed. Emphasis will be put on various known inhibitors, as well as on newly investigated natural products, which can also inhibit MPO activity.

  12. Proton pump inhibitors and osteoporosis

    DEFF Research Database (Denmark)

    Andersen, Bjarne Nesgaard; Johansen, Per Birger; Abrahamsen, Bo

    2016-01-01

    PURPOSE OF REVIEW: The purpose of the review is to provide an update on recent advances in the evidence based on proton pump inhibitors (PPI) as a possible cause of osteoporosis and osteoporotic fractures. This review focuses, in particular, on new studies published in the last 18 months and a di......PURPOSE OF REVIEW: The purpose of the review is to provide an update on recent advances in the evidence based on proton pump inhibitors (PPI) as a possible cause of osteoporosis and osteoporotic fractures. This review focuses, in particular, on new studies published in the last 18 months...... and a discussion of these findings and how this has influenced our understanding of this association, the clinical impact and the underlying pathophysiology. RECENT FINDINGS: New studies have further strengthened existing evidence linking use of PPIs to osteoporosis. Short-term use does not appear to pose a lower...... risk than long-term use. There is a continued lack of conclusive studies identifying the pathogenesis. Direct effects on calcium absorption or on osteoblast or osteoclast action cannot at present plausibly explain the mechanism. SUMMARY: The use of PPIs is a risk factor for development of osteoporosis...

  13. Glycine Transporters and Their Inhibitors

    Science.gov (United States)

    Gilfillan, Robert; Kerr, Jennifer; Walker, Glenn; Wishart, Grant

    Glycine plays a ubiquitous role in many biological processes. In the central nervous system it serves as an important neurotransmitter acting as an agonist at strychnine-sensitive glycine receptors and as an essential co-agonist with glutamate at the NMDA receptor complex. Control of glycine concentrations in the vicinity of these receptors is mediated by the specific glycine transporters, GlyT1 and GlyT2. Inhibition of these transporters has been postulated to be of potential benefit in several therapeutic indications including schizophrenia and pain. In this review we discuss our current knowledge of glycine transporters and focus on recent advances in the medicinal chemistry of GlyT1 and GlyT2 inhibitors.

  14. TYROSINE KINASE INHIBITORS AND PREGNANCY

    Directory of Open Access Journals (Sweden)

    Elisabetta Abruzzese

    2014-04-01

    Full Text Available The management of patients with chronic myeloid leukemia (CML during pregnancy has became recently a matter of continuous debate.  The introduction of the Tyrosine Kinase Inhibitors (TKIs in clinical practice has dramatically changed the prognosis of CML patients.  Patients diagnosed in chronic phase can reasonably expect many years of excellent disease control and good quality of life, as well as a normal life expectancy.  This fact has come the necessity to address issues relating to fertility and pregnancy. Physicians are not infrequently being asked for advice regarding the need for, and or the appropriateness of, stopping treatment in order to conceive. In this report we will review the data published in terms of fertility, conception, pregnancy, pregnancy outcome and illness control for all the approved TKIs, as well as suggest how to manage a planned and/or unplanned pregnancy.

  15. Aromatase inhibitors in gynecologic cancers.

    Science.gov (United States)

    Krasner, Carolyn

    2007-01-01

    The female genital tract is hormonally responsive, and consequently some tumors, which arise within in it, may be treated at least in part, with hormonal manipulation. The range of responses in clinical trials and case reports will be reviewed. Many of these diseases are too rare for clinical trial testing, and in some cases evidence is anecdotal at best. Recurrences of ovarian cancer have been treated with tamoxifen and megesterol acetate with variable response rates from 0 to 56%. The favorable toxicity profile of aromatase inhibitors led to trials of these agents for the treatment of relapsed epithelial ovarian cancer. These agents have proved tolerable with minor response rates but a significant disease stabilization rate, which may be prolonged in a minority of cases. It is unclear if these responses may be predicted by estrogen receptor expression or aromatase expression. Anastrazole has also been tried in combination with an EGFR receptor-inhibitor, again showing minor responses but possibly an increase in TTT in some patients. Granulosa cell tumors of the ovary are rare, hormonally sensitive tumors, with reported responses to a variety of hormonal manipulations, including aromatase inhibition. In addition, combined endocrine blockade, including aromatase inhibition, has been tried with reports of success. Endometrial cancers, particularly type I lesions, are often treated with hormonal manipulation, most commonly with progestins, but also with antiestrogens such as tamoxifen. A trial of aromatase inhibition in the treatment of recurrent endometrial cancer showed minimal responses. Endometrial stromal sarcoma, an uncommon uterine malignancy, has shown response to hormonal treatments, with multiple case reports of efficacy of aromatase inhibition. Despite the rarity of some of these tumor types, rare tumor study groups, such as within the Gynecologic Oncology Group, should make an effort to prospectively define the utility of these treatments.

  16. Advances of Inhibitors in Drilling Fluid

    Institute of Scientific and Technical Information of China (English)

    杨仕伟; 周丹

    2012-01-01

    The development history of the inhibitors of drilling fluid reviewed in this paper. The advances of inhibitors commonly used at home and abroad were included. That the inhibitive ability was good enough whose inhibiting mechanisms and effects were introduced in the past 10 years.

  17. [Interaction between clopidogrel and proton pump inhibitors

    NARCIS (Netherlands)

    Harmsze, A.M.; Boer, A. de; Boot, H.; Deneer, V.H.; Heringa, M.; Mol, P.G.; Schalekamp, T.; Verduijn, M.M.; Verheugt, F.W.A.; Comte, M. le

    2011-01-01

    The drug interaction between proton pump inhibitors and clopidogrel has been the subject of much study in recent years. Contradictory results regarding the effect of proton pump inhibitors on platelet reactivity and on clinical outcome in clopidogrel-treated patients have been reported in literature

  18. A cyclic peptidic serine protease inhibitor

    DEFF Research Database (Denmark)

    Zhao, Baoyu; Xu, Peng; Jiang, Longguang;

    2014-01-01

    Peptides are attracting increasing interest as protease inhibitors. Here, we demonstrate a new inhibitory mechanism and a new type of exosite interactions for a phage-displayed peptide library-derived competitive inhibitor, mupain-1 (CPAYSRYLDC), of the serine protease murine urokinase...

  19. Histone deacetylase inhibitors (HDACIs: multitargeted anticancer agents

    Directory of Open Access Journals (Sweden)

    Ververis K

    2013-02-01

    Full Text Available Katherine Ververis,1 Alison Hiong,1 Tom C Karagiannis,1,* Paul V Licciardi2,*1Epigenomic Medicine, Alfred Medical Research and Education Precinct, 2Allergy and Immune Disorders, Murdoch Childrens Research Institute, Melbourne, VIC, Australia*These authors contributed equally to this workAbstract: Histone deacetylase (HDAC inhibitors are an emerging class of therapeutics with potential as anticancer drugs. The rationale for developing HDAC inhibitors (and other chromatin-modifying agents as anticancer therapies arose from the understanding that in addition to genetic mutations, epigenetic changes such as dysregulation of HDAC enzymes can alter phenotype and gene expression, disturb homeostasis, and contribute to neoplastic growth. The family of HDAC inhibitors is large and diverse. It includes a range of naturally occurring and synthetic compounds that differ in terms of structure, function, and specificity. HDAC inhibitors have multiple cell type-specific effects in vitro and in vivo, such as growth arrest, cell differentiation, and apoptosis in malignant cells. HDAC inhibitors have the potential to be used as monotherapies or in combination with other anticancer therapies. Currently, there are two HDAC inhibitors that have received approval from the US FDA for the treatment of cutaneous T-cell lymphoma: vorinostat (suberoylanilide hydroxamic acid, Zolinza and depsipeptide (romidepsin, Istodax. More recently, depsipeptide has also gained FDA approval for the treatment of peripheral T-cell lymphoma. Many more clinical trials assessing the effects of various HDAC inhibitors on hematological and solid malignancies are currently being conducted. Despite the proven anticancer effects of particular HDAC inhibitors against certain cancers, many aspects of HDAC enzymes and HDAC inhibitors are still not fully understood. Increasing our understanding of the effects of HDAC inhibitors, their targets and mechanisms of action will be critical for the

  20. Susceptibility to Phoxim and Acetyl Cholinesterase Activity of The Red Imported Fire Ant (Solenopsis invicta Buren)%红火蚁对辛硫磷敏感性及其乙酰胆碱酯酶活性的研究

    Institute of Scientific and Technical Information of China (English)

    苗建忠; 马伏宁; 曾鑫年

    2009-01-01

    用点滴法测定了辛硫磷对红火蚁不同品级的毒力,并用乙酰硫代胆碱-二硫双对硝基苯甲酸法(ASCh-DTNB法)测定了各品级乙酰胆碱酯酶(acetyl cholinesterase,AChE)的活性,以探明蚁群中不同品级个体对辛硫磷的敏感性差异及其与靶标酶的关系.毒力测定结果表明,处理后24 h,辛硫磷对工蚁、兵蚁、有翅雄蚁、有翅雌蚁和蚁后的毒力(LC50值)分别为1.04、2.06、7.38、9.39和7.81 μg/ml,显示不同品级红火蚁对辛硫磷的敏感性差异非常大,其中工蚁最敏感,而有翅雌蚁蚁后敏感性最低.靶标酶活性测定结果表明,红火蚁不同品级个体中乙酰胆碱酯酶的活性存在极大差异,其中以有翅雄蚁的总活性最低,为0.0469 nmol/(min·头),而以有翅雌蚁的最高,为14.8929 nmol/(min·头).不同品级红火蚁对辛硫磷的敏感性与其乙酰胆碱酯酶活性不存在显著相关性(r=0.7456).

  1. Designing Inhibitors of Anthrax Toxin

    Science.gov (United States)

    Nestorovich, Ekaterina M.; Bezrukov, Sergey M.

    2014-01-01

    Introduction Present-day rational drug design approaches are based on exploiting unique features of the target biomolecules, small- or macromolecule drug candidates, and physical forces that govern their interactions. The 2013 Nobel Prize in chemistry awarded “for the development of multiscale models for complex chemical systems” once again demonstrated the importance of the tailored drug discovery that reduces the role of the trial and error approach to a minimum. The “rational drug design” term is rather comprehensive as it includes all contemporary methods of drug discovery where serendipity and screening are substituted by the information-guided search for new and existing compounds. Successful implementation of these innovative drug discovery approaches is inevitably preceded by learning the physics, chemistry, and physiology of functioning of biological structures under normal and pathological conditions. Areas covered This article provides an overview of the recent rational drug design approaches to discover inhibitors of anthrax toxin. Some of the examples include small-molecule and peptide-based post-exposure therapeutic agents as well as several polyvalent compounds. The review also directs the reader to the vast literature on the recognized advances and future possibilities in the field. Expert opinion Existing options to combat anthrax toxin lethality are limited. With the only anthrax toxin inhibiting therapy (PA-targeting with a monoclonal antibody, raxibacumab) approved to treat inhalational anthrax, in our view, the situation is still insecure. The FDA’s animal rule for drug approval, which clears compounds without validated efficacy studies on humans, creates a high level of uncertainty, especially when a well-characterized animal model does not exist. Besides, unlike PA, which is known to be unstable, LF remains active in cells and in animal tissues for days. Therefore, the effectiveness of the post-exposure treatment of the individuals

  2. Leflunomide, a Reversible Monoamine Oxidase Inhibitor.

    Science.gov (United States)

    Petzer, Jacobus P; Petzer, Anél

    2016-01-01

    A screening study aimed at identifying inhibitors of the enzyme, monoamine oxidase (MAO), among clinically used drugs have indicated that the antirheumatic drug, leflunomide, is an inhibitor of both MAO isoforms. Leflunomide inhibits human MAO-A and MAO-B and exhibits IC50 values of 19.1 μM and 13.7 μM, respectively. The corresponding Ki values are 17.7 μM (MAO-A) and 10.1 μM (MAO-B). Dialyses of mixtures of the MAO enzymes and leflunomide show that inhibition of the MAOs by leflunomide is reversible. The principal metabolite of leflunomide, teriflunomide (A77 1726), in contrast is not an MAO inhibitor. This study concludes that, although leflunomide is only moderately potent as an MAO inhibitor, isoxazole derivatives may represent a general class of MAO inhibitors and this heterocycle may find application in MAO inhibitor design. In this respect, MAO inhibitors are used in the clinic for the treatment of depressive illness and Parkinson's disease, and are under investigation as therapy for certain types of cancer, Alzheimer's disease and age-related impairment of cardiac function.

  3. Vascular calcification: Inducers and inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Donghyun, E-mail: dhlee@cau.ac.kr [Department of Biomedical Engineering, Division of Integrative Engineering, Chung-Ang University, 221 Heukseok-Dong, Dongjak-Gu, Seoul 156-756 (Korea, Republic of)

    2011-09-15

    Highlights: {center_dot} Types of vascular calcification processes. {center_dot} Inducers of vascular calcification. {center_dot} Inhibitors of vascular calcifications. {center_dot} Clinical utility for vascular calcification therapy. {center_dot} Implications for the development of new tissue engineering strategies. - Abstract: Unlike the traditional beliefs, there are mounting evidences suggesting that ectopic mineral depositions, including vascular calcification are mostly active processes, many times resembling that of the bone mineralization. Numbers of agents are involved in the differentiation of certain subpopulation of smooth muscle cells (SMCs) into the osteoblast-like entity, and the activation and initiation of extracellular matrix ossification process. On the other hand, there are factors as well, that prevent such differentiation and ectopic calcium phosphate formation. In normal physiological environments, activities of such procalcific and anticalcific regulatory factors are in harmony, prohibiting abnormal calcification from occurring. However, in certain pathophysiological conditions, such as atherosclerosis, chronic kidney disease (CKD), and diabetes, such balances are altered, resulting in abnormal ectopic mineral deposition. Understanding the factors that regulate the formation and inhibition of ectopic mineral formation would be beneficial in the development of tissue engineering strategies for prevention and/or treatment of such soft-tissue calcification. Current review focuses on the factors that seem to be clinically relevant and/or could be useful in developing future tissue regeneration strategies. Clinical utilities and implications of such factors are also discussed.

  4. ALK inhibitors, a pharmaceutical perspective

    Directory of Open Access Journals (Sweden)

    Arturo eGalvani

    2012-02-01

    Full Text Available In 2007, the ALK tyrosine kinase, already known to be translocated and activated in Anaplastic Large Cell Lymphoma, and a few other rare cancers, was described as a potential therapeutic target for a subset of non small-cell lung cancer (NSCLC patients. Clinical proof of concept, culminating in the recent approval by the FDA of the Pfizer drug Xalkori (crizotinib, formerly known as PF-02341066 followed in record time. The drug was approved together with a companion diagnostic, the Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular, Inc. for detection of eligible patients. This remarkable example of the coming of age of personalized medicine in cancer therapy is hopefully only an auspice of things to come in this rapidly developing field. Perhaps unsurprisingly, however, the appearance of clinical acquired resistance to crizotinib has already been observed early on in clinical testing, with the identification of several ALK secondary point mutations which diminish drug efficacy, and which open the way for development of second-generation inhibitors. It is also emerging that acquired resistance to crizotinib may also occur through ALK-independent mechanisms, which still need to be elucidated in detail.

  5. Design and Synthesis of Caspase Inhibitors

    Institute of Scientific and Technical Information of China (English)

    BAI Xu

    2001-01-01

    @@ Apoptosis (programmed cell death) is an evolutionarily conserved process of cell suicide. It requires specialized machinery which involving a family of proteases named caspases. Manipulation of apoptosis through inhibiting or activating caspases has been of great therapeutic interests in the pharmaceutical industry. Using substrate based approach, a systematic investigation of conformationally constrained peptidomimetic inhibitors has led to the discovery of highly selective ones against selected members of the caspase family. It also resulted novel dipeptide inhibitors as useful tools and possible therapeutic agents against diseases caused by excessive apoptotic cell death. This presentation will focus on the design, synthesis and application of novel caspase inhibitors.

  6. Migrating corrosion inhibitor protection of concrete

    Energy Technology Data Exchange (ETDEWEB)

    Bjegovic, D.; Miksic, B.

    1999-11-01

    Migrating corrosion inhibitors (MCI) were developed to protect steel rebar from corrosion in concrete. They were designed to be incorporated as an admixture during concrete batching or used for surface impregnation of existing concrete structures. Two investigations are summarized. One studied the effectiveness of MCIs as a corrosion inhibitor for steel rebar when used as an admixture in fresh concrete mix. The other is a long-term study of MCI concrete impregnation that chronicles corrosion rates of rebar in concrete specimens. Based on data from each study, it was concluded that migrating corrosion inhibitors are compatible with concrete and effectively delay the onset of corrosion.

  7. Design and Synthesis of Caspase Inhibitors

    Institute of Scientific and Technical Information of China (English)

    BAI; Xu

    2001-01-01

    Apoptosis (programmed cell death) is an evolutionarily conserved process of cell suicide. It requires specialized machinery which involving a family of proteases named caspases. Manipulation of apoptosis through inhibiting or activating caspases has been of great therapeutic interests in the pharmaceutical industry.  Using substrate based approach, a systematic investigation of conformationally constrained peptidomimetic inhibitors has led to the discovery of highly selective ones against selected members of the caspase family. It also resulted novel dipeptide inhibitors as useful tools and possible therapeutic agents against diseases caused by excessive apoptotic cell death. This presentation will focus on the design, synthesis and application of novel caspase inhibitors.  ……

  8. An Updated Review of Tyrosinase Inhibitors

    Directory of Open Access Journals (Sweden)

    Te-Sheng Chang

    2009-05-01

    Full Text Available Tyrosinase is a multifunctional, glycosylated, and copper-containing oxidase, which catalyzes the first two steps in mammalian melanogenesis and is responsible for enzymatic browning reactions in damaged fruits during post-harvest handling and processing. Neither hyperpigmentation in human skin nor enzymatic browning in fruits are desirable. These phenomena have encouraged researchers to seek new potent tyrosinase inhibitors for use in foods and cosmetics. This article surveys tyrosinase inhibitors newly discovered from natural and synthetic sources. The inhibitory strength is compared with that of a standard inhibitor, kojic acid, and their inhibitory mechanisms are discussed.

  9. Musical hallucinations treated with acetylcholinesterase inhibitors

    Directory of Open Access Journals (Sweden)

    Jan Dirk eBlom

    2015-04-01

    Full Text Available Musical hallucinations are relatively rare auditory percepts which, due to their intrusive nature and the accompanying fear of impending mental decline, tend to cause significant distress and impairment. Although their etiology and pathophysiology appear to be heterogeneous and no evidence-based treatment methods are available, case reports indicate that acetylcholinesterase inhibitors may yield positive results in patients with comorbid hearing loss. We present two female patients (aged 76 and 78 years both of whom suffered from hearing impairment and practically incessant musical hallucinations. Both patients were successfully treated with the acetylcholinesterase inhibitor rivastigmine. Based on these two case descriptions and an overview of studies describing the use of acetylcholinesterase inhibitors in similar patients, we discuss possible mechanisms and propose further research on the use of acetylcholinesterase inhibitors for musical hallucinations experienced in concordance with hearing loss.

  10. Drug design from the cryptic inhibitor envelope.

    Science.gov (United States)

    Lee, Chul-Jin; Liang, Xiaofei; Wu, Qinglin; Najeeb, Javaria; Zhao, Jinshi; Gopalaswamy, Ramesh; Titecat, Marie; Sebbane, Florent; Lemaitre, Nadine; Toone, Eric J; Zhou, Pei

    2016-02-25

    Conformational dynamics plays an important role in enzyme catalysis, allosteric regulation of protein functions and assembly of macromolecular complexes. Despite these well-established roles, such information has yet to be exploited for drug design. Here we show by nuclear magnetic resonance spectroscopy that inhibitors of LpxC--an essential enzyme of the lipid A biosynthetic pathway in Gram-negative bacteria and a validated novel antibiotic target--access alternative, minor population states in solution in addition to the ligand conformation observed in crystal structures. These conformations collectively delineate an inhibitor envelope that is invisible to crystallography, but is dynamically accessible by small molecules in solution. Drug design exploiting such a hidden inhibitor envelope has led to the development of potent antibiotics with inhibition constants in the single-digit picomolar range. The principle of the cryptic inhibitor envelope approach may be broadly applicable to other lead optimization campaigns to yield improved therapeutics.

  11. Strategies for discontinuation of proton pump inhibitors

    DEFF Research Database (Denmark)

    Haastrup, Peter; Paulsen, Maja S; Begtrup, Luise M

    2014-01-01

    PURPOSE: Proton pump inhibitors (PPIs) are considered to be overprescribed. Consensus on how to attempt discontinuation is, however, lacking. We therefore conducted a systematic review of clinical studies on discontinuation of PPIs. METHODS: Systematic review based on clinical studies investigating...

  12. Musical hallucinations treated with acetylcholinesterase inhibitors.

    Science.gov (United States)

    Blom, Jan Dirk; Coebergh, Jan Adriaan F; Lauw, René; Sommer, Iris E C

    2015-01-01

    Musical hallucinations are relatively rare auditory percepts which, due to their intrusive nature and the accompanying fear of impending mental decline, tend to cause significant distress and impairment. Although their etiology and pathophysiology appear to be heterogeneous and no evidence-based treatment methods are available, case reports indicate that acetylcholinesterase inhibitors may yield positive results in patients with comorbid hearing loss. We present two female patients (aged 76 and 78 years) both of whom suffered from hearing impairment and practically incessant musical hallucinations. Both patients were successfully treated with the acetylcholinesterase inhibitor rivastigmine. Based on these two case descriptions and an overview of studies describing the use of acetylcholinesterase inhibitors in similar patients, we discuss possible mechanisms and propose further research on the use of acetylcholinesterase inhibitors for musical hallucinations experienced in concordance with hearing loss.

  13. Morphology and Mechanism of Benign Inhibitors

    Science.gov (United States)

    2012-07-01

    the water response of vanadate inhibitor films can be determined. Because the absorbed water usually resides in molecular-level free space inside...Schaefer, Water absorption and transport in bis- silane films. Physical Chemistry Chemical Physics, 2009. 11(1), p. 161 - 166. 23. Y. Wang, E. Watkins, J...Ooij, Effects of addition of corrosion inhibitors to silane films on the performance of AA2024-T3 in a 0.5M NaCl solution. Progress in Organic

  14. Enzyme-inhibitor mediated red cell labelling

    Energy Technology Data Exchange (ETDEWEB)

    Ackery, D.M.; Singh, J.; Wyeth, P. (Southampton Univ. (UK). Dept. of Chemistry)

    Red blood cells contain 90% of the body's enzyme carbonic anhydrase to which aromatic sulphonamide inhibitors bind tightly. P-iodo-benzene sulphonamide (PIBS) is a lipophilic inhibitor which would afford rapid cell labelling. Radioiodinated PIBS was prepared, in high yield, by radio ion exchange in the presence of ammonium sulphate. After intravenous injection of /sup 131/I-PIBS the radiolabel was found in the blood pool.

  15. Polypeptide Inhibitors of Mineral Scaling and Corrosion

    Science.gov (United States)

    1989-06-01

    peptides are based on natural protein inhibitors of mineral formation and generally are enriched in aspartic acid and phosphoserine. Specifically, the...the protein inhibitors of mineral formation , we evaluated several methods of preparation of phosphopeptides. These included direct polymerization of 2...number of assays have been developed to measure the ability of the peptides to inhibit mineral formation . These include methods for assessing effects on

  16. Inhibitor development in nonsevere hemophilia A

    OpenAIRE

    2014-01-01

    Hemophilia A is an X-linked inherited bleeding disorder that affects approximately 1 in 5000 male live births. It is caused by a deficient plasma level of clotting factor VIII and can be treated by the intravenous administration of factor VIII concentrates. A severe complication of the treatment with factor VIII concentrates is the development of inhibiting antibodies against factor VIII, also called inhibitors. Inhibitors challenge the treatment of hemophilia A as they inactivate factor VIII...

  17. Development of Radiosensitizer using farnesyltransferase inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Lim, Jong Seok; Choe, Yong Kyung; Han, Mi Young; Kim, Kwang Dong [Korea Research Institute of Bioscience and Biotechnology, Taejon (Korea)

    1999-03-01

    We selected some compounds that were reported to have an activity of farneyltransferase inhibitor and tested the hypothesis that they might be used to radiosensitize cells transformed by ras oncogenes. The inhibition of ras processing using some, but not all, inhibitors resulted in higher levels of cell death after {gamma}-irradiation and increased radiosensitivity in H-ras-transformed NIH3T3 cells and MCF-10A human tumor cells. They did not induce additional cell death in control cells that doe not have ras mutation. Furthermore, the treatment of inhibitors alone induced a weak G0/G1 block, whereas inhibitors in combination with {gamma}-irradiation induced an additional enrichment in the G2/M phase of the cell cycle that typically represents irradiation-induced growth arrest. At present, the underling mechanism by which the farnesylltransferase inhibitors exert radiosensitizing effect is not known. In summary, our results suggest and lead to the possibility that some of farnesylation inhibitors may prove clinically useful not only as antitumor agents, but also radiosensitizers of tumors whose growth is dependent on ras function. (author). 15 refs., 10 figs., 4 tabs.

  18. PARP1 Inhibitors: antitumor drug design.

    Science.gov (United States)

    Malyuchenko, N V; Kotova, E Yu; Kulaeva, O I; Kirpichnikov, M P; Studitskiy, V M

    2015-01-01

    The poly (ADP-ribose) polymerase 1 (PARP1) enzyme is one of the promising molecular targets for the discovery of antitumor drugs. PARP1 is a common nuclear protein (1-2 million molecules per cell) serving as a "sensor" for DNA strand breaks. Increased PARP1 expression is sometimes observed in melanomas, breast cancer, lung cancer, and other neoplastic diseases. The PARP1 expression level is a prognostic indicator and is associated with a poor survival prognosis. There is evidence that high PARP1 expression and treatment-resistance of tumors are correlated. PARP1 inhibitors are promising antitumor agents, since they act as chemo- and radiosensitizers in the conventional therapy of malignant tumors. Furthermore, PARP1 inhibitors can be used as independent, effective drugs against tumors with broken DNA repair mechanisms. Currently, third-generation PARP1 inhibitors are being developed, many of which are undergoing Phase II clinical trials. In this review, we focus on the properties and features of the PARP1 inhibitors identified in preclinical and clinical trials. We also describe some problems associated with the application of PARP1 inhibitors. The possibility of developing new PARP1 inhibitors aimed at DNA binding and transcriptional activity rather than the catalytic domain of the protein is discussed.

  19. The Use of Inhibitors of Mechanosensitive Ion Channels as Local Inhibitors of Peripheral Pain

    Science.gov (United States)

    2015-01-01

    type currents are more closely associated with  nociception .  Although the current associated with the two main types of  pain  are not restricted to a...Award Number: W81XWH-11-2-0125 TITLE: The Use of Inhibitors of Mechanosensitive Ion Channels as Local Inhibitors of Peripheral Pain PRINCIPAL...2011 - 24 Oct 2014 4. TITLE AND SUBTITLE The Use of Inhibitors of Mechanosensitive Ion Channels as Local Inhibitors of Peripheral Pain 5a. CONTRACT

  20. Discovering anti-platelet drug combinations with an integrated model of activator-inhibitor relationships, activator-activator synergies and inhibitor-inhibitor synergies.

    Directory of Open Access Journals (Sweden)

    Federica Lombardi

    2015-04-01

    Full Text Available Identifying effective therapeutic drug combinations that modulate complex signaling pathways in platelets is central to the advancement of effective anti-thrombotic therapies. However, there is no systems model of the platelet that predicts responses to different inhibitor combinations. We developed an approach which goes beyond current inhibitor-inhibitor combination screening to efficiently consider other signaling aspects that may give insights into the behaviour of the platelet as a system. We investigated combinations of platelet inhibitors and activators. We evaluated three distinct strands of information, namely: activator-inhibitor combination screens (testing a panel of inhibitors against a panel of activators; inhibitor-inhibitor synergy screens; and activator-activator synergy screens. We demonstrated how these analyses may be efficiently performed, both experimentally and computationally, to identify particular combinations of most interest. Robust tests of activator-activator synergy and of inhibitor-inhibitor synergy required combinations to show significant excesses over the double doses of each component. Modeling identified multiple effects of an inhibitor of the P2Y12 ADP receptor, and complementarity between inhibitor-inhibitor synergy effects and activator-inhibitor combination effects. This approach accelerates the mapping of combination effects of compounds to develop combinations that may be therapeutically beneficial. We integrated the three information sources into a unified model that predicted the benefits of a triple drug combination targeting ADP, thromboxane and thrombin signaling.

  1. Research on Cholinesterase Inhibitory Action and Chemical Constituents in the Volatile Oil of Radix Peucedani%前胡挥发油胆碱酯酶抑制作用及化学成分研究

    Institute of Scientific and Technical Information of China (English)

    刘亚旻; 宋波; 李宗阳; 姜保平; 潘瑞乐

    2012-01-01

    Using micro plate high-throughput screening assay to investigate the cholinesterase inhibitory action, and analyzing the main chemical constituents in the volatile oil of Radix Peucedani by the means of Gas Chromatography-Masa Spectrometer combined with Kovats index. The result shows that the volatile oil of Radix Peucedani has significant inhibitory activities of both Acetylcholinesterase ( AChE) and Butyr-ylcholinesterase (BuChE) ,the inhibition ratio of which were (63.76±1.99) % ,(51.53 ±1.70) % .respectively, when the content of the volatile oil of Radix Peucedani was lμL/mL. Meanwhile,32 main chemical constituents in the volatile oil of Radix Peueedani has been identified,the main constituents are alpha-pinene, beta-pinene, myrcene, 1 -Methyl-3 - (1 -methylethyl) -benzene, (R ) -1 -Methyl-4- (1 -methyl-ethenyl)-cyclohexene,2-(4-Methtlcyclohex-3-enyl)-propan-2-ol,2-hydroxyl-5-methyl-acetophenone,etc. The result suggests that Radix Peucedani maybe have a certain curative effect on neurodegenerative diseases,such as Alzheimer's disease.%运用微孔高通量筛选方法研究前胡挥发油胆碱酯酶抑制活性,并用气相色谱-质谱联用技术辅以Kovats 指数鉴定挥发油的主要化学成分.结果显示前胡挥发油对乙酰胆碱酯酶和丁酰胆碱酯酶均具有明显的抑制作用,当前胡挥发油浓度为1 μL/mL时,其抑制率分别为(63.76±1.99)%和(51.53±1.70)%;其挥发油共鉴定出32种化学成分,主要有α-蒎烯、左旋-β-蒎烯、月桂烯、1-甲基-3-(1-甲基乙基)苯、(R)-1-甲基-4-(1-甲基乙烯基)环己烯、萜品醇、2-羟基-5-甲基苯乙酮等.本研究结果提示前胡有可能对老年痴呆等神经退行性疾病有一定的治疗作用.

  2. Selective serotonin reuptake inhibitor exposure.

    Science.gov (United States)

    Fitzgerald, Kevin T; Bronstein, Alvin C

    2013-02-01

    Many antidepressants inhibit serotonin or norepinephrine reuptake or both to achieve their clinical effect. The selective serotonin reuptake inhibitor class of antidepressants (SSRIs) includes citalopram, escitalopram (active enantiomer of citalopram), fluoxetine, fluvoxamine, paroxetine, and sertraline. The SSRIs are as effective as tricyclic antidepressants in treatment of major depression with less significant side effects. As a result, they have become the largest class of medications prescribed to humans for depression. They are also used to treat obsessive-compulsive disorder, panic disorders, alcoholism, obesity, migraines, and chronic pain. An SSRI (fluoxetine) has been approved for veterinary use in treatment of canine separation anxiety. SSRIs act specifically on synaptic serotonin concentrations by blocking its reuptake in the presynapse and increasing levels in the presynaptic membrane. Clinical signs of SSRI overdose result from excessive amounts of serotonin in the central nervous system. These signs include nausea, vomiting, mydriasis, hypersalivation, and hyperthermia. Clinical signs are dose dependent and higher dosages may result in the serotonin syndrome that manifests itself as ataxia, tremors, muscle rigidity, hyperthermia, diarrhea, and seizures. Current studies reveal no increase in appearance of any specific clinical signs of serotonin toxicity with regard to any SSRI medication. In people, citalopram has been reported to have an increased risk of electrocardiographic abnormalities. Diagnosis of SSRI poisoning is based on history, clinical signs, and response to therapy. No single clinical test is currently available to confirm SSRI toxicosis. The goals of treatment in this intoxication are to support the animal, prevent further absorption of the drug, support the central nervous system, control hyperthermia, and halt any seizure activity. The relative safety of the SSRIs in overdose despite the occurrence of serotonin syndrome makes them

  3. Combined effects of EGFR tyrosine kinase inhibitors and vATPase inhibitors in NSCLC cells

    Energy Technology Data Exchange (ETDEWEB)

    Jin, Hyeon-Ok [KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Hong, Sung-Eun [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Kim, Chang Soon [Department of Microbiological Engineering, Kon-Kuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 143–701 (Korea, Republic of); Park, Jin-Ah; Kim, Jin-Hee; Kim, Ji-Young; Kim, Bora [KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Chang, Yoon Hwan; Hong, Seok-Il; Hong, Young Jun [Department of Laboratory Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Park, In-Chul, E-mail: parkic@kirams.re.kr [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Lee, Jin Kyung, E-mail: jklee@kirams.re.kr [KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Department of Laboratory Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of)

    2015-08-15

    Despite excellent initial clinical responses of non-small cell lung cancer (NSCLC) patients to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), many patients eventually develop resistance. According to a recent report, vacuolar H + ATPase (vATPase) is overexpressed and is associated with chemotherapy drug resistance in NSCLC. We investigated the combined effects of EGFR TKIs and vATPase inhibitors and their underlying mechanisms in the regulation of NSCLC cell death. We found that combined treatment with EGFR TKIs (erlotinib, gefitinib, or lapatinib) and vATPase inhibitors (bafilomycin A1 or concanamycin A) enhanced synergistic cell death compared to treatments with each drug alone. Treatment with bafilomycin A1 or concanamycin A led to the induction of Bnip3 expression in an Hif-1α dependent manner. Knock-down of Hif-1α or Bnip3 by siRNA further enhanced cell death induced by bafilomycin A1, suggesting that Hif-1α/Bnip3 induction promoted resistance to cell death induced by the vATPase inhibitors. EGFR TKIs suppressed Hif-1α and Bnip3 expression induced by the vATPase inhibitors, suggesting that they enhanced the sensitivity of the cells to these inhibitors by decreasing Hif-1α/Bnip3 expression. Taken together, we conclude that EGFR TKIs enhance the sensitivity of NSCLC cells to vATPase inhibitors by decreasing Hif-1α/Bnip3 expression. We suggest that combined treatment with EGFR TKIs and vATPase inhibitors is potentially effective for the treatment of NSCLC. - Highlights: • Co-treatment with EGFR TKIs and vATPase inhibitors induces synergistic cell death • EGFR TKIs enhance cell sensitivity to vATPase inhibitors via Hif-1α downregulation • Co-treatment of these inhibitors is potentially effective for the treatment of NSCLC.

  4. Screening of protein kinase inhibitors identifies PKC inhibitors as inhibitors of osteoclastic acid secretion and bone resorption

    Directory of Open Access Journals (Sweden)

    Boutin Jean A

    2010-10-01

    Full Text Available Abstract Background Bone resorption is initiated by osteoclastic acidification of the resorption lacunae. This process is mediated by secretion of protons through the V-ATPase and chloride through the chloride antiporter ClC-7. To shed light on the intracellular signalling controlling extracellular acidification, we screened a protein kinase inhibitor library in human osteoclasts. Methods Human osteoclasts were generated from CD14+ monocytes. The effect of different kinase inhibitors on lysosomal acidification in human osteoclasts was investigated using acridine orange for different incubation times (45 minutes, 4 and 24 hours. The inhibitors were tested in an acid influx assay using microsomes isolated from human osteoclasts. Bone resorption by human osteoclasts on bone slices was measured by calcium release. Cell viability was measured using AlamarBlue. Results Of the 51 compounds investigated only few inhibitors were positive in both acidification and resorption assays. Rottlerin, GF109203X, Hypericin and Ro31-8220 inhibited acid influx in microsomes and bone resorption, while Sphingosine and Palmitoyl-DL-carnitine-Cl showed low levels of inhibition. Rottlerin inhibited lysosomal acidification in human osteoclasts potently. Conclusions In conclusion, a group of inhibitors all indicated to inhibit PKC reduced acidification in human osteoclasts, and thereby bone resorption, indicating that acid secretion by osteoclasts may be specifically regulated by PKC in osteoclasts.

  5. The therapeutic potential of aromatase inhibitors.

    Science.gov (United States)

    Miller, W R; Jackson, J

    2003-03-01

    The third generation aromatase inhibitors are both remarkably potent and specific endocrine agents inhibiting aromatase activity and reducing circulating oestrogen levels in postmenopausal women to levels never previously seen. Their therapeutic potential is consequently much greater than the earlier prototype drugs. Their excellent side-effect profile also allows for potential wider indications in the treatment of oestrogen-related diseases, including breast cancer. It still remains to determine whether their potent endocrine effects translate into increased therapeutic benefit. In advanced breast cancer, aromatase inhibitors have been shown to have improved efficacy and toxicity profiles when compared with progestins, aminoglutethimide and tamoxifen. Aromatase inhibitors have also been used in the neoadjuvant setting, where they have been shown to achieve higher response rates than tamoxifen and to be more successful at downstaging tumours. Early results comparing an aromatase inhibitor with tamoxifen in the adjuvant setting in early breast cancer show anastrozole to be superior to tamoxifen in terms of both disease-free survival and a lower incidence of new contralateral tumours. There was also a more favourable side-effect profile, which has implications for potential future prophylactic treatment. Additionally, since aromatase inhibitors have different mechanisms of action, unlike antioestrogens, they may be particularly useful as chemopreventive agents if oestrogens are themselves genotoxic. Aromatase inhibitors have been used to date almost exclusively in postmenopausal women. The potential of combining them with luteinising hormone-releasing hormone analogues allows the possibility of treating premenopausal women with either oestrogen receptor-positive breast cancer or benign conditions such as cyclical breast pain, fibroadenomata, recurrent cystic disease or endometriosis. There is also the potential for their use in men with conditions such as

  6. Proteasome inhibitor treatment in alcoholic liver disease

    Institute of Scientific and Technical Information of China (English)

    Fawzia Bardag-Gorce

    2011-01-01

    Oxidative stress, generated by chronic ethanol consumption, is a major cause of hepatotoxicity and liver injury. Increased production of oxygen-derived free radicals due to ethanol metabolism by CYP2E1 is principally located in the cytoplasm and in the mitochondria, which does not only injure liver cells, but also other vital organs, such as the heart and the brain. Therefore, there is a need for better treatment to enhance the antioxidant response elements. To date, there is no established treatment to attenuate high levels of oxidative stress in the liver of alcoholic patients. To block this oxidative stress, proteasome inhibitor treatment has been found to significantly enhance the antioxidant response elements of hepatocytes exposed to ethanol. Recent studies have shown in an experimental model of alcoholic liver disease that proteasome inhibitor treatment at low dose has cytoprotective effects against ethanol-induced oxidative stress and liver steatosis. The beneficial effects of proteasome inhibitor treatment against oxidative stress occurred because antioxidant response elements (glutathione peroxidase 2, superoxide dismutase 2, glutathione synthetase, glutathione reductase, and GCLC) were upregulated when rats fed alcohol were treated with a low dose of PS-341 (Bortezomib, Velcade(r)). This is an important finding because proteasome inhibitor treatment up-regulated reactive oxygen species removal and glutathione recycling enzymes, while ethanol feeding alone down-regulated these antioxidant elements. For the first time, it was shown that proteasome inhibition by a highly specific and reversible inhibitor is different from the chronic ethanol feeding-induced proteasome inhibition. As previously shown by our group, chronic ethanol feeding causes a complex dysfunction in the ubiquitin proteasome pathway, which affects the proteasome system, as well as the ubiquitination system. The beneficial effects of proteasome inhibitor treatment in alcoholic liver disease

  7. The granzyme B inhibitor proteinase inhibitor 9 (PI9) is expressed by human mast cells.

    NARCIS (Netherlands)

    Bladergroen, B.A.; Strik, M.C.; Wolbink, A.M.; Wouters, D.; Broekhuizen, R.; Kummer, J.A.; Hack, C.E.

    2005-01-01

    The activity of granzyme B, a main effector molecule of cytotoxic T lymphocytes (CTL) and natural killer cells, is regulated by the human intracellular serpin proteinase inhibitor 9 (PI9). This inhibitor is particularly expressed by CTL and dendritic cells, in which it serves to protect these cells

  8. Acrosin inhibitor detection along the boar epididymis.

    Science.gov (United States)

    Maňásková-Postlerová, Pavla; Cozlová, Nina; Dorosh, Andriy; Šulc, Miroslav; Guyonnet, Benoit; Jonáková, Věra

    2016-01-01

    Epididymal sperm maturation represents a key step in the reproduction process. Spermatozoa are exposed to epididymal fluid components representing the natural environment essential for their post-testicular maturation. Changes in sperm membrane proteins are influenced by proteolytic, glycosylation and deglycosylation enzymes present in the epididymal fluid. Accordingly, the occurrence of inhibitors of these enzymes in the epididymis is very important for the regulation of sperm membrane protein processing. In the present study, we monitored acrosin inhibitor distribution in boar epididymal fluid and in spermatozoa from different segments of the organ. Using specific polyclonal antibody we registered increasing signal of the acrosin inhibitor (AI) from caput to cauda epididymis. Mass spectroscopy examination of the immunoprecipitated acrosin inhibitor (12 kDa) unequivocally identified sperm-associated acrosin inhibitor (SAAI) in the epididymal tissue. Lectin staining showed N-glycosylation in AI from boar epididymis. Protein detection of AI was supported by the results of semi-quantitative RT-PCR showing the presence of mRNA specifically coding for SAAI and similarly increasing throughout the epididymal duct, from its proximal to distal part. Additionally, the immunofluorescence technique showed the AI localization in the secretory tissue of caput, corpus and cauda epididymis, and in the acrosome region and midpiece of the sperm.

  9. Evolutionary mechanisms acting on proteinase inhibitor variability.

    Science.gov (United States)

    Christeller, John T

    2005-11-01

    The interaction of proteinase inhibitors produced, in most cases, by host organisms and the invasive proteinases of pathogens or parasites or the dietary proteinases of predators, results in an evolutionary 'arms race' of rapid and ongoing change in both interacting proteins. The importance of these interactions in pathogenicity and predation is indicated by the high level and diversity of observable evolutionary activity that has been found. At the initial level of evolutionary change, recruitment of other functional protein-folding families has occurred, with the more recent evolution of one class of proteinase inhibitor from another, using the same mechanism and proteinase contact residues. The combination of different inhibitor domains into a single molecule is also observed. The basis from which variation is possible is shown by the high rate of retention of gene duplication events and by the associated process of inhibitory domain multiplication. At this level of reorganization, mutually exclusive splicing is also observed. Finally, the major mechanism by which variation is achieved rapidly is hypervariation of contact residues, an almost ubiquitous feature of proteinase inhibitors. The diversity of evolutionary mechanisms in a single class of proteins is unlikely to be common, because few systems are under similar pressure to create variation. Proteinase inhibitors are therefore a potential model system in which to study basic evolutionary process such as functional diversification.

  10. Resistance to AHAS inhibitor herbicides: current understanding.

    Science.gov (United States)

    Yu, Qin; Powles, Stephen B

    2014-09-01

    Acetohydroxyacid synthase (AHAS) inhibitor herbicides currently comprise the largest site-of-action group (with 54 active ingredients across five chemical groups) and have been widely used in world agriculture since they were first introduced in 1982. Resistance evolution in weeds to AHAS inhibitors has been rapid and identified in populations of many weed species. Often, evolved resistance is associated with point mutations in the target AHAS gene; however non-target-site enhanced herbicide metabolism occurs as well. Many AHAS gene resistance mutations can occur and be rapidly enriched owing to a high initial resistance gene frequency, simple and dominant genetic inheritance and lack of major fitness cost of the resistance alleles. Major advances in the elucidation of the crystal structure of the AHAS (Arabidopsis thaliana) catalytic subunit in complex with various AHAS inhibitor herbicides have greatly improved current understanding of the detailed molecular interactions between AHAS, cofactors and herbicides. Compared with target-site resistance, non-target-site resistance to AHAS inhibitor herbicides is less studied and hence less understood. In a few well-studied cases, non-target-site resistance is due to enhanced rates of herbicide metabolism (metabolic resistance), mimicking that occurring in tolerant crop species and often involving cytochrome P450 monooxygenases. However, the specific herbicide-metabolising, resistance-endowing genes are yet to be identified in resistant weed species. The current state of mechanistic understanding of AHAS inhibitor herbicide resistance is reviewed, and outstanding research issues are outlined.

  11. Protease Inhibitors from Plants with Antimicrobial Activity

    Directory of Open Access Journals (Sweden)

    Yoonkyung Park

    2009-06-01

    Full Text Available Antimicrobial proteins (peptides are known to play important roles in the innate host defense mechanisms of most living organisms, including plants, insects, amphibians and mammals. They are also known to possess potent antibiotic activity against bacteria, fungi, and even certain viruses. Recently, the rapid emergence of microbial pathogens that are resistant to currently available antibiotics has triggered considerable interest in the isolation and investigation of the mode of action of antimicrobial proteins (peptides. Plants produce a variety of proteins (peptides that are involved in the defense against pathogens and invading organisms, including ribosome-inactivating proteins, lectins, protease inhibitors and antifungal peptides (proteins. Specially, the protease inhibitors can inhibit aspartic, serine and cysteine proteinases. Increased levels of trypsin and chymotrypsin inhibitors correlated with the plants resistance to the pathogen. Usually, the purification of antimicrobial proteins (peptides with protease inhibitor activity was accomplished by salt-extraction, ultrafiltration and C18 reverse phase chromatography, successfully. We discuss the relation between antimicrobial and anti-protease activity in this review. Protease inhibitors from plants potently inhibited the growth of a variety of pathogenic bacterial and fungal strains and are therefore excellent candidates for use as the lead compounds for the development of novel antimicrobial agents.

  12. Corrosion inhibitors; Los inhibidores de corrosion

    Energy Technology Data Exchange (ETDEWEB)

    Godinez, L. A.; Meas, Y.; Ortega-Borges, R.; Corona, A.

    2003-07-01

    In this paper, we briefly describe the characteristics, cost and electrochemical nature of the corrosion phenomena as well as some of the technologies that are currently employed to minimize its effect. The main subject of the paper however, deals with the description, classification and mechanism of protection of the so-called corrosion inhibitors. Examples of the use of these substances in different aggressive environments are also presented as means to show that these compounds, or their combination, can in fact be used as excellent and relatively cheap technologies to control the corrosion of some metals. In the last part of the paper, the most commonly used techniques to evaluate the efficiency and performance of corrosion inhibitors are presented as well as some criteria to make a careful and proper selection of a corrosion inhibitor technology in a given situation. (Author) 151 refs.

  13. LDL Cholesterol, Statins And PCSK 9 Inhibitors

    Science.gov (United States)

    Gupta, Sanjiv

    2015-01-01

    Reduction of low density lipoprotein cholesterol (LDLc) is of vital importance for the prevention of atherosclerotic cardiovascular disease (ASCVD). Statin is the most effective therapy today to lower LDLc by inhibiting HMG-CoA-reductase. However despite intensive statin therapy, there remains a residual risk of recurrent myocardial infarction in about 20–30% cases. Moreover a few patients develop statin intolerance. For severe hypercholesterolemia, statins alone or in combination of ezetimibe, niacin and fenofibrate have been advocated. For homozygous familial hypercholesterolemia (HOFH), a microsomal triglyceride transfer protein MTP inhibitor (Lopitamide) and antisense oligonucleotide (ASO) (Mipomersen) have recently been approved by FDA, USA through ‘Risk evaluation and Mitigation Strategy (REMS)’. Possible future therapies include PCSK-9 inhibitors which have excellent lipid lowering properties. Three monoclonal antibodies (PCSK 9 Inhibitors) alirocumab, evolocumab and Bococizumab are under advanced clinical stage IV trials and awaiting approval by FDA and European Medicines Agency. PMID:26432726

  14. SHH inhibitors for the treatment of medulloblastoma.

    Science.gov (United States)

    Samkari, Ayman; White, Jason; Packer, Roger

    2015-01-01

    Medulloblastoma is the most common malignant brain tumor of childhood. It is currently stratified into four molecular variants through the advances in transcriptional profiling. They include: wingless, sonic hedgehog (SHH), Group III, and Group IV. The SHH group is characterized by constitutive activation of the SHH signaling pathway, and genetically characterized by mutations in patched homolog 1 (PTCH1) or other downstream pathway mutations. SHH inhibitors have become of great clinical interest in treating SHH-driven medulloblastoma. Many inhibitors are currently in different stages of development, some already approved for other SHH-driven cancers, such as basal cell carcinoma. In vitro and in vivo medulloblastoma studies have shown efficacy and these findings have been translated into Phase I and II clinical trials. In this review, we present an overview of SHH medulloblastoma, as well as a discussion of currently available SHH inhibitors, and the challenges associated with their use.

  15. Drug screening for influenza neuraminidase inhibitors

    Institute of Scientific and Technical Information of China (English)

    LIU; Ailin; CAO; Hongpeng; DU; Guanhua

    2005-01-01

    Neuraminidase (NA) is one of the most important targets to screen the drugs of anti-influenza virus A and B. After virtual screening approaches were applied to a compound database which possesses more than 10000 compound structures, 160 compounds were selected for bioactivity assay, then a High Throughput Screening (HTS) model established for influenza virus NA inhibitors was applied to detect these compounds. Finally, three compounds among them displayed higher inhibitory activities, the range of their IC50 was from 0.1 μmol/L to 3μmol/L. Their structural scaffolds are novel and different from those of NA inhibitors approved for influenza treatment, and will be useful for the design and research of new NA inhibitors. The resuit indicated that the combination of virtual screening with HTS was very significant to drug screening and drug discovery.

  16. Hereditary angioedema with normal C1 inhibitor.

    Science.gov (United States)

    Bork, Konrad

    2013-11-01

    Until recently it was assumed that hereditary angioedema was a disease that results exclusively from a genetic deficiency of the C1 inhibitor. In 2000, families with hereditary angioedema, normal C1 inhibitor activity, and protein in plasma were described. Since then, numerous patients and families with that condition have been reported. Most of the patients were women. In many of the affected women, oral contraceptives, hormone replacement therapy containing estrogens, and pregnancies triggered the clinical symptoms. In some families mutations in the coagulation factor XII (Hageman factor) gene were detected.

  17. Rational design of protein kinase inhibitors

    Directory of Open Access Journals (Sweden)

    Yarmoluk S. M.

    2013-07-01

    Full Text Available Modern methodological approaches to rational design of low molecular weight compounds with specific activity in relation to predetermined biomolecular targets are considered by example of development of high effective protein kinase inhibitors. The application of new computational methods that allow to significantly improve the quality of computational experiments (in, particular, accuracy of low molecular weight compounds activity prediction without increase of computational and time costs are highlighted. The effectiveness of strategy of rational design is demonstrated by examples of several own investigations devoted to development of new inhibitors that are high effective and selective towards protein kinases CK2, FGFR1 and ASK1.

  18. New cholinesterase inhibitory constituents from Lonicera quinquelocularis.

    Directory of Open Access Journals (Sweden)

    Dilfaraz Khan

    Full Text Available A phytochemical investigation on the ethyl acetate soluble fraction of Lonicera quinquelocularis (whole plant led to the first time isolation of one new phthalate; bis(7-acetoxy-2-ethyl-5-methylheptyl phthalate (3 and two new benzoates; neopentyl-4-ethoxy-3, 5-bis (3-methyl-2-butenyl benzoate (4 and neopentyl-4-hydroxy-3, 5-bis (3-methyl-2-butenyl benzoate (5 along with two known compounds bis (2-ethylhexyl phthalate (1 and dioctyl phthalate (2. Their structures were established on the basis of spectroscopic analysis and by comparison with available data in the literature. All the compounds (1-5 were tested for their acetylcholinesterase (AChE and butyrylcholinesterase (BChE inhibitory activities in dose dependent manner. The IC50 (50% inhibitory effect values of compounds 3 and 5 against AChE were 1.65 and 3.43 µM while the values obtained against BChE were 5.98 and 9.84 µM respectively. Compounds 2 and 4 showed weak inhibition profile.

  19. Antiviral cytokines induce hepatic expression of the granzyme B inhibitors, proteinase inhibitor 9 and serine proteinase inhibitor 6.

    Science.gov (United States)

    Barrie, Mahmoud B; Stout, Heather W; Abougergi, Marwan S; Miller, Bonnie C; Thiele, Dwain L

    2004-05-15

    Expression of the granzyme B inhibitors, human proteinase inhibitor 9 (PI-9), or the murine orthologue, serine proteinase inhibitor 6 (SPI-6), confers resistance to CTL or NK killing by perforin- and granzyme-dependent effector mechanisms. In light of prior studies indicating that virally infected hepatocytes are selectively resistant to this CTL effector mechanism, the present studies investigated PI-9 and SPI-6 expression in hepatocytes and hepatoma cells in response to adenoviral infection and to cytokines produced during antiviral immune responses. Neither PI-9 nor SPI-6 expression was detected by immunoblotting in uninfected murine or human hepatocytes. Similarly, human Huh-7 hepatoma cells were found to express only very low levels of PI-9 relative to levels detected in perforin- and granzyme-resistant CTL or lymphokine-activated killer cells. Following in vivo adenoviral infection or in vitro culture with IFN-alphabeta or IFN-gamma, SPI-6 expression was induced in murine hepatocytes. Similarly, after culture with IFN-alpha, induction of PI-9 mRNA and protein expression was observed in human hepatocytes and Huh-7 cells. IFN-gamma and TNF-alpha also induced 4- to 10-fold higher levels of PI-9 mRNA expression in Huh-7 cells, whereas levels of mRNA encoding a related serine proteinase inhibitor, proteinase inhibitor 8, were unaffected by culture of Huh-7 cells with IFN-alpha, IFN-gamma, or TNF-alpha. These findings indicate that cytokines that promote antiviral cytopathic responses also regulate expression of the cytoprotective molecules, PI-9 and SPI-6, in hepatocytes that are potential targets of CTL and NK effector mechanisms.

  20. [Application of process engineering to remove lignocellulose fermentation inhibitors].

    Science.gov (United States)

    Wang, Lan; Xia, Menglei; Chen, Hongzhang

    2014-05-01

    Fermentation inhibitors are toxic to cells, which is one of the bottlenecks for lignocellulose bio-refinery process. How to remove those inhibitors serves a key role in the bioconversion of lignocellulose. This article reviews the sources and the types of the inhibitors, especially the updated removal strategies including physical methods, chemical methods, biological methods and inhibitor-tolerant strain construction strategies. Based on these, we introduce a new bio-refinery model named "fractional conversion", which reduces the production of inhibitors at pretreatment stage, and a novel in situ detoxification method named "fermentation promoter exploitation technology". This review could provide new research ideas on the removal of fermentation inhibitors.

  1. Developmental expression of a catalase inhibitor in maize

    Energy Technology Data Exchange (ETDEWEB)

    Sorenson, J.C.; Scandalios, J.G.

    1976-01-01

    The expression of an endogenous catalase inhibitor has been studied during development of Zea mays. In the 3-day seedling, the inhibitor is expressed primarily in the scutellum and in the aleurone layer of the endosperm. These tissues also show the highest catalase activity at this stage. Inhibitor expression has also been studied temporally in the scutellum, roots, and shoot over the first 12 days of germination. Inhibitor expression shows an inverse relationship with catalase activity in the scutellum and in the shoot. The relationship is less rigid in the root, due probably to the low levels of inhibitor found in that tissue. The role of the inhibitor in catalase regulation is discussed.

  2. Proton pump inhibitors affect the gut microbiome

    NARCIS (Netherlands)

    Imhann, Floris; Bonder, Marc Jan; Vich Vila, Arnau; Fu, Jingyuan; Mujagic, Zlatan; Vork, Lisa; Tigchelaar, Ettje F; Jankipersadsing, Soesma A; Cenit, Maria Carmen; Harmsen, Hermie J M; Dijkstra, Gerard; Franke, Lude; Xavier, Ramnik J; Jonkers, Daisy; Wijmenga, Cisca; Weersma, Rinse K; Zhernakova, Alexandra

    2015-01-01

    BACKGROUND AND AIMS: Proton pump inhibitors (PPIs) are among the top 10 most widely used drugs in the world. PPI use has been associated with an increased risk of enteric infections, most notably Clostridium difficile. The gut microbiome plays an important role in enteric infections, by resisting or

  3. Corrosion inhibitors for intermediate cooling systems

    Energy Technology Data Exchange (ETDEWEB)

    Falk, I.; Suhr, L.

    1985-04-01

    The selected inhibitors were tested for heat and radiation stability and corrosion protection on the bench scale. Based on the results from these tests two of the products were selected, Bycoguard 81 and Bycoguard MP4S for continuing corrosion tests in an autoclave loop at 90 degrees C and 120 degrees C. Oxygen saturated deionized water with an addition of 1 ppm chloride was recirculated in the loop. Samples of copper and carbon steel were exposed to the water in the autoclave for periods up to 10 weeks. The purpose of this project was to find a substitute for hydrazine and chromates. Besides good corrosion protection qualities the toxic and environmental effect of the inhibitors should be minimal. The investigation has shown that the copper inhibitor BTA (benzotriazole) loses its corrosion protection qualities at a water temperature of 120 degrees C. The protection effects at 90 degrees C were satisfactory for both of the materials. The corrosion rates measured were 0.01 mm/y or less for the copper and carbon steel samples. The environment in the autoclave during the testing was more corrosive than is to be found in intermediate cooling systems. Due to the low corrosion rates measured the two inhibitors are to be recommended as alternatives to hydrazine and chromates.

  4. Inhibitors for Androgen Receptor Activation Surfaces

    Science.gov (United States)

    2007-09-01

    mortality after heart attack (6), and RU486, which is used as emergency birth control (7). New NR inhibitors would most likely be useful for...mifepristone and levonorgestrel when used for emergency contraception. Hum Reprod Update 10:341-348 8. Webb P NN, Chiellini G, Yoshihara HA, Cunha Lima ST

  5. Inhibitors of p21-activated kinases (PAKs).

    Science.gov (United States)

    Rudolph, Joachim; Crawford, James J; Hoeflich, Klaus P; Wang, Weiru

    2015-01-08

    The p21-activated kinase (PAK) family of serine/threonine protein kinases plays important roles in cytoskeletal organization, cellular morphogenesis, and survival, and members of this family have been implicated in many diseases including cancer, infectious diseases, and neurological disorders. Owing to their large and flexible ATP binding cleft, PAKs, particularly group I PAKs (PAK1, -2, and -3), are difficult to drug; hence, few PAK inhibitors with satisfactory kinase selectivity and druglike properties have been reported to date. Examples are a recently discovered group II PAK (PAK4, -5, -6) selective inhibitor series based on a benzimidazole core, a group I PAK selective series based on a pyrido[2,3-d]pyrimidine-7-one core, and an allosteric dibenzodiazepine PAK1 inhibitor series. Only one compound, an aminopyrazole based pan-PAK inhibitor, entered clinical trials but did not progress beyond phase I trials. Clinical proof of concept for pan-group I, pan-group II, or PAK isoform selective inhibition has yet to be demonstrated.

  6. Novel proteinase inhibitor promotes resistance to insects

    Science.gov (United States)

    A novel Beta vulgaris serine proteinase inhibitor gene (BvSTI) and its protein are identified in response to insect feeding on B. vulgaris seedlings. BvSTI is cloned into an expression vector with constitutive promoter and transformed into Nicotiana benthamiana plants to assess BvSTI’s ability to ...

  7. Phenyltriazolinones as potent factor Xa inhibitors.

    Science.gov (United States)

    Quan, Mimi L; Pinto, Donald J P; Rossi, Karen A; Sheriff, Steven; Alexander, Richard S; Amparo, Eugene; Kish, Kevin; Knabb, Robert M; Luettgen, Joseph M; Morin, Paul; Smallwood, Angela; Woerner, Francis J; Wexler, Ruth R

    2010-02-15

    We have discovered that phenyltriazolinone is a novel and potent P1 moiety for coagulation factor Xa. X-ray structures of the inhibitors with a phenyltriazolinone in the P1 position revealed that the side chain of Asp189 has reoriented resulting in a novel S1 binding pocket which is larger in size to accommodate the phenyltriazolinone P1 substrate.

  8. Curcumin derivatives as HIV-1 protease inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Sui, Z.; Li, J.; Craik, C.S.; Ortiz de Montellano, P.R. [Univ. of California, San Francisco, CA (United States)

    1993-12-31

    Curcumin, a non-toxic natural compound from Curcuma longa, has been found to be an HIV-1 protease inhibitor. Some of its derivatives were synthesized and their inhibitory activity against the HIV-1 protease was tested. Curcumin analogues containing boron enhanced the inhibitory activity. At least of the the synthesized compounds irreversibly inhibits the HIV-1 protease.

  9. Structure-Based Design of Ricin Inhibitors

    Directory of Open Access Journals (Sweden)

    Jon D. Robertus

    2011-10-01

    Full Text Available Ricin is a potent cytotoxin easily purified in large quantities. It presents a significant public health concern due to its potential use as a bioterrorism agent. For this reason, extensive efforts have been underway to develop antidotes against this deadly poison. The catalytic A subunit of the heterodimeric toxin has been biochemically and structurally well characterized, and is an attractive target for structure-based drug design. Aided by computer docking simulations, several ricin toxin A chain (RTA inhibitors have been identified; the most promising leads belonging to the pterin family. Development of these lead compounds into potent drug candidates is a challenging prospect for numerous reasons, including poor solubility of pterins, the large and highly polar secondary binding pocket of RTA, as well as the enzyme’s near perfect catalytic efficiency and tight binding affinity for its natural substrate, the eukaryotic ribosome. To date, the most potent RTA inhibitors developed using this approach are only modest inhibitors with apparent IC50 values in the 10−4 M range, leaving significant room for improvement. This review highlights the variety of techniques routinely employed in structure-based drug design projects, as well as the challenges faced in the design of RTA inhibitors.

  10. Dissolution properties of cerium dibutylphosphate corrosion inhibitors

    NARCIS (Netherlands)

    Soestbergen, M. van; Erich, S.J.F.; Huinink, H.P.; Adan, O.C.G.

    2013-01-01

    The corrosion inhibitor cerium dibutylphosphate, Ce(dbp)3, prevents corrosion by cerium and dbp deposition at the alkaline cathode and acidic anode respectively. The pH dependent Ce(dbp)3 solubility seems to play an essential role in the inhibition degree. We found that Ce(dbp) 3 scarcely dissolves

  11. Novel bis-arylalkylamines as myeloperoxidase inhibitors

    DEFF Research Database (Denmark)

    Aldib, Iyas; Gelbcke, Michel; Soubhye, Jalal;

    2016-01-01

    Human myeloperoxidase (MPO) plays an important role in innate immunity but also aggravates tissue damage by oxidation of biomolecules at sites of inflammation. As a result from a recent high-throughput virtual screening approach for MPO inhibitors, bis-2,2'-[(dihydro-1,3(2H,4H) pyrimidinediyl)bis...

  12. Protease inhibitor mediated resistance to insects

    NARCIS (Netherlands)

    Outchkourov, N.S.

    2003-01-01

    Protease inhibitors (PIs) are among the defensive molecules that plants produce in order to defend themselves against herbivores. A major aim of this thesis is to develop novel insect resistance traits usingheterologous, non-plant PIs. Prerequisite for the success of the th

  13. Discovery of inhibitors of bacterial histidine kinases

    NARCIS (Netherlands)

    Velikova, N.R.

    2014-01-01

    Discovery of Inhibitors of Bacterial Histidine Kinases

    Summary

    The thesis is on novel antibacterial drug discovery (http://youtu.be/NRMWOGgeysM). Using structure-based and fragment-based dru

  14. Cost of care of haemophilia with inhibitors.

    Science.gov (United States)

    Di Minno, M N D; Di Minno, G; Di Capua, M; Cerbone, A M; Coppola, A

    2010-01-01

    In Western countries, the treatment of patients with inhibitors is presently the most challenging and serious issue in haemophilia management, direct costs of clotting factor concentrates accounting for >98% of the highest economic burden absorbed for the healthcare of patients in this setting. Being designed to address questions of resource allocation and effectiveness, decision models are the golden standard to reliably assess the overall economic implications of haemophilia with inhibitors in terms of mortality, bleeding-related morbidity, and severity of arthropathy. However, presently, most data analyses stem from retrospective short-term evaluations, that only allow for the analysis of direct health costs. In the setting of chronic diseases, the cost-utility analysis, that takes into account the beneficial effects of a given treatment/healthcare intervention in terms of health-related quality of life, is likely to be the most appropriate approach. To calculate net benefits, the quality adjusted life year, that significantly reflects such health gain, has to be compared with specific economic impacts. Differences in data sources, in medical practice and/or in healthcare systems and costs, imply that most current pharmacoeconomic analyses are confined to a narrow healthcare payer perspective. Long-term/lifetime prospective or observational studies, devoted to a careful definition of when to start a treatment; of regimens (dose and type of product) to employ, and of inhibitor population (children/adults, low-responding/high responding inhibitors) to study, are thus urgently needed to allow for newer insights, based on reliable data sources into resource allocation, effectiveness and cost-utility analysis in the treatment of haemophiliacs with inhibitors.

  15. Dermatologic adverse events to chemotherapeutic agents, Part 2: BRAF inhibitors, MEK inhibitors, and ipilimumab.

    Science.gov (United States)

    Choi, Jennifer Nam

    2014-03-01

    The advent of novel targeted chemotherapeutic agents and immunotherapies has dramatically changed the arena of cancer treatment in recent years. BRAF inhibitors, MEK inhibitors, and ipilimumab are among the newer chemotherapy drugs that are being used at an increasing rate. Dermatologic adverse events to these medications are common, and it is important for dermatologists and oncologists alike to learn to recognize and treat such side effects in order to maintain both patients' quality of life and their anticancer treatment. This review describes the cutaneous side effects seen with BRAF inhibitors (eg, maculopapular eruption, photosensitivity, squamoproliferative growths, melanocytic proliferations), MEK inhibitors (eg, papulopustular eruption), and ipilimumab (eg, maculopapular eruption, vitiligo), with a mention of vismodegib and anti-PD-1 agents.

  16. Calcineurin inhibitor minimisation versus continuation of calcineurin inhibitor treatment for liver transplant recipients

    DEFF Research Database (Denmark)

    Penninga, Luit; Wettergren, Andre; Chan, An-Wen;

    2012-01-01

    The therapeutic success of liver transplantation has been largely attributable to the development of effective immunosuppressive treatment regimens. In particular, calcineurin inhibitors were essential in reducing acute rejection and improving early survival. Currently, more than 90% of all liver...

  17. Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors.

    Science.gov (United States)

    Tan, Li; Wang, Jun; Tanizaki, Junko; Huang, Zhifeng; Aref, Amir R; Rusan, Maria; Zhu, Su-Jie; Zhang, Yiyun; Ercan, Dalia; Liao, Rachel G; Capelletti, Marzia; Zhou, Wenjun; Hur, Wooyoung; Kim, NamDoo; Sim, Taebo; Gaudet, Suzanne; Barbie, David A; Yeh, Jing-Ruey Joanna; Yun, Cai-Hong; Hammerman, Peter S; Mohammadi, Moosa; Jänne, Pasi A; Gray, Nathanael S

    2014-11-11

    The human FGF receptors (FGFRs) play critical roles in various human cancers, and several FGFR inhibitors are currently under clinical investigation. Resistance usually results from selection for mutant kinases that are impervious to the action of the drug or from up-regulation of compensatory signaling pathways. Preclinical studies have demonstrated that resistance to FGFR inhibitors can be acquired through mutations in the FGFR gatekeeper residue, as clinically observed for FGFR4 in embryonal rhabdomyosarcoma and neuroendocrine breast carcinomas. Here we report on the use of a structure-based drug design to develop two selective, next-generation covalent FGFR inhibitors, the FGFR irreversible inhibitors 2 (FIIN-2) and 3 (FIIN-3). To our knowledge, FIIN-2 and FIIN-3 are the first inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. Because of the conformational flexibility of the reactive acrylamide substituent, FIIN-3 has the unprecedented ability to inhibit both the EGF receptor (EGFR) and FGFR covalently by targeting two distinct cysteine residues. We report the cocrystal structure of FGFR4 with FIIN-2, which unexpectedly exhibits a "DFG-out" covalent binding mode. The structural basis for dual FGFR and EGFR targeting by FIIN3 also is illustrated by crystal structures of FIIN-3 bound with FGFR4 V550L and EGFR L858R. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance and provide the first example, to our knowledge, of a kinase inhibitor that covalently targets cysteines located in different positions within the ATP-binding pocket.

  18. Comparative Study on the Protease Inhibitors from Fish Eggs

    Institute of Scientific and Technical Information of China (English)

    Ustadi; K.Y.Kim; S.M.Kim

    2005-01-01

    The protease inhibitor was purified from five different fish eggs. The molecular weights of Pacific herring, chum salmon, pond smelt, glassfish, and Alaska pollock egg protease inhibitors were 120, 89, 84.5, 17, and 16.8kDa, respectively. The specific inhibitory activity of glassfish egg protease inhibitor was the highest followed by those of Pacific herring and Alaska pollock in order. The specific inhibitory activity and purity of glassfish egg protease inhibitor were 19.70 U mg-1 protein and 164.70 folds of purification, respectively. Glassfish egg protease inhibitor was reasonably stable at 50 - 65 ℃ and pH 8,which was more stable at high temperature and pH than protease inhibitors from the other fish species. Glassfish egg protease inhibitor was noncompetitive with inhibitor constant (Ki) of 4.44 nmol L-1.

  19. SGLT2 Inhibitors: Benefit/Risk Balance.

    Science.gov (United States)

    Scheen, André J

    2016-10-01

    Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) reduce hyperglycemia by increasing urinary glucose excretion. They have been evaluated in patients with type 2 diabetes treated with diet/exercise, metformin, dual oral therapy or insulin. Three agents are available in Europe and the USA (canagliflozin, dapagliflozin, empagliflozin) and others are commercialized in Japan or in clinical development. SGLT2 inhibitors reduce glycated hemoglobin, with a minimal risk of hypoglycemia. They exert favorable effects beyond glucose control with consistent body weight, blood pressure, and serum uric acid reductions. Empagliflozin showed remarkable reductions in cardiovascular/all-cause mortality and in hospitalization for heart failure in patients with previous cardiovascular disease. Positive renal outcomes were also shown with empagliflozin. Mostly reported adverse events are genital mycotic infections, while urinary tract infections and events linked to volume depletion are rather rare. Concern about a risk of ketoacidosis and bone fractures has been recently raised, which deserves caution and further evaluation.

  20. Inhibitors of the Cellular Trafficking of Ricin

    Directory of Open Access Journals (Sweden)

    Daniel Gillet

    2012-01-01

    Full Text Available Throughout the last decade, efforts to identify and develop effective inhibitors of the ricin toxin have focused on targeting its N-glycosidase activity. Alternatively, molecules disrupting intracellular trafficking have been shown to block ricin toxicity. Several research teams have recently developed high-throughput phenotypic screens for small molecules acting on the intracellular targets required for entry of ricin into cells. These screens have identified inhibitory compounds that can protect cells, and sometimes even animals against ricin. We review these newly discovered cellular inhibitors of ricin intoxication, discuss the advantages and drawbacks of chemical-genetics approaches, and address the issues to be resolved so that the therapeutic development of these small-molecule compounds can progress.

  1. Raltegravir: first in class HIV integrase inhibitor

    Directory of Open Access Journals (Sweden)

    Zelalem Temesgen

    2008-06-01

    Full Text Available Zelalem Temesgen1, Dawd S Siraj21Mayo Clinic, Rochester, MN, USA; 2East Carolina University Greenville, NC, USAAbstract: On October 16, 2007, the US Food and Drug Administration (FDA approved raltegravir for treatment of human immunodeficiency virus (HIV-1 infection in combination with other antiretroviral agents in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents. Raltegravir is first in a novel class of antiretroviral drugs known as integrase inhibitors. It has demonstrated potent anti HIV activity in both antiretroviral treatment-naïve and experienced patients. The most common adverse events reported with raltegravir during phase 2 and 3 clinical trials were diarrhea, nausea, and headache. Laboratory abnormalities include mild elevations in liver transaminases and creatine phosphokinase.Keywords: raltegravir, HIV, antiretroviral agents, integrase inhibitors

  2. New potential AChE inhibitor candidates.

    Science.gov (United States)

    de Paula, A A N; Martins, J B L; dos Santos, M L; Nascente, L de C; Romeiro, L A S; Areas, T F M A; Vieira, K S T; Gambôa, N F; Castro, N G; Gargano, R

    2009-09-01

    We have theoretically studied new potential candidates of acetylcholinesterase (AChE) inhibitors designed from cardanol, a non-isoprenoid phenolic lipid of cashew Anacardium occidentale nut-shell liquid. The electronic structure calculations of fifteen molecule derivatives from cardanol were performed using B3LYP level with 6-31G, 6-31G(d), and 6-311+G(2d,p) basis functions. For this study we used the following groups: methyl, acetyl, N,N-dimethylcarbamoyl, N,N-dimethylamine, N,N-diethylamine, piperidine, pyrrolidine, and N,N-methylbenzylamine. Among the proposed compounds we identified that the structures with substitution by N,N-dimethycarbamoyl, N,N-dimethylamine, and pyrrolidine groups were better correlated to rivastigmine, and represent possible AChE inhibitors against Alzheimer disease.

  3. Inhibitors of the AAA+ Chaperone p97

    Directory of Open Access Journals (Sweden)

    Eli Chapman

    2015-02-01

    Full Text Available It is remarkable that a pathway as ubiquitous as protein quality control can be targeted to treat cancer. Bortezomib, an inhibitor of the proteasome, was first approved by the US Food and Drug Administration (FDA more than 10 years ago to treat refractory myeloma and later extended to lymphoma. Its use has increased the survival rate of myeloma patients by as much as three years. This success was followed with the recent accelerated approval of the natural product derived proteasome inhibitor carfilzomib (Kyprolis®, which is used to treat patients with bortezomib-resistant multiple myeloma. The success of these two drugs has validated protein quality control as a viable target to fight select cancers, but begs the question why are proteasome inhibitors limited to lymphoma and myeloma? More recently, these limitations have encouraged the search for additional targets within the protein quality control system that might offer heightened cancer cell specificity, enhanced clinical utility, a lower rate of resistance, reduced toxicity, and mitigated side effects. One promising target is p97, an ATPase associated with various cellular activities (AAA+ chaperone. p97 figures prominently in protein quality control as well as serving a variety of other cellular functions associated with cancer. More than a decade ago, it was determined that up-regulation of p97 in many forms of cancer correlates with a poor clinical outcome. Since these initial discoveries, a mechanistic explanation for this observation has been partially illuminated, but details are lacking. Understandably, given this clinical correlation, myriad roles within the cell, and its importance in protein quality control, p97 has emerged as a potential therapeutic target. This review provides an overview of efforts towards the discovery of small molecule inhibitors of p97, offering a synopsis of efforts that parallel the excellent reviews that currently exist on p97 structure, function, and

  4. GSK-3 inhibitors induce chromosome instability

    Directory of Open Access Journals (Sweden)

    Staples Oliver D

    2007-08-01

    Full Text Available Abstract Background Several mechanisms operate during mitosis to ensure accurate chromosome segregation. However, during tumour evolution these mechanisms go awry resulting in chromosome instability. While several lines of evidence suggest that mutations in adenomatous polyposis coli (APC may promote chromosome instability, at least in colon cancer, the underlying mechanisms remain unclear. Here, we turn our attention to GSK-3 – a protein kinase, which in concert with APC, targets β-catenin for proteolysis – and ask whether GSK-3 is required for accurate chromosome segregation. Results To probe the role of GSK-3 in mitosis, we inhibited GSK-3 kinase activity in cells using a panel of small molecule inhibitors, including SB-415286, AR-A014418, 1-Azakenpaullone and CHIR99021. Analysis of synchronised HeLa cells shows that GSK-3 inhibitors do not prevent G1/S progression or cell division. They do, however, significantly delay mitotic exit, largely because inhibitor-treated cells have difficulty aligning all their chromosomes. Although bipolar spindles form and the majority of chromosomes biorient, one or more chromosomes often remain mono-oriented near the spindle poles. Despite a prolonged mitotic delay, anaphase frequently initiates without the last chromosome aligning, resulting in chromosome non-disjunction. To rule out the possibility of "off-target" effects, we also used RNA interference to selectively repress GSK-3β. Cells deficient for GSK-3β exhibit a similar chromosome alignment defect, with chromosomes clustered near the spindle poles. GSK-3β repression also results in cells accumulating micronuclei, a hallmark of chromosome missegregation. Conclusion Thus, not only do our observations indicate a role for GSK-3 in accurate chromosome segregation, but they also raise the possibility that, if used as therapeutic agents, GSK-3 inhibitors may induce unwanted side effects by inducing chromosome instability.

  5. A new "brew" of MALT1 inhibitors.

    Science.gov (United States)

    Young, Ryan M; Staudt, Louis M

    2012-12-11

    The activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL) is an aggressive lymphoma that is addicted to NF-κB signaling through the CARD11-BCL10-MALT1 complex. In this issue of Cancer Cell, Nagel and colleagues and Fontan and colleagues describe MALT1 inhibitors suitable for clinical use that are selectively toxic to this malignancy.

  6. Cyclooxygenase (COX) Inhibitors and the Newborn Kidney

    OpenAIRE

    Wei Qi; Smith, Francine G.; Megan L. Lewis; Wade, Andrew W

    2012-01-01

    This review summarizes our current understanding of the role of cyclo-oxygenase inhibitors (COXI) in influencing the structural development as well as the function of the developing kidney. COXI administered either during pregnancy or after birth can influence kidney development including nephronogenesis, and can decrease renal perfusion and ultrafiltration potentially leading to acute kidney injury in the newborn period. To date, which COX isoform (COX-1 or COX-2) plays a more important role...

  7. Transition State Analog Inhibitors for Esterases.

    Science.gov (United States)

    1983-06-02

    Propanones." SCIENTIFIC PERSONNEL SUPPORTED BY THIS PROJECT AND DEGREES AWARDED DURING THIS REPORTING PERIOD Dr. Alan Dafforn Dr. Antoon Brouwer Dr. John P...294, Raven Press, New York. 11. Hansch, C. and Leo , A., (1979) "Substituent Constants for Correlation Analysis in Chemistry and Biology," pp. 69-70...BORONIC ACIDS AS 1INSITION STATE ANALOG INHIBITORS OF ACTYLCHOLINESTERASE by Alan Dafforn and Antoon C. Brouwer Department of Chemistry Bowling Green

  8. A Bacterial Cell Shape-Determining Inhibitor.

    Science.gov (United States)

    Liu, Yanjie; Frirdich, Emilisa; Taylor, Jennifer A; Chan, Anson C K; Blair, Kris M; Vermeulen, Jenny; Ha, Reuben; Murphy, Michael E P; Salama, Nina R; Gaynor, Erin C; Tanner, Martin E

    2016-04-15

    Helicobacter pylori and Campylobacter jejuni are human pathogens and causative agents of gastric ulcers/cancer and gastroenteritis, respectively. Recent studies have uncovered a series of proteases that are responsible for maintaining the helical shape of these organisms. The H. pylori metalloprotease Csd4 and its C. jejuni homologue Pgp1 cleave the amide bond between meso-diaminopimelate and iso-d-glutamic acid in truncated peptidoglycan side chains. Deletion of either csd4 or pgp1 results in bacteria with a straight rod phenotype, a reduced ability to move in viscous media, and reduced pathogenicity. In this work, a phosphinic acid-based pseudodipeptide inhibitor was designed to act as a tetrahedral intermediate analog against the Csd4 enzyme. The phosphinic acid was shown to inhibit the cleavage of the alternate substrate, Ac-l-Ala-iso-d-Glu-meso-Dap, with a Ki value of 1.5 μM. Structural analysis of the Csd4-inhibitor complex shows that the phosphinic acid displaces the zinc-bound water and chelates the metal in a bidentate fashion. The phosphinate oxygens also interact with the key acid/base residue, Glu222, and the oxyanion-stabilizing residue, Arg86. The results are consistent with the "promoted-water pathway" mechanism for carboxypeptidase A catalysis. Studies on cultured bacteria showed that the inhibitor causes significant cell straightening when incubated with H. pylori at millimolar concentrations. A diminished, yet observable, effect on the morphology of C. jejuni was also apparent. Cell straightening was more pronounced with an acapsular C. jejuni mutant strain compared to the wild type, suggesting that the capsule impaired inhibitor accessibility. These studies demonstrate that a highly polar compound is capable of crossing the outer membrane and altering cell shape, presumably by inhibiting cell shape determinant proteases. Peptidoglycan proteases acting as cell shape determinants represent novel targets for the development of antimicrobials

  9. Corrosion protection with eco-friendly inhibitors

    Science.gov (United States)

    Shahid, Muhammad

    2011-12-01

    Corrosion occurs as a result of the interaction of a metal with its environment. The extent of corrosion depends on the type of metal, the existing conditions in the environment and the type of aggressive ions present in the medium. For example, CO3-2 and NO-3 produce an insoluble deposit on the surface of iron, resulting in the isolation of metal and consequent decrease of corrosion. On the other hand, halide ions are adsorbed selectively on the metal surface and prevent formation of the oxide phase on the metal surface, resulting in continuous corrosion. Iron, aluminum and their alloys are widely used, both domestically and industrially. Linear alkylbenzene and linear alkylbenzene sulfonate are commonly used as detergents. They have also been found together in waste water. It is claimed that these chemicals act as inhibitors for stainless steel and aluminum. Release of toxic gases as a result of corrosion in pipelines may lead in certain cases to air pollution and possible health hazards. Therefore, there are two ways to look at the relationship between corrosion and pollution: (i) corrosion of metals and alloys due to environmental pollution and (ii) environmental pollution as a result of corrosion protection. This paper encompasses the two scenarios and possible remedies for various cases, using 'green' inhibitors obtained either from plant extracts or from pharmaceutical compounds. In the present study, the effect of piperacillin sodium as a corrosion inhibitor for mild steel was investigated using a weight-loss method as well as a three-electrode dc electrochemical technique. It was found that the corrosion rate decreased as the concentration of the inhibitor increased up to 9×10-4 M 93% efficiency was exhibited at this concentration.

  10. DABIGATRAN ETEXILATE: NEW DIRECT THROMBIN INHIBITORS ANTICOAGULANTS

    OpenAIRE

    Patel Kinjal B; Galani Varsha; Patel Paresh B; Mehta Hiren R

    2011-01-01

    Thrombin plays a key role in thrombotic events, and therefore thrombin inhibition represents a therapeutic target for numerous thromboembolic diseases. Thrombin is responsible for the conversion of soluble fibrinogen to fibrin; clot stabilization through activation of factor XIII and the formation of cross-linkage among fibrin molecules; and the generation of additional thrombin through activation of factors V, VIII, and XI. Direct thrombin inhibitors are an innovative class of anticoagulant...

  11. The hunt for HIV-1 integrase inhibitors.

    Science.gov (United States)

    Lataillade, Max; Kozal, Michael J

    2006-07-01

    Currently, there are three distinct mechanistic classes of antiretrovirals: inhibitors of the HIV- 1 reverse transcriptase and protease enzymes and inhibitors of HIV entry, including receptor and coreceptor binding and cell fusion. A new drug class that inhibits the HIV-1 integrase enzyme (IN) is in development and may soon be available in the clinic. IN is an attractive drug target because it is essential for a stable and productive HIV-1 infection and there is no mammalian homologue of IN. Inhibitors of integrase enzyme (INI) block the integration of viral double-stranded DNA into the host cell's chromosomal DNA. HIV-1 integration has many potential steps that can be inhibited and several new compounds that target specific integration steps have been identified by drug developers. Recently, two INIs, GS-9137 and MK-0518, demonstrated promising early clinical trial results and have been advanced into later stage trials. In this review, we describe how IN facilitates HIV-1 integration, the needed enzyme cofactors, and the resultant byproducts created during integration. Furthermore, we review the different INIs under development, their mechanism of actions, site of IN inhibition, potency, resistance patterns, and discuss the early clinical trial results.

  12. Therapeutic Innovations: Tyrosine Kinase Inhibitors in Cancer

    Directory of Open Access Journals (Sweden)

    Nikolaos Dervisis

    2016-01-01

    Full Text Available Conventional cytotoxic chemotherapy involving DNA-interacting agents and indiscriminate cell death is no longer the future of cancer management. While chemotherapy is not likely to completely disappear from the armamentarium; the use of targeted therapies in combination with conventional treatment is becoming the standard of care in human medicine. Tyrosine kinases are pivotal points of functional cellular pathways and have been implicated in malignancy, inflammatory, and immune-mediated diseases. Pharmaceutical interventions targeting aberrant tyrosine kinase signaling has exploded and is the second most important area of drug development. The “Valley of Death” between drug discovery and approval threatens to blunt the enormous strides in cancer management seen thus far. Kinase inhibitors, as targeted small molecules, hold promise in the treatment and diagnosis of cancer. However, there are still many unanswered questions regarding the use of kinase inhibitors in the interpretation and management of cancer. Comparative oncology has the potential to address restrictions and limitations in the advancement in kinase inhibitor therapy.

  13. A porphodimethene chemical inhibitor of uroporphyrinogen decarboxylase.

    Directory of Open Access Journals (Sweden)

    Kenneth W Yip

    Full Text Available Uroporphyrinogen decarboxylase (UROD catalyzes the conversion of uroporphyrinogen to coproporphyrinogen during heme biosynthesis. This enzyme was recently identified as a potential anticancer target; its inhibition leads to an increase in reactive oxygen species, likely mediated by the Fenton reaction, thereby decreasing cancer cell viability and working in cooperation with radiation and/or cisplatin. Because there is no known chemical UROD inhibitor suitable for use in translational studies, we aimed to design, synthesize, and characterize such a compound. Initial in silico-based design and docking analyses identified a potential porphyrin analogue that was subsequently synthesized. This species, a porphodimethene (named PI-16, was found to inhibit UROD in an enzymatic assay (IC50 = 9.9 µM, but did not affect porphobilinogen deaminase (at 62.5 µM, thereby exhibiting specificity. In cellular assays, PI-16 reduced the viability of FaDu and ME-180 cancer cells with half maximal effective concentrations of 22.7 µM and 26.9 µM, respectively, and only minimally affected normal oral epithelial (NOE cells. PI-16 also combined effectively with radiation and cisplatin, with potent synergy being observed in the case of cisplatin in FaDu cells (Chou-Talalay combination index <1. This work presents the first known synthetic UROD inhibitor, and sets the foundation for the design, synthesis, and characterization of higher affinity and more effective UROD inhibitors.

  14. Functional Stability of Plasminogen Activator Inhibitor-1

    Directory of Open Access Journals (Sweden)

    Songul Yasar Yildiz

    2014-01-01

    Full Text Available Plasminogen activator inhibitor-1 (PAI-1 is the main inhibitor of plasminogen activators, such as tissue-type plasminogen activator (t-PA and urokinase-type plasminogen activator (u-PA, and a major regulator of the fibrinolytic system. PAI-1 plays a pivotal role in acute thrombotic events such as deep vein thrombosis (DVT and myocardial infarction (MI. The biological effects of PAI-1 extend far beyond thrombosis including its critical role in fibrotic disorders, atherosclerosis, renal and pulmonary fibrosis, type-2 diabetes, and cancer. The conversion of PAI-1 from the active to the latent conformation appears to be unique among serpins in that it occurs spontaneously at a relatively rapid rate. Latency transition is believed to represent a regulatory mechanism, reducing the risk of thrombosis from a prolonged antifibrinolytic action of PAI-1. Thus, relying solely on plasma concentrations of PAI-1 without assessing its function may be misleading in interpreting the role of PAI-1 in many complex diseases. Environmental conditions, interaction with other proteins, mutations, and glycosylation are the main factors that have a significant impact on the stability of the PAI-1 structure. This review provides an overview on the current knowledge on PAI-1 especially importance of PAI-1 level and stability and highlights the potential use of PAI-1 inhibitors for treating cardiovascular disease.

  15. Functional analysis of Hsp70 inhibitors.

    Directory of Open Access Journals (Sweden)

    Rainer Schlecht

    Full Text Available The molecular chaperones of the Hsp70 family have been recognized as targets for anti-cancer therapy. Since several paralogs of Hsp70 proteins exist in cytosol, endoplasmic reticulum and mitochondria, we investigated which isoform needs to be down-regulated for reducing viability of cancer cells. For two recently identified small molecule inhibitors, VER-155008 and 2-phenylethynesulfonamide (PES, which are proposed to target different sites in Hsp70s, we analyzed the molecular mode of action in vitro. We found that for significant reduction of viability of cancer cells simultaneous knockdown of heat-inducible Hsp70 (HSPA1 and constitutive Hsc70 (HSPA8 is necessary. The compound VER-155008, which binds to the nucleotide binding site of Hsp70, arrests the nucleotide binding domain (NBD in a half-open conformation and thereby acts as ATP-competitive inhibitor that prevents allosteric control between NBD and substrate binding domain (SBD. Compound PES interacts with the SBD of Hsp70 in an unspecific, detergent-like fashion, under the conditions tested. None of the two inhibitors investigated was isoform-specific.

  16. Knipholone, a selective inhibitor of leukotriene metabolism.

    Science.gov (United States)

    Wube, A A; Bucar, F; Asres, K; Gibbons, S; Adams, M; Streit, B; Bodensieck, A; Bauer, R

    2006-06-01

    Inhibition of leukotriene formation is one of the approaches to the treatment of asthma and other inflammatory diseases. We have investigated knipholone, isolated from the roots of Kniphofia foliosa, Hochst (Asphodelaceae), for inhibition of leukotriene biosynthesis in an ex vivo bioassay using activated human neutrophile granulocytes. Moreover, activities on 12-lipoxygenase from human platelets and cycloxygenase (COX)-1 and -2 from sheep cotyledons and seminal vesicles, respectively, have been evaluated. Knipholone was found to be a selective inhibitor of leukotriene metabolism in a human blood assay with an IC(50) value of 4.2microM. However, at a concentration of 10microg/ml, the compound showed weak inhibition of 12(S)-HETE production in human platelets and at a concentration of 50microM it produced no inhibition of COX-1 and -2. In our attempt to explain the mechanism of inhibition, we examined the antioxidant activity of knipholone using various in vitro assay systems including free radical scavenging, non-enzymatic lipid peroxidation, and metal chelation. Knipholone was found to be a weak dose-independent free radical scavenger and lipid peroxidation inhibitor, but not a metal chelator. Therefore, the leukotriene biosynthesis inhibitory effect of knipholone was evident by its ability either to inhibit the 5-lipoxygenase activating protein (FLAP) or as a competitive (non-redox) inhibitor of the enzyme. Cytotoxicity results also provided evidence that knipholone exhibits less toxicity for a mammalian host cell.

  17. Scale Inhibition of Green Inhibitor Polyepoxysuccinic Sodium

    Institute of Scientific and Technical Information of China (English)

    Feng Hui-xia; Wang Yi; Yu Shu-rong; Liang Bao-feng

    2004-01-01

    Polyepoxysuccinic acid (PESA) is the green water treatment agents recognized all over the world[1-3]. It is found that when PESA is used alone, it had good scale inhibition. PESA should be included in the category of green scale inhibitor.PESA is synthesized with maleicanhydride in the presence of catalysts. The effect on scale-in-hibiting property of the product from amount and feed times of catalyst, the reaction temperature, the reaction time were investigated. The optimum reaction conditions are as follows:n(maleic anhydride):n(Ca(OH)2):n(NaOH)=1:0.05-0.2:0.5, reaction temperature 95C, reaction time 4h.In all the references about PESA, PESA is researched as a kind of highly effective scale inhibitor or chelate. In this paper, the performance of scale inhibition of PESA is evaluated by scale static inhibitor.The results are shown in Figture1.It is evident from our experimental data (Figture1) that when inhibition for CaCO3.With the increase of PESA dosage, scale inhibition increases. When dosage is more than 6mg/L, inhibition efficiency is over 50%. The formulas give scale inhibition efficiency more than 95% at 12mg/L of total dosage.

  18. Cardiale neveneffecten van cholinesteraseremmers : een reden tot terughoudendheid in voorschrijven?

    NARCIS (Netherlands)

    Salarbaks, A M; Boomkamp-Snoeren, C M; van Puijenbroek, E; Jansen, P A F; van Marum, R J

    2009-01-01

    Cholinesterase inhibitors are prescribed in the treatment of mild to moderate Alzheimer's dementia. Little is known about the cardiac safety of these drugs. We present two different cases in which cardiac events occurred during the use of a cholinesterase inhibitor. The pathophysiology, the effects

  19. Recent advances in designing substrate-competitive protein kinase inhibitors.

    Science.gov (United States)

    Han, Ki-Cheol; Kim, So Yeon; Yang, Eun Gyeong

    2012-01-01

    Protein kinases play central roles in cellular signaling pathways and their abnormal phosphorylation activity is inseparably linked with various human diseases. Therefore, modulation of kinase activity using potent inhibitors is an attractive strategy for the treatment of human disease. While most protein kinase inhibitors in clinical development are mainly targeted to the highly conserved ATP-binding sites and thus likely promiscuously inhibit multiple kinases including kinases unrelated to diseases, protein substrate-competitive inhibitors are more selective and expected to be promising therapeutic agents. Most substrate-competitive inhibitors mimic peptides derived from substrate proteins, or from inhibitory domains within kinases or inhibitor proteins. In addition, bisubstrate inhibitors are generated by conjugating substrate-competitive peptide inhibitors to ATP-competitive inhibitors to improve affinity and selectivity. Although structural information on protein kinases provides invaluable guidance in designing substrate-competitive inhibitors, other strategies including bioinformatics, computational modeling, and high-throughput screening are often employed for developing specific substrate-competitive kinase inhibitors. This review focuses on recent advances in the design and discovery of substrate-competitive inhibitors of protein kinases.

  20. PP2A Inhibitor PME-1 Drives Kinase Inhibitor Resistance in Glioma Cells.

    Science.gov (United States)

    Kaur, Amanpreet; Denisova, Oxana V; Qiao, Xi; Jumppanen, Mikael; Peuhu, Emilia; Ahmed, Shafiq U; Raheem, Olayinka; Haapasalo, Hannu; Eriksson, John; Chalmers, Anthony J; Laakkonen, Pirjo; Westermarck, Jukka

    2016-12-01

    Glioblastoma multiforme lacks effective therapy options. Although deregulated kinase pathways are drivers of malignant progression in glioblastoma multiforme, glioma cells exhibit intrinsic resistance toward many kinase inhibitors, and the molecular basis of this resistance remains poorly understood. Here, we show that overexpression of the protein phosphatase 2A (PP2A) inhibitor protein PME-1 drives resistance of glioma cells to various multikinase inhibitors. The PME-1-elicited resistance was dependent on specific PP2A complexes and was mediated by a decrease in cytoplasmic HDAC4 activity. Importantly, both PME-1 and HDAC4 associated with human glioma progression, supporting clinical relevance of the identified mechanism. Synthetic lethality induced by both PME-1 and HDAC4 inhibition was dependent on the coexpression of proapoptotic protein BAD. Thus, PME-1-mediated PP2A inhibition is a novel mechanistic explanation for multikinase inhibitor resistance in glioma cells. Clinically, these results may inform patient stratification strategies for future clinical trials with selected kinase inhibitors in glioblastoma multiforme. Cancer Res; 76(23); 7001-11. ©2016 AACR.

  1. [Treatment of endometriosis by aromatase inhibitors: efficacy and side effects].

    Science.gov (United States)

    Racine, A-C; Legrand, E; Lefebvre-Lacoeuille, C; Hoppe, E; Catala, L; Sentilhes, L; Descamps, P

    2010-05-01

    The recent demonstration that aromatase is expressed at higher levels in endometriosis implants than in normal endometrium has led to pilot studies using inhibitor aromatasis in patients with endometriosis. We conducted a systematic review of the literature and studied the efficacy of aromatase inhibitors on endometriosis. There were seventeen studies (case reports/series) evaluating outcomes of aromatase inhibitors. Studies suggest that aromatase inhibitors alone or co-administered with progestins, oral contraceptives or gonadotrophin releasing hormone (GnRH) agonist could reduce pain and endometriosis. There is only one randomized controlled trial comparing aromatase inhibitor+GnRH agonist and GnRH agonist and one study with eighty patients. Side-effects profiles of aromatase inhibitor regimens are favorable; it does not appear a significant bone loss. Aromatase inhibitors seem to have a promising effect on endometriosis but randomized controlled trials are needed to prove their effects and their safety.

  2. Docking and scoring of metallo-beta-lactamases inhibitors

    DEFF Research Database (Denmark)

    Olsen, Lars; Pettersson, Ingrid; Hemmingsen, Lars

    2004-01-01

    The performance of the AutoDock, GOLD and FlexX docking programs was evaluated for docking of dicarboxylic acid inhibitors into metallo-beta-lactamases (MBLs). GOLD provided the best overall performance, with RMSDs between experimental and docked structures of 1.8-2.6 A and a good correlation...... between the experimentally determined MBL-inhibitor affinities and the GOLD scores. GOLD was selected for a test including a broad spectrum of inhibitors for which experimental MBL-inhibitor binding affinities are available. This study revealed that (1) for most compound classes (dicarboxylic acids...... and descriptors associated with binding of the IMP-1 inhibitors to the enzyme. The external Q2 for the test set is 0.73. This final model for prediction of IMP-1 MBL-inhibitor affinity handled all known classes of MBL-inhibitors, except small sulphur compounds....

  3. xtraction and Characterization of Cathepsin Inhibitor from Milkfish

    Directory of Open Access Journals (Sweden)

    Tati Nurhayati

    2015-06-01

    Full Text Available Abstract Proteolytic enzyme is distributed acros all organism including fish. Cysteine proteases are the largest group of proteolytic enzyme. Lysosomal cathepsin, one of cysteine protease enzyme, cause softening and degradation of myofibril protein and it’s activity is regulated by endogenous inhibitors. The purposes of this study were to optimize the extraction cathepsin inhibitors from the skin, muscles, and viscera of fish, to partially purify the cathepsin inhibitors of selected sources, and to study the characteristics of the cathepsin inhibitor. The cathepsin inhibitor could be extracted from muscle fish and partially purified using ammonium sulfate of 70%. The purified cathepsin inhibitor had optimum temperature at 40°C and the optimum at pH 8. Metal ions decreased the activity of the protease inhibitor, except 1 mM of metal ion Mn2+ and Na+.

  4. Evaluation of Encapsulated Inhibitor for Autonomous Corrosion Protection

    Science.gov (United States)

    Johnsey, M. N.; Li, W.; Buhrow, J. W.; Calle, L. M.; Pearman, B. P.; Zhang, X.

    2015-01-01

    This work concerns the development of smart coating technologies based on microencapsulation for the autonomous control of corrosion. Microencapsulation allows the incorporation of corrosion inhibitors into coating which provides protection through corrosion-controlled release of these inhibitors.One critical aspect of a corrosion protective smart coating is the selection of corrosion inhibitor for encapsulation and comparison of the inhibitor function before and after encapsulation. For this purpose, a systematic approach is being used to evaluate free and encapsulated corrosion inhibitors by salt immersion. Visual, optical microscope, and Scanning Electron Microscope (with low-angle backscatter electron detector) are used to evaluate these inhibitors. It has been found that the combination of different characterization tools provide an effective method for evaluation of early stage localized corrosion and the effectiveness of corrosion inhibitors.

  5. Characterization of the Annonaceous acetogenin, annonacinone, a natural product inhibitor of plasminogen activator inhibitor-1

    Science.gov (United States)

    Pautus, Stéphane; Alami, Mouad; Adam, Fréderic; Bernadat, Guillaume; Lawrence, Daniel A.; de Carvalho, Allan; Ferry, Gilles; Rupin, Alain; Hamze, Abdallah; Champy, Pierre; Bonneau, Natacha; Gloanec, Philippe; Peglion, Jean-Louis; Brion, Jean-Daniel; Bianchini, Elsa P.; Borgel, Delphine

    2016-11-01

    Plasminogen activator inhibitor-1 (PAI-1) is the main inhibitor of the tissue type and urokinase type plasminogen activators. High levels of PAI-1 are correlated with an increased risk of thrombotic events and several other pathologies. Despite several compounds with in vitro activity being developed, none of them are currently in clinical use. In this study, we evaluated a novel PAI-1 inhibitor, annonacinone, a natural product from the Annonaceous acetogenins group. Annonacinone was identified in a chromogenic screening assay and was more potent than tiplaxtinin. Annonacinone showed high potency ex vivo on thromboelastography and was able to potentiate the thrombolytic effect of tPA in vivo in a murine model. SDS-PAGE showed that annonacinone inhibited formation of PAI-1/tPA complex via enhancement of the substrate pathway. Mutagenesis and molecular dynamics allowed us to identify annonacinone binding site close to helix D and E and β-sheets 2A.

  6. The "SWOT" of BRAF inhibition in melanoma: RAF inhibitors, MEK inhibitors or both?

    Science.gov (United States)

    Nissan, Moriah H; Solit, David B

    2011-12-01

    Activating mutations in the BRAF gene are among the most prevalent kinase mutations in human cancer. BRAF mutations are most frequent in patients with melanoma where they occur in approximately 50% of patients with advanced disease. Remarkable clinical activity has recently been reported with highly selective RAF inhibitors in melanoma patients whose tumors harbor V600E BRAF mutations. The response rates of RAF inhibitors in patients with BRAF-mutant melanomas far exceed the activity level of any prior therapy studied in this disease. The results suggest that we have entered an era of personalized therapy for patients with metastatic melanoma in which treatment selection will be guided by BRAF mutational status. This review will discuss the strengths, weaknesses, opportunities and threats ("SWOT") of developing RAF and MEK selective inhibitors as anti-cancer therapies, recent insights into the mechanisms of intrinsic and acquired resistance to these agents, and current efforts to develop mechanism-based combination therapies.

  7. Structural analysis of Golgi alpha-mannosidase II inhibitors identified from a focused glycosidase inhibitor screen.

    Science.gov (United States)

    Kuntz, Douglas A; Tarling, Chris A; Withers, Stephen G; Rose, David R

    2008-09-23

    The N-glycosylation pathway is a target for pharmaceutical intervention in a number of pathological conditions including cancer. Golgi alpha-mannosidase II (GMII) is the final glycoside hydrolase in the pathway and has been the target for a number of synthetic efforts aimed at providing more selective and effective inhibitors. Drosophila GMII (dGMII) has been extensively studied due to the ease of obtaining high resolution structural data, allowing the observation of substrate distortion upon binding and after formation of a trapped covalent reaction intermediate. However, attempts to find new inhibitor leads by high-throughput screening of large commercial libraries or through in silico docking were unsuccessful. In this paper we provide a kinetic and structural analysis of five inhibitors derived from a small glycosidase-focused library. Surprisingly, four of these were known inhibitors of beta-glucosidases. X-ray crystallographic analysis of the dGMII:inhibitor complexes highlights the ability of the zinc-containing GMII active site to deform compounds, even ones designed as conformationally restricted transition-state mimics of beta-glucosidases, into binding entities that have inhibitory activity. Although these deformed conformations do not appear to be on the expected conformational itinerary of the enzyme, and are thus not transition-state mimics of GMII, they allow positioning of the three vicinal hydroxyls of the bound gluco-inhibitors into similar locations to those found with mannose-containing substrates, underlining the importance of these hydrogen bonds for binding. Further, these studies show the utility of targeting the acid-base catalyst using appropriately positioned positively charged nitrogen atoms, as well as the challenges associated with aglycon substitutions.

  8. Drug-drug interactions between HMG-CoA reductase inhibitors (statins) and antiviral protease inhibitors.

    Science.gov (United States)

    Chauvin, Benoit; Drouot, Sylvain; Barrail-Tran, Aurélie; Taburet, Anne-Marie

    2013-10-01

    The HMG-CoA reductase inhibitors are a class of drugs also known as statins. These drugs are effective and widely prescribed for the treatment of hypercholesterolemia and prevention of cardiovascular morbidity and mortality. Seven statins are currently available: atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. Although these drugs are generally well tolerated, skeletal muscle abnormalities from myalgia to severe lethal rhabdomyolysis can occur. Factors that increase statin concentrations such as drug-drug interactions can increase the risk of these adverse events. Drug-drug interactions are dependent on statins' pharmacokinetic profile: simvastatin, lovastatin and atorvastatin are metabolized through cytochrome P450 (CYP) 3A, while the metabolism of the other statins is independent of this CYP. All statins are substrate of organic anion transporter polypeptide 1B1, an uptake transporter expressed in hepatocyte membrane that may also explain some drug-drug interactions. Many HIV-infected patients have dyslipidemia and comorbidities that may require statin treatment. HIV-protease inhibitors (HIV PIs) are part of recommended antiretroviral treatment in combination with two reverse transcriptase inhibitors. All HIV PIs except nelfinavir are coadministered with a low dose of ritonavir, a potent CYP3A inhibitor to improve their pharmacokinetic properties. Cobicistat is a new potent CYP3A inhibitor that is combined with elvitegravir and will be combined with HIV-PIs in the future. The HCV-PIs boceprevir and telaprevir are both, to different extents, inhibitors of CYP3A. This review summarizes the pharmacokinetic properties of statins and PIs with emphasis on their metabolic pathways explaining clinically important drug-drug interactions. Simvastatin and lovastatin metabolized through CYP3A have the highest potency for drug-drug interaction with potent CYP3A inhibitors such as ritonavir- or cobicistat-boosted HIV-PI or the

  9. Ability of the Met kinase inhibitor crizotinib and new generation EGFR inhibitors to overcome resistance to EGFR inhibitors.

    Directory of Open Access Journals (Sweden)

    Shigeki Nanjo

    Full Text Available PURPOSE: Although EGF receptor tyrosine kinase inhibitors (EGFR-TKI have shown dramatic effects against EGFR mutant lung cancer, patients ultimately develop resistance by multiple mechanisms. We therefore assessed the ability of combined treatment with the Met inhibitor crizotinib and new generation EGFR-TKIs to overcome resistance to first-generation EGFR-TKIs. EXPERIMENTAL DESIGN: Lung cancer cell lines made resistant to EGFR-TKIs by the gatekeeper EGFR-T790M mutation, Met amplification, and HGF overexpression and mice with tumors induced by these cells were treated with crizotinib and a new generation EGFR-TKI. RESULTS: The new generation EGFR-TKI inhibited the growth of lung cancer cells containing the gatekeeper EGFR-T790M mutation, but did not inhibit the growth of cells with Met amplification or HGF overexpression. In contrast, combined therapy with crizotinib plus afatinib or WZ4002 was effective against all three types of cells, inhibiting EGFR and Met phosphorylation and their downstream molecules. Crizotinib combined with afatinib or WZ4002 potently inhibited the growth of mouse tumors induced by these lung cancer cell lines. However, the combination of high dose crizotinib and afatinib, but not WZ4002, triggered severe adverse events. CONCLUSIONS: Our results suggest that the dual blockade of mutant EGFR and Met by crizotinib and a new generation EGFR-TKI may be promising for overcoming resistance to reversible EGFR-TKIs but careful assessment is warranted clinically.

  10. Kynurenine Aminotransferase Isozyme Inhibitors: A Review

    Directory of Open Access Journals (Sweden)

    Alireza Nematollahi

    2016-06-01

    Full Text Available Kynurenine aminotransferase isozymes (KATs 1–4 are members of the pyridoxal-5’-phosphate (PLP-dependent enzyme family, which catalyse the permanent conversion of l-kynurenine (l-KYN to kynurenic acid (KYNA, a known neuroactive agent. As KATs are found in the mammalian brain and have key roles in the kynurenine pathway, involved in different categories of central nervous system (CNS diseases, the KATs are prominent targets in the quest to treat neurodegenerative and cognitive impairment disorders. Recent studies suggest that inhibiting these enzymes would produce effects beneficial to patients with these conditions, as abnormally high levels of KYNA are observed. KAT-1 and KAT-3 share the highest sequence similarity of the isozymes in this family, and their active site pockets are also similar. Importantly, KAT-2 has the major role of kynurenic acid production (70% in the human brain, and it is considered therefore that suitable inhibition of this isozyme would be most effective in managing major aspects of CNS diseases. Human KAT-2 inhibitors have been developed, but the most potent of them, chosen for further investigations, did not proceed in clinical studies due to the cross toxicity caused by their irreversible interaction with PLP, the required cofactor of the KAT isozymes, and any other PLP-dependent enzymes. As a consequence of the possibility of extensive undesirable adverse effects, it is also important to pursue KAT inhibitors that reversibly inhibit KATs and to include a strategy that seeks compounds likely to achieve substantial interaction with regions of the active site other than the PLP. The main purpose of this treatise is to review the recent developments with the inhibitors of KAT isozymes. This treatise also includes analyses of their crystallographic structures in complex with this enzyme family, which provides further insight for researchers in this and related studies.

  11. Sifuvirtide, a potent HIV fusion inhibitor peptide

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Rui-Rui; Yang, Liu-Meng; Wang, Yun-Hua [Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223 (China); Pang, Wei [Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223 (China); Department of Molecular Virology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100080 (China); Tam, Siu-Cheung [Department of Physiology, Chinese University of Hong Kong, Shatin, N.T., Hong Kong (China); Tien, Po [Department of Molecular Virology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100080 (China); Zheng, Yong-Tang, E-mail: zhengyt@mail.kiz.ac.cn [Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223 (China)

    2009-05-08

    Enfuvirtide (ENF) is currently the only FDA approved HIV fusion inhibitor in clinical use. Searching for more drugs in this category with higher efficacy and lower toxicity seems to be a logical next step. In line with this objective, a synthetic peptide with 36 amino acid residues, called Sifuvirtide (SFT), was designed based on the crystal structure of gp41. In this study, we show that SFT is a potent anti-HIV agent with relatively low cytotoxicity. SFT was found to inhibit replication of all tested HIV strains. The effective concentrations that inhibited 50% viral replication (EC{sub 50}), as determined in all tested strains, were either comparable or lower than benchmark values derived from well-known anti-HIV drugs like ENF or AZT, while the cytotoxic concentrations causing 50% cell death (CC{sub 50}) were relatively high, rendering it an ideal anti-HIV agent. A GST-pull down assay was performed to confirm that SFT is a fusion inhibitor. Furthermore, the activity of SFT on other targets in the HIV life cycle was also investigated, and all assays showed negative results. To further understand the mechanism of action of HIV peptide inhibitors, resistant variants of HIV-1{sub IIIB} were derived by serial virus passage in the presence of increasing doses of SFT or ENF. The results showed that there was cross-resistance between SFT and ENF. In conclusion, SFT is an ideal anti-HIV agent with high potency and low cytotoxicity, but may exhibit a certain extent of cross-resistance with ENF.

  12. Nanomolar Inhibitors of Trypanosoma brucei RNA Triphosphatase

    Directory of Open Access Journals (Sweden)

    Paul Smith

    2016-02-01

    Full Text Available Eukaryal taxa differ with respect to the structure and mechanism of the RNA triphosphatase (RTPase component of the mRNA capping apparatus. Protozoa, fungi, and certain DNA viruses have a metal-dependent RTPase that belongs to the triphosphate tunnel metalloenzyme (TTM superfamily. Because the structures, active sites, and chemical mechanisms of the TTM-type RTPases differ from those of mammalian RTPases, the TTM RTPases are potential targets for antiprotozoal, antifungal, and antiviral drug discovery. Here, we employed RNA interference (RNAi knockdown methods to show that Trypanosoma brucei RTPase Cet1 (TbCet1 is necessary for proliferation of procyclic cells in culture. We then conducted a high-throughput biochemical screen for small-molecule inhibitors of the phosphohydrolase activity of TbCet1. We identified several classes of chemicals—including chlorogenic acids, phenolic glycopyranosides, flavonoids, and other phenolics—that inhibit TbCet1 with nanomolar to low-micromolar 50% inhibitory concentrations (IC50s. We confirmed the activity of these compounds, and tested various analogs thereof, by direct manual assays of TbCet1 phosphohydrolase activity. The most potent nanomolar inhibitors included tetracaffeoylquinic acid, 5-galloylgalloylquinic acid, pentagalloylglucose, rosmarinic acid, and miquelianin. TbCet1 inhibitors were less active (or inactive against the orthologous TTM-type RTPases of mimivirus, baculovirus, and budding yeast (Saccharomyces cerevisiae. Our results affirm that a TTM RTPase is subject to potent inhibition by small molecules, with the caveat that parallel screens against TTM RTPases from multiple different pathogens may be required to fully probe the chemical space of TTM inhibition.

  13. A new urease inhibitor from Viola betonicifolia.

    Science.gov (United States)

    Muhammad, Naveed; Saeed, Muhammad; Khan, Ajmal; Adhikari, Achyut; Wadood, Abdul; Khan, Khalid Mohammed; De Feo, Vincenzo

    2014-10-17

    Urease has attracted much attention, as it is directly involved in the formation of infection stones and contributes to the pathogenesis of urolithiasis, pyelonephritis, ammonia and hepatic encephalopathy, hepatic coma and urinary catheter encrustation. Moreover, urease is the major cause of pathologies induced by H. pylori, such as gastritis and peptic ulcer. In the present work, the new natural compound, 3-methoxydalbergione, was isolated from Viola betonicifolia. A mechanistic study of this compound as a natural urease inhibitor was performed by using enzyme kinetics and docking studies. 3-Methoxydalbergione could be considered as a lead molecule for drugs useful in the urease associated diseases.

  14. Modified 5-fluorouracil: Uridine phosphorylase inhibitor

    Science.gov (United States)

    Lashkov, A. A.; Shchekotikhin, A. A.; Shtil, A. A.; Sotnichenko, S. E.; Mikhailov, A. M.

    2016-09-01

    5-Fluorouracil (5-FU) is a medication widely used in chemotherapy to treat various types of cancer. Being a substrate for the reverse reaction catalyzed by uridine phosphorylase (UPase), 5-FU serves as a promising prototype molecule (molecular scaffold) for the design of a selective UPase inhibitor that enhances the antitumor activity of 5-FU and exhibits intrinsic cytostatic effects on cancer cells. The chemical formula of the new compound, which binds to the uracil-binding site and, in the presence of a phosphate anion, to the phosphate-binding site of UPase, is proposed and investigated by molecular simulation methods.

  15. Proton Pump Inhibitors in Cardiovascular Disease

    DEFF Research Database (Denmark)

    Würtz, Morten; Grove, Erik L

    2016-01-01

    prescribed.PPIs provide gastroprotection by changing the intragastric milieu, essentially by raising intragastric pH. In recent years, it has been heavily discussed whether PPIs may reduce the cardiovascular protection by aspirin and, even more so, clopidogrel. Pharmacodynamic and pharmacokinetic studies......-treatment.Given the large number of patients treated with antithrombotic drugs and PPIs, even a minor reduction of platelet inhibition potentially carries considerable clinical impact. The present book chapter summarizes the evidence regarding the widespread use of platelet inhibitors and PPIs in combination. Moreover...

  16. Patient compliance with MAO inhibitor therapy.

    Science.gov (United States)

    Walker, J I; Davidson, J; Zung, W W

    1984-07-01

    Exaggerated fears of monoamine oxidase inhibitors (MAOIs) and of their interactions with foods often restrict their use. A review of the literature reveals seven food items most likely to produce a hypertensive crisis in combination with MAOI administration: aged cheeses, smoked or pickled fish, beef or chicken liver, dry fermented sausage, pods of broad beans, brewer's yeast products, and certain alcoholic beverages. Improved understanding of the dietary restrictions, benefits, and mechanism of action of the MAOIs can enhance cooperation with the prescribed treatment program.

  17. Improving cancer immunotherapy with DNA methyltransferase inhibitors.

    Science.gov (United States)

    Saleh, Mohammad H; Wang, Lei; Goldberg, Michael S

    2016-07-01

    Immunotherapy confers durable clinical benefit to melanoma, lung, and kidney cancer patients. Challengingly, most other solid tumors, including ovarian carcinoma, are not particularly responsive to immunotherapy, so combination with a complementary therapy may be beneficial. Recent findings suggest that epigenetic modifying drugs can prime antitumor immunity by increasing expression of tumor-associated antigens, chemokines, and activating ligands by cancer cells as well as cytokines by immune cells. This review, drawing from both preclinical and clinical data, describes some of the mechanisms of action that enable DNA methyltransferase inhibitors to facilitate the establishment of antitumor immunity.

  18. A New Urease Inhibitor from Viola betonicifolia

    Directory of Open Access Journals (Sweden)

    Naveed Muhammad

    2014-10-01

    Full Text Available Urease has attracted much attention, as it is directly involved in the formation of infection stones and contributes to the pathogenesis of urolithiasis, pyelonephritis, ammonia and hepatic encephalopathy, hepatic coma and urinary catheter encrustation. Moreover, urease is the major cause of pathologies induced by H. pylori, such as gastritis and peptic ulcer. In the present work, the new natural compound, 3-methoxydalbergione, was isolated from Viola betonicifolia. A mechanistic study of this compound as a natural urease inhibitor was performed by using enzyme kinetics and docking studies. 3-Methoxydalbergione could be considered as a lead molecule for drugs useful in the urease associated diseases.

  19. Protease Inhibitors Targeting Coronavirus and Filovirus Entry

    Science.gov (United States)

    Zhou, Yanchen; Vedantham, Punitha; Lu, Kai; Agudelo, Juliet; Carrion, Ricardo; Nunneley, Jerritt W.; Barnard, Dale; Pöhlmann, Stefan; McKerrow, James H.; Renslo, Adam R.; Simmons, Graham

    2016-01-01

    In order to gain entry into cells, diverse viruses, including Ebola virus, SARS-coronavirus and the emerging MERS-coronavirus, depend on activation of their envelope glycoproteins by host cell proteases. The respective enzymes are thus excellent targets for antiviral intervention. In cell culture, activation of Ebola virus, as well as SARS- and MERS-coronavirus can be accomplished by the endosomal cysteine proteases, cathepsin L (CTSL) and cathepsin B (CTSB). In addition, SARS- and MERS-coronavirus can use serine proteases localized at the cell surface, for their activation. However, it is currently unclear which protease(s) facilitate viral spread in the infected host. We report here that the cysteine protease inhibitor K11777, ((2S)-N-[(1E,3S)-1-(benzenesulfonyl)-5-phenylpent-1-en-3-yl]-2-{[(E)-4-methylpiperazine-1-carbonyl]amino}-3-phenylpropanamide) and closely-related vinylsulfones act as broad-spectrum antivirals by targeting cathepsin-mediated cell entry. K11777 is already in advanced stages of development for a number of parasitic diseases, such as Chagas disease, and has proven to be safe and effective in a range of animal models. K11777 inhibition of SARS-CoV and Ebola virus entry was observed in the sub-nanomolar range. In order to assess, whether cysteine or serine proteases promote viral spread in the host, we compared the antiviral activity of an optimized K11777-derivative with that of camostat, an inhibitor of TMPRSS2 and related serine proteases. Employing a pathogenic animal model of SARS-CoV infection, we demonstrated that viral spread and pathogenesis of SARS-CoV is driven by serine rather than cysteine proteases and can be effectively prevented by camostat. Camostat has been clinically used to treat chronic pancreatitis, and thus represents an exciting potential therapeutic for respiratory coronavirus infections. Our results indicate that camostat, or similar serine protease inhibitors, might be an effective option for treatment of SARS and

  20. Development of effective combined kinetic hydrate inhibitor/corrosion inhibitor (KHI/CI) products

    Energy Technology Data Exchange (ETDEWEB)

    Clark, Len. W.; Anderson, Joh.

    2006-03-15

    Low Dosage Hydrate Inhibitors (LDHIs) are gaining worldwide acceptance as a viable alternative to the more conventional methods of hydrate flow assurance control. Use of this LDHI technology in combination with Corrosion Inhibitors (CI) in production systems such as sub sea developments enables operating companies to further significantly reduce capital costs. CI can have a significant impact of the efficacy of Kinetic Hydrate Inhibitors (KHI). This paper will review the experience of developing combined KHI and CI products (KHI/CI) with the aim of producing effective products whilst also incorporating the goal of the use of more environmentally friendly CI. Relevant KHI/CI product case histories will be considered. The development of KHI to be used in the presence of CI will also be considered in different production scenarios. This relates to the typical situation of continuous CI usage with the seasonal application of KHI. Experience is also shown of how the incorporation of Thermodynamic Hydrate Inhibitors (THI) to KHI/CI products, in order to enable the combined product to control hydrates in higher subcooling systems, can also have a role to play in the influence that the CI has on the efficiency of the KHI. (author) (tk)

  1. Internet Selling Expansion Inhibitors: A Mixed Method Approach

    Directory of Open Access Journals (Sweden)

    Shahriar Azizi

    2013-01-01

    Full Text Available This research based on providing five questions has tried to identify and prioritize the main and sub inhibitors of internet selling boosting in Iran. A mixed method research (QUAN has been used in this research. In the qualitative phase, individual in-depth interviews have been done with seven e-shop managers. In this phase, 45 detailed inhibitors have been detected. These 45 inhibitors have been categorized in nine sub categories and four main categories. In the quantitative phase a 51-items questionnaires has been designed including six demographical and 45 specialized questions. Findings of the quantitative phase reveal that the main obstacles include legal, cultural, infrastructural and managerial inhibitors. In addition, sub category inhibitors include legal, governmental, telecommunication, society, human resource, transportation, financial and customer related.     Keywords: e-selling, Iran, Inhibitors, Mixed method.

  2. The Place of protease inhibitors in antiretroviral treatment

    Directory of Open Access Journals (Sweden)

    S.B. Tenore

    2009-10-01

    Full Text Available With the introduction of highly active antiretroviral therapy, a number of drugs have been developed. The best choice concerning which antiretroviral analogs to start is always under discussion, especially in the choice between non-nucleoside reverse transcriptase inhibitors-based therapies and ritonavir-boosted protease inhibitors. Both are proven to control viral replication and lead to immunological gain. The choice between a non-nucleoside analog reverse transcriptase inhibitor and a protease inhibitor as a third antiretroviral drug in the therapy should consider factors related to the individual, as well as the inclusion of the best therapy in the patient's daily activities and potential adherence. The protease inhibitor-based therapies showed similar efficacy among the various inhibitors with characteristics concerning the adverse events from each medicine. For the treatment of protease-resistant patients, darunavir and tipranavir showed good efficacy with higher genetic barrier to resistance.

  3. Towards a green hydrate inhibitor: imaging antifreeze proteins on clathrates.

    Directory of Open Access Journals (Sweden)

    Raimond Gordienko

    Full Text Available The formation of hydrate plugs in oil and gas pipelines is a serious industrial problem and recently there has been an increased interest in the use of alternative hydrate inhibitors as substitutes for thermodynamic inhibitors like methanol. We show here that antifreeze proteins (AFPs possess the ability to modify structure II (sII tetrahydrofuran (THF hydrate crystal morphologies by adhering to the hydrate surface and inhibiting growth in a similar fashion to the kinetic inhibitor poly-N-vinylpyrrolidone (PVP. The effects of AFPs on the formation and growth rate of high-pressure sII gas mix hydrate demonstrated that AFPs are superior hydrate inhibitors compared to PVP. These results indicate that AFPs may be suitable for the study of new inhibitor systems and represent an important step towards the development of biologically-based hydrate inhibitors.

  4. HTCC: Broad Range Inhibitor of Coronavirus Entry.

    Directory of Open Access Journals (Sweden)

    Aleksandra Milewska

    Full Text Available To date, six human coronaviruses have been known, all of which are associated with respiratory infections in humans. With the exception of the highly pathogenic SARS and MERS coronaviruses, human coronaviruses (HCoV-NL63, HCoV-OC43, HCoV-229E, and HCoV-HKU1 circulate worldwide and typically cause the common cold. In most cases, infection with these viruses does not lead to severe disease, although acute infections in infants, the elderly, and immunocompromised patients may progress to severe disease requiring hospitalization. Importantly, no drugs against human coronaviruses exist, and only supportive therapy is available. Previously, we proposed the cationically modified chitosan, N-(2-hydroxypropyl-3-trimethylammonium chitosan chloride (HTCC, and its hydrophobically-modified derivative (HM-HTCC as potent inhibitors of the coronavirus HCoV-NL63. Here, we show that HTCC inhibits interaction of a virus with its receptor and thus blocks the entry. Further, we demonstrate that HTCC polymers with different degrees of substitution act as effective inhibitors of all low-pathogenic human coronaviruses.

  5. Polyphenol Compound as a Transcription Factor Inhibitor

    Directory of Open Access Journals (Sweden)

    Seyeon Park

    2015-10-01

    Full Text Available A target-based approach has been used to develop novel drugs in many therapeutic fields. In the final stage of intracellular signaling, transcription factor–DNA interactions are central to most biological processes and therefore represent a large and important class of targets for human therapeutics. Thus, we focused on the idea that the disruption of protein dimers and cognate DNA complexes could impair the transcriptional activation and cell transformation regulated by these proteins. Historically, natural products have been regarded as providing the primary leading compounds capable of modulating protein–protein or protein-DNA interactions. Although their mechanism of action is not fully defined, polyphenols including flavonoids were found to act mostly as site-directed small molecule inhibitors on signaling. There are many reports in the literature of screening initiatives suggesting improved drugs that can modulate the transcription factor interactions responsible for disease. In this review, we focus on polyphenol compound inhibitors against dimeric forms of transcription factor components of intracellular signaling pathways (for instance, c-jun/c-fos (Activator Protein-1; AP-1, c-myc/max, Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB and β-catenin/T cell factor (Tcf.

  6. Inhibitors and pathways of hepatocytic protein degradation.

    Science.gov (United States)

    Seglen, P O; Gordon, P B; Grinde, B; Solheim, A; Kovács, A L; Poli, A

    1981-01-01

    On the basis of experiments using amino acids and various inhibitors (lysosomotropic amines, leupeptin, chymostatin, vanadate, vinblastine, anoxia, methylaminopurines), five different modes of endogenous protein degradation in isolated rat hepatocytes can be distinguished. The two non-lysosomal (amine-resistant) mechanisms preferentially degrade relatively labile (short-lived) proteins: one of these mechanisms is energy-dependent and chymostatin-sensitive, the other is not. Of the three lysosomal (amine-sensitive) mechanisms, one--quantitatively minor--is amino acid-resistant and preferentially degrades labile proteins. The two amino acid-sensitive mechanisms each seen account for about one-half of the degradation of relatively stable (long-lived) proteins; one of them is suppressed by leucine and apparently corresponds to the formation of electron microscopically visible autophagosomes; the other may represent a different type of autophagy, inhibited by asparagine and glutamine. A new class of inhibitors, the purine derivatives (methylated 6-aminopurines, and 6-mercaptopurines) appear to specifically suppress autophagic/lysosomal protein degradation, and may help to further elucidate the mechanisms of autophagy.

  7. Synthesis of Novel Chalcones as Acetylcholinesterase Inhibitors

    Directory of Open Access Journals (Sweden)

    Thanh-Dao Tran

    2016-07-01

    Full Text Available A new series of benzylaminochalcone derivatives with different substituents on ring B were synthesized and evaluated as inhibitors of acetylcholinesterase. The study is aimed at identification of novel benzylaminochalcones capable of blocking acetylcholinesterase activity for further development of an approach to Alzheimer’s disease treatment. These compounds were produced in moderate to good yields via Claisen-Schmidt condensation and subjected to an in vitro acetylcholinesterase inhibition assay, using Ellman’s method. The in silico docking procedure was also employed to identify molecular interactions between the chalcone compounds and the enzyme. Compounds with ring B bearing pyridin-4-yl, 4-nitrophenyl, 4-chlorophenyl and 3,4-dimethoxyphenyl moieties were discovered to exhibit significant inhibitory activities against acetylcholinesterase, with IC50 values ranging from 23 to 39 µM. The molecular modeling studies are consistent with the hypothesis that benzylaminochalcones could exert their effects as dual-binding-site acetylcholinesterase inhibitors, which might simultaneously enhance cholinergic neurotransmission and inhibit β-amyloid aggregation through binding to both catalytic and peripheral sites of the enzyme. These derivatives could be further developed to provide novel leads for the discovery of new anti-Alzheimer drugs in the future.

  8. DABIGATRAN ETEXILATE: NEW DIRECT THROMBIN INHIBITORS ANTICOAGULANTS

    Directory of Open Access Journals (Sweden)

    Patel Kinjal B

    2011-04-01

    Full Text Available Thrombin plays a key role in thrombotic events, and therefore thrombin inhibition represents a therapeutic target for numerous thromboembolic diseases. Thrombin is responsible for the conversion of soluble fibrinogen to fibrin; clot stabilization through activation of factor XIII and the formation of cross-linkage among fibrin molecules; and the generation of additional thrombin through activation of factors V, VIII, and XI. Direct thrombin inhibitors are an innovative class of anticoagulants that bind directly to thrombin to inhibit its actions and impede the clotting process. Dabigatran is the first direct thrombin inhibitor, orally available first approval by US Food and Drugs Administration in 2010. Specifically and reversibly inhibits thrombin, so the duration of action is predictable. The anticoagulant effect correlates well with plasma drug concentrations, which implies an effective anticoagulation with low bleeding risk without major problems of interactions with other drugs. The predictable pharmacokinetics and pharmacodynamics characteristics of dabigatran may facilitate dental management of patients who until now have been in treatment with traditional anticoagulants, given that it doesn’t require routine laboratory monitoring in the vast majority of patients treated. They also present a profile of drug interactions very favorable.

  9. Peptidomimetics and metalloprotease inhibitors as anticancer drugs

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Peptidomimetics with three types, as the structural or functional mimetics of natural active peptides, can preserve the bioactivity and improve the bioavailability and the specificity towards the targets of the lead peptides. Peptidomimetics of high bioactivity can be designed through various ways including conformation restriction, modification and non-peptide design. Recently the concentration on the de-velopment of cancer chemotherapeutic drugs was transferred from cytotoxic drugs to target-based drugs, and many proteases and peptidases that play key roles in the process of tumor genesis and development was discovered, which means that peptidomimetics as potential cancer chemotherapeu-tic drugs should be paid close attention to. Our laboratory has focused on the development of small-molecule peptidomimetic inhibitors of APN, MMPs and HDACs as target-based anticancer agents. These three zinc-dependent metalloproteinases play very important roles in the process of tumor genesis, invasion, metastasis, angiogenesis and matrix degradation, so small-molecule peptidomimetic inhibitors based on them would be quite potential in the development of chemotherapeutic drugs with high selectivity.

  10. Replication and Inhibitors of Enteroviruses and Parechoviruses

    Directory of Open Access Journals (Sweden)

    Lonneke van der Linden

    2015-08-01

    Full Text Available The Enterovirus (EV and Parechovirus genera of the picornavirus family include many important human pathogens, including poliovirus, rhinovirus, EV-A71, EV-D68, and human parechoviruses (HPeV. They cause a wide variety of diseases, ranging from a simple common cold to life-threatening diseases such as encephalitis and myocarditis. At the moment, no antiviral therapy is available against these viruses and it is not feasible to develop vaccines against all EVs and HPeVs due to the great number of serotypes. Therefore, a lot of effort is being invested in the development of antiviral drugs. Both viral proteins and host proteins essential for virus replication can be used as targets for virus inhibitors. As such, a good understanding of the complex process of virus replication is pivotal in the design of antiviral strategies goes hand in hand with a good understanding of the complex process of virus replication. In this review, we will give an overview of the current state of knowledge of EV and HPeV replication and how this can be inhibited by small-molecule inhibitors.

  11. Lonafarnib is a potential inhibitor for neovascularization.

    Directory of Open Access Journals (Sweden)

    Linlin Sun

    Full Text Available Atherosclerosis is a common cardiovascular disease that involves the build-up of plaque on the inner walls of the arteries. Intraplaque neovacularization has been shown to be essential in the pathogenesis of atherosclerosis. Previous studies showed that small-molecule compounds targeting farnesyl transferase have the ability to prevent atherosclerosis in apolipoprotein E-deficient mice, but the underlying mechanism remains to be elucidated. In this study, we found that lonafarnib, a specific inhibitor of farnesyl transferase, elicits inhibitory effect on vascular endothelial capillary assembly in vitro in a dose-dependent manner. In addition, we showed that lonafarnib treatment led to a dose-dependent decrease in scratch wound closure in vitro, whereas it had little effect on endothelial cell proliferation. These data indicate that lonafarnib inhibits neovascularization via directly targeting endothelial cells and disturbing their motility. Moreover, we demonstrated that pharmacological inhibition of farnesyl transferase by lonafarnib significantly impaired centrosome reorientation toward the leading edge of endothelial cells. Mechanistically, we found that the catalytic β subunit of farnesyl transferase associated with a cytoskeletal protein important for the establishment and maintenance of cell polarity. Additionally, we showed that lonafarnib remarkably inhibited the expression of the cytoskeletal protein and interrupted its interaction with farnesyl transferase. Our findings thus offer novel mechanistic insight into the protective effect of farnesyl transferase inhibitors on atherosclerosis and provide encouraging evidence for the potential use of this group of agents in inhibiting plaque neovascularization.

  12. Corrosion inhibitor for aqueous ammonia absorption system

    Science.gov (United States)

    Phillips, Benjamin A.; Whitlow, Eugene P.

    1998-09-22

    A method of inhibiting corrosion and the formation of hydrogen and thus improving absorption in an ammonia/water absorption refrigeration, air conditioning or heat pump system by maintaining the hydroxyl ion concentration of the aqueous ammonia working fluid within a selected range under anaerobic conditions at temperatures up to 425.degree. F. This hydroxyl ion concentration is maintained by introducing to the aqueous ammonia working fluid an inhibitor in an amount effective to produce a hydroxyl ion concentration corresponding to a normality of the inhibitor relative to the water content ranging from about 0.015 N to about 0.2 N at 25.degree. C. Also, working fluids for inhibiting the corrosion of carbon steel and resulting hydrogen formation and improving absorption in an ammonia/water absorption system under anaerobic conditions at up to 425.degree. F. The working fluids may be aqueous solutions of ammonia and a strong base or aqueous solutions of ammonia, a strong base, and a specified buffer.

  13. Aromatase inhibitors in men: effects and therapeutic options

    Directory of Open Access Journals (Sweden)

    de Jong Frank H

    2011-06-01

    Full Text Available Abstract Aromatase inhibitors effectively delay epiphysial maturation in boys and improve testosterone levels in adult men Therefore, aromatase inhibitors may be used to increase adult height in boys with gonadotropin-independent precocious puberty, idiopathic short stature and constitutional delay of puberty. Long-term efficacy and safety of the use of aromatase inhibitors has not yet been established in males, however, and their routine use is therefore not yet recommended.

  14. Nitrogen heterocycles as potential monoamine oxidase inhibitors: Synthetic aspects

    Directory of Open Access Journals (Sweden)

    Pravin O. Patil

    2014-12-01

    Full Text Available The present review highlights the synthetic methods of monoamine oxidase inhibitors (MAO belonging to a group of nitrogen heterocycles such as pyrazoline, indole, xanthine, oxadiazole, benzimidazole, pyrrole, quinoxaline, thiazole and other related compounds (1990–2012. Moreover, it emphasizes salient findings related to chemical structures and the bioactivities of these heterocycles as MAO inhibitors. The aim of this review is to find out different methods for the synthesis of nitrogen containing heterocycles and their bioactivity related aspects as MAO inhibitors.

  15. Engineering Performance of a New Siloxane-Based Corrosion Inhibitor

    OpenAIRE

    Holmes, Niall; O'Brien, R.; Basheer, P. A.M.

    2013-01-01

    This paper presents an evaluation of a new non-toxic corrosion inhibitor on selected engineering properties of concrete mixes with different cementitious materials following a corrosion and durability study on concrete samples. Corrosion inhibitors consist of powders or solutions which are added to concrete when mixed to prevent or delay corrosion of steel by their reaction with ferrous ions to form a stable and passive ferric oxide film on the steel surface. The new inhibitor functions sligh...

  16. Natural compounds as corrosion inhibitors for highly cycled systems

    Energy Technology Data Exchange (ETDEWEB)

    Quraishi, M.A.; Farooqi, I.H.; Saini, P.A. [Corrosion Research Lab., Aligarh (India)

    1999-11-01

    Strict environmental legislations have led to the development of green inhibitors in recent years. In continuation of the authors` research work on development of green inhibitors, they have investigated the aqueous extracts of three plants namely: Azadirachta indica, Punica Granatum and Momordica charantia as corrosion inhibitors for mild steel in 3% NaCl using weight loss and electrochemical methods. All the investigated compounds exhibited excellent corrosion inhibition properties comparable to that of HEDP. Azadirachta showed better scale inhibition effect than HEDP.

  17. 胆碱酯酶抑制剂治疗阿尔茨海默病神经精神症状和功能损害的效果汇总分析%Efficacy of Cholinesterase Inhibitors in the Treatment of Neuropsychiatric Symptoms and Functional Impairment in Alzheimer Disease A Meta-analysis

    Institute of Scientific and Technical Information of China (English)

    Nhi-Ha Trinh; Jennifer Hoblyn; Subhanjoy Mohanty; Kristine Yaffe

    2004-01-01

    背景:胆碱酯酶抑制剂是阿尔茨海默病(Alzheimer disease,AD)认知症状的主要治疗药物。胆碱能功能障碍也可能导致神经精神和功能缺陷,但胆碱酯酶抑制剂随机对照试验的结果并不一致。目的:进行系统综述和汇总分析,定量显示胆碱酯酶抑制剂治疗轻至中度AD病人神经精神症状和功能减退的疗效。资料来源:我们应用MEDLINE(1966年1月-2001年12月)、在线论文摘要、PSYCHINFO、BIOSIS、PubMed和Cochrane对照试验登记查找相关试验的文献。我们检索了英语和非英语综述文章,从综述、研究原著及其他相关论文收集参考文献。我们查找了已发表和未发表的试验报告,并与研究者和制药公司取得联系。研究选择:我们入选平行组或交叉随机、双盲、安慰剂对照试验29项,参试者为诊断为轻至中度疑似AD并接受胆碱酯酶抑制剂治疗1个月以上的门诊病人。16项试验包括神经精神症状指标,18项试验包括功能指标。数据提取:两位研究者(N.H.T.和J.H.)分别提取研究方法、偏倚来源和预后指标。神经精神症状的预后采用神经精神症状调查表(NPI,0—120分)和阿尔茨海默病评估量表中的非认知量表(ADAS—noncog,0~50分)进行测定,并采用加权平均差法进行分析。功能的预后采用数项日常生活活动(ADL)量表或器械辅助日常生活活动(IADL)量表测定,用标准平均差法分析。数据综合:关于神经精神症状预后,10项试验有ADAS—noncog测定结果,6项试验有NPI测定结果。与安慰剂相比,随机使用胆碱酯酶抑制剂的病人NPI测定改善了1.72分(95%可信区间[CI],0.87~2.57分),A.DAS—noncog测定改善了0.03分(95%CI,0.00—0.05分)。关于生理功能预后,14项试验采用ADL量表,13项试验采用IADL量表。与安慰剂相比,随机使用胆碱酯酶抑制剂的病人ADL量表测定改善了0.1SDs(95%CI,0.00—0.19SDs),IADL量表测定改善了0.09SDs(95%CI,0.01~0.17SDs)。各种胆碱酯酶抑制剂的疗效无差异。结论:上述结果表明,胆碱酯酶抑制剂对AD病人的神经精神症状和功能预后有一定效果。今后的研究应致力于如何将这种改善转化为病人生活质量、医疗保健机构入住和保健提供者负担等方面的长期后果。

  18. Solderability preservation through the use of organic inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Sorensen, N.R.; Hosking, F.M.

    1994-12-01

    Organic inhibitors can be used to prevent corrosion of metals and have application in the electronics industry as solderability preservatives. We have developed a model to describe the action of two inhibitors (benzotriazole and imidazole) during the environmental aging and soldering process. The inhibitors bond with the metal surface and form a barrier that prevents or retards oxidation. At soldering temperatures, the metal-organic complex breaks down leaving an oxide-free metal surface that allows excellent wetting by molten solder. The presence of the inhibitor retards the wetting rate relative to clean copper, but provides a vast improvement relative to oxidized copper.

  19. Discovery of a selective irreversible BMX inhibitor for prostate cancer.

    Science.gov (United States)

    Liu, Feiyang; Zhang, Xin; Weisberg, Ellen; Chen, Sen; Hur, Wooyoung; Wu, Hong; Zhao, Zheng; Wang, Wenchao; Mao, Mao; Cai, Changmeng; Simon, Nicholas I; Sanda, Takaomi; Wang, Jinhua; Look, A Thomas; Griffin, James D; Balk, Steven P; Liu, Qingsong; Gray, Nathanael S

    2013-07-19

    BMX is a member of the TEC family of nonreceptor tyrosine kinases. We have used structure-based drug design in conjunction with kinome profiling to develop a potent, selective, and irreversible BMX kinase inhibitor, BMX-IN-1, which covalently modifies Cys496. BMX-IN-1 inhibits the proliferation of Tel-BMX-transformed Ba/F3 cells at two digit nanomolar concentrations but requires single digit micromolar concentrations to inhibit the proliferation of prostate cancer cell lines. Using a combinatorial kinase inhibitor screening strategy, we discovered that the allosteric Akt inhibitor, MK2206, is able to potentiate BMX inhibitor's antiproliferation efficacy against prostate cancer cells.

  20. Cysteine peptidases and their inhibitors in breast and genital cancer.

    Directory of Open Access Journals (Sweden)

    Magdalena Milan

    2010-11-01

    Full Text Available Cysteine proteinases and their inhibitors probably play the main role in carcinogenesis and metastasis. The metastasis process need external proteolytic activities that pass several barriers which are membranous structures of the connective tissue which includes, the basement membrane of blood vessels. Activities of the proteinases are regulated by endogenous inhibitors and activators. The imbalance between cysteine proteinases and cystatins seems to be associated with an increase in metastatic potential in some tumors. It has also been reported that proteinase inhibitors, specific antibodies for these enzymes and inhibition of the urokinase receptor may prevent cancer cell invasion. Some proteinase inhibitor could serve as agents for cancer treatment.

  1. Achievements, challenges and unmet needs for haemophilia patients with inhibitors

    Science.gov (United States)

    DARGAUD, Y.; PAVLOVA, A.; LACROIX-DESMAZES, S.; FISCHER, K.; SOUCIE, M.; CLAEYSSENS, S.; SCOTT, D.W.; d’OIRON, R.; LAVIGNE-LISSALDE, G.; KENET, G.; ETTINGSHAUSEN, C. ESCURIOLA; BOREL-DERLON, A.; LAMBERT, T.; PASTA, G.; NÉGRIER, C.

    2016-01-01

    Summary Over the past 20 years, there have been many advances in haemophilia treatment that have allowed patients to take greater control of their disease. However, the development of factor VIII (FVIII) inhibitors is the greatest complication of the disease and a challenge in the treatment of haemophilia making management of bleeding episodes difficult and surgical procedures very challenging. A meeting to discuss the unmet needs of haemophilia patients with inhibitors was held in Paris on 20 November 2014. Topics discussed were genetic and non-genetic risk factors for the development of inhibitors, immunological aspects of inhibitor development, FVIII products and inhibitor development, generation and functional properties of engineered antigen-specific T regulatory cells, suppression of immune responses to FVIII, prophylaxis in haemophilia patients with inhibitors, epitope mapping of FVIII inhibitors, current controversies in immune tolerance induction therapy, surgery in haemophilia patients with inhibitors and future perspectives for the treatment of haemophilia patients with inhibitors. A summary of the key points discussed is presented in this paper. PMID:26728503

  2. Predicting DPP-IV inhibitors with machine learning approaches

    Science.gov (United States)

    Cai, Jie; Li, Chanjuan; Liu, Zhihong; Du, Jiewen; Ye, Jiming; Gu, Qiong; Xu, Jun

    2017-02-01

    Dipeptidyl peptidase IV (DPP-IV) is a promising Type 2 diabetes mellitus (T2DM) drug target. DPP-IV inhibitors prolong the action of glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), improve glucose homeostasis without weight gain, edema, and hypoglycemia. However, the marketed DPP-IV inhibitors have adverse effects such as nasopharyngitis, headache, nausea, hypersensitivity, skin reactions and pancreatitis. Therefore, it is still expected for novel DPP-IV inhibitors with minimal adverse effects. The scaffolds of existing DPP-IV inhibitors are structurally diversified. This makes it difficult to build virtual screening models based upon the known DPP-IV inhibitor libraries using conventional QSAR approaches. In this paper, we report a new strategy to predict DPP-IV inhibitors with machine learning approaches involving naïve Bayesian (NB) and recursive partitioning (RP) methods. We built 247 machine learning models based on 1307 known DPP-IV inhibitors with optimized molecular properties and topological fingerprints as descriptors. The overall predictive accuracies of the optimized models were greater than 80%. An external test set, composed of 65 recently reported compounds, was employed to validate the optimized models. The results demonstrated that both NB and RP models have a good predictive ability based on different combinations of descriptors. Twenty "good" and twenty "bad" structural fragments for DPP-IV inhibitors can also be derived from these models for inspiring the new DPP-IV inhibitor scaffold design.

  3. Behaviour of tetramine inhibitors during pickling of hot rolled steels

    Energy Technology Data Exchange (ETDEWEB)

    Cornu, Marie-José, E-mail: marie-jose.cornu@arcelormittal.com [ArcelorMittal Maizières Research, Voie Romaine, 57280 Maizières-lès-Metz (France); Koltsov, Alexey, E-mail: alexey.koltsov@arcelormittal.com [ArcelorMittal Maizières Research, Voie Romaine, 57280 Maizières-lès-Metz (France); Nicolas, Sabrina, E-mail: sabrina_nicolas@live.fr [ArcelorMittal Maizières Research, Voie Romaine, 57280 Maizières-lès-Metz (France); Laboratoire de Chimie Physique et Microbiologie pour l’Environnement (LCPME) – UMR 7564 CNRS – Université de Lorraine, 405 rue de Vandoeuvre, 54602 Villers-lès-Nancy (France); Colom, Lydia, E-mail: Lydia.colom@sfr.fr [ArcelorMittal Maizières Research, Voie Romaine, 57280 Maizières-lès-Metz (France); Dossot, Manuel, E-mail: manuel.dossot@univ-lorraine.fr [Laboratoire de Chimie Physique et Microbiologie pour l’Environnement (LCPME) – UMR 7564 CNRS – Université de Lorraine, 405 rue de Vandoeuvre, 54602 Villers-lès-Nancy (France)

    2014-02-28

    To avoid the dissolution of steel in industrial pickling process, tetramine inhibitors are added to the pickling bath. This study is devoted to the understanding of the action mechanism of these inhibitors in hydrochloric and sulphuric baths on non-alloyed and alloyed steels. Pickling experiments and characterization with XPS, Raman and infrared spectroscopies have shown that inhibitors work only in acid media and leached out from the steel surfaces during the rinsing operation just after pickling. The effectiveness of inhibitors depends on the acid media and the temperature. Experimental data are consistent with a surface mechanism, i.e., the so-called “outer-sphere” adsorption.

  4. Identification of fermentation inhibitors in wood hydrolyzates and removal of inhibitors by ion exchange and liquid-liquid extraction

    Science.gov (United States)

    Luo, Caidian

    1998-12-01

    Common methods employed in the ethanol production from biomass consist of chemical or enzymatic degradation of biomass into sugars and then fermentation of sugars into ethanol or other chemicals. However, some degradation products severely inhibit the fermentation processes and substantially reduce the efficiency of ethanol production. How to remove inhibitors from the reaction product mixture and increase the production efficiency are critical in the commercialization of any processes of energy from biomass. The present study has investigated anion exchange and liquid-liquid extraction as potential methods for inhibitor removal. An analytical method has been developed to identify the fermentation inhibitors in a hydrolyzate. The majority of inhibitors present in hybrid poplar hydrolyzate have positively been identified. Ion exchange with weak basic Dowex-MWA-1 resin has been proved to be an effective mean to remove fermentation inhibitors from hybrid poplar hydrolyzate and significantly increase the fermentation productivity. Extraction with n-butanol might be a preferred way to remove inhibitors from wood hydrolyzates and improve the fermentability of sugars in the hydrolyzates. n-Butanol also removes some glucose, mannose and xylose from the hydrolyzate. Inhibitor identification reveals that lignin and sugar degradation compounds including both aromatic and aliphatic aldehydes and carboxylic acids formed in hydrolysis, plus fatty acids and other components from wood extractives are major fermentation inhibitors in Sacchromyces cerevisiae fermentation. There are 35 components identified as fermentation inhibitors. Among them, 4-hydroxy benzoic acid, 3,4-dihydroxy benzoic acid, syringic acid, syringaldehyde, and ferulic acid are among the most abundant aromatic inhibitors in hybrid poplar hydrolyzate. The conversion of aldehyde groups into carboxylic acid groups in the nitric acid catalyzed hydrolysis reduces the toxicity of the hydrolyzate. A wide spectrum of

  5. The effects of residual platelets in plasma on plasminogen activator inhibitor-1 and plasminogen activator inhibitor-1-related assays

    Science.gov (United States)

    Barnard, Sunelle A.; Loots, Du Toit; Rijken, Dingeman C.

    2017-01-01

    Due to controversial evidence in the literature pertaining to the activity of plasminogen activator inhibitor-1 in platelets, we examined the effects of residual platelets present in plasma (a potential pre-analytical variable) on various plasminogen activator inhibitor-1 and plasminogen activator inhibitor-1-related assays. Blood samples were collected from 151 individuals and centrifuged at 352 and 1500 g to obtain plasma with varying numbers of platelet. In a follow-up study, blood samples were collected from an additional 23 individuals, from whom platelet-poor (2000 g), platelet-containing (352 g) and platelet-rich plasma (200 g) were prepared and analysed as fresh-frozen and after five defrost-refreeze cycles (to determine the contribution of in vitro platelet degradation). Plasminogen activator inhibitor-1 activity, plasminogen activator inhibitor-1 antigen, tissue plasminogen activator/plasminogen activator inhibitor-1 complex, plasma clot lysis time, β-thromboglobulin and plasma platelet count were analysed. Platelet α-granule release (plasma β-thromboglobulin) showed a significant association with plasminogen activator inhibitor-1 antigen levels but weak associations with plasminogen activator inhibitor-1 activity and a functional marker of fibrinolysis, clot lysis time. Upon dividing the study population into quartiles based on β-thromboglobulin levels, plasminogen activator inhibitor-1 antigen increased significantly across the quartiles while plasminogen activator inhibitor-1 activity and clot lysis time tended to increase in the 4th quartile only. In the follow-up study, plasma plasminogen activator inhibitor-1 antigen was also significantly influenced by platelet count in a concentration-dependent manner. Plasma plasminogen activator inhibitor-1 antigen levels increased further after complete platelet degradation. Residual platelets in plasma significantly influence plasma plasminogen activator inhibitor-1 antigen levels mainly through release of

  6. Profiling of differentially expressed genes in haemophilia A with inhibitor.

    Science.gov (United States)

    Hwang, S H; Lim, J A; Kim, M J; Kim, H C; Lee, H W; Yoo, K Y; You, C W; Lee, K S; Kim, H S

    2012-05-01

    Inhibitor development is the most significant complication in the therapy of haemophilia A (HA) patients. In spite of many studies, not much is known regarding the mechanism underlying inhibitor development. To understand the mechanism, we analysed profiles of differentially expressed genes (DEGs) between inhibitor and non-inhibitor HA via a microarray technique. Twenty unrelated Korean HAs were studied: 11 were non-inhibitor and nine were HA with inhibitor (≥5 BU mL(-1)). Microarray analysis was conducted using a Human Ref-8 expression Beadchip system (Illumina) and the data were analysed using Beadstudio software. We identified 545 DEGs in inhibitor HA as compared with the non-inhibitor patients; 384 genes were up-regulated and 161 genes were down-regulated. Among them, 75 genes whose expressions were altered by at least two-fold (>+2 or genes differed significantly in the two groups. For validation of the DEGs, semi-quantitative RT-PCR (semi-qRT-PCR) was conducted with the six selected DEGs. The results corresponded to the microarray data, with the exception of one gene. We also examined the expression of the genes associated with the antigen presentation process via real-time PCR. The average levels of IL10, CTLA4 and TNFα slightly reduced, whereas that of IFNγ increased in the inhibitor HA group. We are currently unable to explain whether this phenomenon is a function of the inhibitor-inducing factor or is an epiphenomenon of antibody production. Nevertheless, our results provide a possible explanation for inhibitor development.

  7. Developing BACE-1 inhibitors for FXS

    Directory of Open Access Journals (Sweden)

    Cara J Westmark

    2013-05-01

    Full Text Available Fragile X syndrome (FXS is a debilitating genetic disorder with no cure and few therapeutic options. Excessive signaling through metabotropic glutamate receptor 5 (mGluR5 in FXS leads to increased translation of numerous synaptic proteins and exaggerated long-term depression (LTD. Two of the overexpressed proteins are amyloid-beta protein precursor (APP and its metabolite amyloid-beta (Aβ, which have been well-studied in Alzheimer’s disease (AD. Here we discus the possibility that pharmaceuticals under study for the modulation of these proteins in AD might be viable therapeutic strategies for FXS. Specifically, a recently identified acetyltransferase (ATase inhibitor that reduces the levels and activity of β-site APP cleaving enzyme (BACE-1 has strong potential to attenuate BACE-1 activity and maintain homeostatic levels APP catabolites in FXS.

  8. Bisarylmaleimides & the Corresponding Indolocarbazoles as Kinase Inhibitors

    Institute of Scientific and Technical Information of China (English)

    Zhu Guoxin; Cathy Ogg; Bharvin Patel; Richard M. Schultz; Charles D. Spencer; Beverly Teicher; Scou A. Watkins; Scott E. Conner; Zhou Xun; Chuan Shih; Li Tiechao; Harold B. Brooks; Eileen Considine; Jack A. Dempsey; Margaret M. Faul

    2004-01-01

    Cyclin dependent kinases (CDKs) have recently raised considerable attention because of their central role in the regulation of cell cycle progression. A high incidence of genetic mutation of CDK substrates and deregulaton of CDK modulators were found in a number of disease states,particularly in cancer. A novel series of unsymmetrical substituted indolocarbazoles were synthesized and their kinase inhibitory capability was evaluated in vitro. 6-Substtuted indolocarbazoles were found to be highly potent and selective D1/CDK4 inhibitors. These indolocarbazoles exhibited ATP competitive D1/CDK4 activity and inhibited tumor cell growth,arrested tumor cell at G1 phase. These molecules demonstrated potent anti-tumor activity and inhibited pRb phosphorylation at S780 in the human lung carcinoma (Calu6) and non-small cell lung carcinoma (NCI-H460) xenograft models. The results indicate that these small molecules have potential as therapeutic agents in cancer chemotherapeutc agents.

  9. Novel peptide-based protease inhibitors

    DEFF Research Database (Denmark)

    Roodbeen, Renée

    This thesis describes the design and synthesis of peptide-based serine protease inhibitors. The targeted protease, urokinase-type plasminogen activator (uPA) activates plasminogen, which plays a major role in cancer metastasis. The peptide upain-2 (S 1 ,S 12-cyclo-AcCSWRGLENHAAC-NH2) is a highly......, the disulfide bridge was replaced with amide bonds of various lengths. The novel peptides did not retain their inhibitory activity, but formed the basis for another strategy. Second, bicyclic peptides were obtained by creating head-to-tail cyclized peptides that were made bicyclic by the addition of a covalent...... increased. Finally, the effect of multivalent display of upain-2 was investigated. Several dimers of upain-2 were made and the attachment of upain-2 via the Copper-catalyzed Azide-Alkyne Cycloaddition (CuAAC) onto an alkyne functionalized carbohydrate scaffold was investigated. Besides the synthesis...

  10. a -Glucosidase Inhibitors from Dendrobium tortile

    Directory of Open Access Journals (Sweden)

    Rachawadee Limpanit

    2016-03-01

    Full Text Available From the whole plant of Dendrobium tortile, a new compound, namely 4-(2-hydroxypropyl-2(5H-furanone, was isolated, together with six known compounds, which included trans-tetracosylferulate (2, cis-docosylferulate (3, p-hydroxybenzaldehyde (4, 3,4-dihydroxy-3,4 ¢ -dimethoxybibenzyl (5, (2S-eriodictyol (6 and dendrofalconerol A (7. The structures of these compounds were determined through analysis of 1-D and 2-D NMR and HR-ESI-MS data. All of the isolates were evaluated for their a -glucosidase inhibitory activity. Compound 7 showed strong a -glucosidase inhibitory activity when compared with the positive control acarbose, whereas compounds 5 and 6 exhibited appreciable effects. An enzyme kinetic study revealed that compound 7 is a non-competitive inhibitor of a -glucosidase. This is the first report of the chemical constituents with biological activity from D. tortile.

  11. Different Pathways Leading to Integrase Inhibitors Resistance

    Science.gov (United States)

    Thierry, Eloïse; Deprez, Eric; Delelis, Olivier

    2017-01-01

    Integrase strand-transfer inhibitors (INSTIs), such as raltegravir (RAL), elvitegravir, or dolutegravir (DTG), are efficient antiretroviral agents used in HIV treatment in order to inhibit retroviral integration. By contrast to RAL treatments leading to well-identified mutation resistance pathways at the integrase level, recent clinical studies report several cases of patients failing DTG treatment without clearly identified resistance mutation in the integrase gene raising questions for the mechanism behind the resistance. These compounds, by impairing the integration of HIV-1 viral DNA into the host DNA, lead to an accumulation of unintegrated circular viral DNA forms. This viral DNA could be at the origin of the INSTI resistance by two different ways. The first one, sustained by a recent report, involves 2-long terminal repeat circles integration and the second one involves expression of accumulated unintegrated viral DNA leading to a basal production of viral particles maintaining the viral information. PMID:28123383

  12. Adnectin-targeted inhibitors: rationale and results.

    Science.gov (United States)

    Sachdev, Esha; Gong, Jun; Rimel, Bobbie; Mita, Monica

    2015-08-01

    Adnectins are a family of binding proteins derived from the 10th type III domain of human fibronectin (10Fn3), which is part of the immunoglobulin superfamily and normally binds integrin. The 10Fn3 has the potential for broad therapeutic applications given its structural stability, ability to be manipulated, and its abundance in the human body. The most commonly studied adnectin is CT-322, which is an inhibitor of vascular endothelial growth factor receptor-2. A bispecific adnectin, El-Tandem, has also been developed and binds to epidermal growth factor receptor and insulin-like growth factor-1 receptor simultaneously. Pre-clinical studies have shown promising results in relation to reducing tumor growth, decreasing microvessel density, and promoting normalization of tumor architecture. The phase I trial with CT-322 demonstrates relatively low toxicities. However, the phase II study done with CT-322 in recurrent glioblastoma does not reveal as promising results.

  13. Proton pump inhibitors inhibit pancreatic secretion

    DEFF Research Database (Denmark)

    Wang, Jing; Barbuskaite, Dagne; Tozzi, Marco

    2015-01-01

    +/K+-ATPases are expressed and functional in human pancreatic ducts and whether proton pump inhibitors (PPIs) have effect on those. Here we show that the gastric HKα1 and HKβ subunits (ATP4A; ATP4B) and non-gastric HKα2 subunits (ATP12A) of H+/K+-ATPases are expressed in human pancreatic cells. Pumps have similar...... of major ions in secretion follow similar excretory curves in control and PPI treated animals. In addition to HCO3-, pancreas also secretes K+. In conclusion, this study calls for a revision of the basic model for HCO3- secretion. We propose that proton transport is driving secretion, and that in addition...

  14. Insect response to plant defensive protease inhibitors.

    Science.gov (United States)

    Zhu-Salzman, Keyan; Zeng, Rensen

    2015-01-07

    Plant protease inhibitors (PIs) are natural plant defense proteins that inhibit proteases of invading insect herbivores. However, their anti-insect efficacy is determined not only by their potency toward a vulnerable insect system but also by the response of the insect to such a challenge. Through the long history of coevolution with their host plants, insects have developed sophisticated mechanisms to circumvent antinutritional effects of dietary challenges. Their response takes the form of changes in gene expression and the protein repertoire in cells lining the alimentary tract, the first line of defense. Research in insect digestive proteases has revealed the crucial roles they play in insect adaptation to plant PIs and has brought about a new appreciation of how phytophagous insects employ this group of molecules in both protein digestion and counterdefense. This review provides researchers in related fields an up-to-date summary of recent advances.

  15. Cyclooxygenase (COX Inhibitors and the Newborn Kidney

    Directory of Open Access Journals (Sweden)

    Wei Qi

    2012-10-01

    Full Text Available This review summarizes our current understanding of the role of cyclo-oxygenase inhibitors (COXI in influencing the structural development as well as the function of the developing kidney. COXI administered either during pregnancy or after birth can influence kidney development including nephronogenesis, and can decrease renal perfusion and ultrafiltration potentially leading to acute kidney injury in the newborn period. To date, which COX isoform (COX-1 or COX-2 plays a more important role in during fetal development and influences kidney function early in life is not known, though evidence points to a predominant role for COX-2. Clinical implications of the use of COXI in pregnancy and in the newborn infant are also evaluated herein, with specific reference to the potential effects of COXI on nephronogenesis as well as newborn kidney function.

  16. The new factor Xa inhibitor: Apixaban

    Directory of Open Access Journals (Sweden)

    Sangeeta Bhanwra

    2014-01-01

    Full Text Available Cardiovascular diseases are still the most important cause of morbidity and mortality worldwide and anti-thrombotic treatment is widely used as a result. The currently used drugs include heparin and its derivatives, vitamin K antagonists, though efficacious, have their own set of limitations like unpredictable pharmacokinetic profile, parenteral route (with heparin and its derivatives only, narrow therapeutic window, and constant laboratory monitoring for their efficacy and safety. This lead to the development of novel factor Xa inhibitors which could be given orally, have predictable dose response relationship and are associated with lesser hemorrhagic complications. They include rivaroxaban, apixaban, and edoxaban among others. Apixaban has currently been approved for use in patients undergoing total knee or hip replacement surgery and to prevent stroke in patients with atrial fibrillation. Many trials are ongoing for apixaban to firmly establish its place in future, among the anti-thrombotic drugs.

  17. Clinical implications of hedgehog signaling pathway inhibitors

    Institute of Scientific and Technical Information of China (English)

    Hailan Liu; Dongsheng Gu; Jingwu Xie

    2011-01-01

    Hedgehog was first described in Drosophila melanogaster by the Nobel laureates Eric Wieschaus and Christiane Nusslein-Volhard. The hedgehog (Hh) pathway is a major regulator of cell differentiation,proliferation, tissue polarity, stem cell maintenance, and carcinogenesis. The first link of Hh signaling to cancer was established through studies of a rare familial disease, Gorlin syndrome, in 1996. Follow-up studies revealed activation of this pathway in basal cell carcinoma, medulloblastoma and, leukemia as well as in gastrointestinal, lung, ovarian, breast, and prostate cancer. Targeted inhibition of Hh signaling is now believed to be effective in the treatment and prevention of human cancer. The discovery and synthesis of specific inhibitors for this pathway are even more exciting. In this review, we summarize major advances in the understanding of Hh signaling pathway activation in human cancer, mouse models for studying Hhmediated carcinogenesis, the roles of Hh signaling in tumor development and metastasis, antagonists for Hh signaling and their clinical implications.

  18. Randomized controlled trials of COX-2 inhibitors

    DEFF Research Database (Denmark)

    Stefansdottir, Gudrun; De Bruin, Marie L; Knol, Mirjam J

    2011-01-01

    BACKGROUND: Naproxen, ibuprofen and diclofenac are frequently used as comparators in randomized controlled trials (RCTs) on the safety and efficacy of cyclooxygenase (COX)-2 inhibitors. Different comparator doses may influence the results of RCTs. It has been hypothesized that RCTs of COX-2...... 1995 and 2009 in which celecoxib or rofecoxib were compared with naproxen, ibuprofen or diclofenac. All articles labelled as RCTs mentioning rofecoxib or celecoxib and one or more of the comparator drugs in the title and/or abstract were included. We extracted information on doses of both non...... dose trends in the case of rofecoxib. CONCLUSIONS: Although the dose trends over time differed for RCTs comparing rofecoxib and celecoxib with diclofenac, ibuprofen or naproxen, the results of our study do not support the hypothesis that dose trends influenced the decision to continue marketing...

  19. Renal effects of immune checkpoint inhibitors.

    Science.gov (United States)

    Izzedine, Hassan; Mateus, Christine; Boutros, Céline; Robert, Caroline; Rouvier, Philippe; Amoura, Zahir; Mathian, Alexis

    2016-12-26

    Recent advances in immune checkpoint inhibitor (ICPI) development have led to major improvements in oncology patient outcomes. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) are two essential immune checkpoint receptors. Ipilimumab and tremelimumab (anti-CTLA-4-blocking antibodies) and pembrolizumab and nivolumab (antibodies targeting PD-1 receptors) have already been approved by US Food and Drug Administration in several malignancies. Two different forms of ICPI-induced renal damage have been identified, including acute (granulomatous) tubulointerstitial nephritis and immune complex glomerulonephritis. The observed acute renal damage can be reversed upon ICPI drug discontinuation and renal function can recover back to normal following the introduction of systemic corticosteroid treatment. Any delay in treating this complication could result in definitive and irreversible renal injury.

  20. Development of Inhibitors of Salicylic Acid Signaling.

    Science.gov (United States)

    Jiang, Kai; Kurimoto, Tetsuya; Seo, Eun-kyung; Miyazaki, Sho; Nakajima, Masatoshi; Nakamura, Hidemitsu; Asami, Tadao

    2015-08-19

    Salicylic acid (SA) plays important roles in the induction of systemic acquired resistance (SAR) in plants. Determining the mechanism of SAR will extend our understanding of plant defenses against pathogens. We recently reported that PAMD is an inhibitor of SA signaling, which suppresses the expression of the pathogenesis-related PR genes and is expected to facilitate the understanding of SA signaling. However, PAMD strongly inhibits plant growth. To minimize the side effects of PAMD, we synthesized a number of PAMD derivatives, and identified compound 4 that strongly suppresses the expression of the PR genes with fewer adverse effects on plant growth than PAMD. We further showed that the adverse effects on plant growth were partially caused the stabilization of DELLA, which is also related to the pathogen responses. These results indicate that compound 4 would facilitate our understanding of SA signaling and its cross talk with other plant hormones.

  1. Inherent formulation issues of kinase inhibitors.

    Science.gov (United States)

    Herbrink, M; Schellens, J H M; Beijnen, J H; Nuijen, B

    2016-10-10

    The small molecular Kinase Inhibitor (smKI) drug class is very promising and rapidly expanding. All of these drugs are administered orally. The clear relationship between structure and function has led to drugs with a general low intrinsic solubility. The majority of the commercial pharmaceutical formulations of the smKIs are physical mixtures that are limited by the low drug solubility of a salt form. This class of drugs is therefore characterized by an impaired and variable bioavailability rendering them costly and their therapies suboptimal. New formulations are sparingly being reported in literature and patents. The presented data suggests that continued research into formulation design can help to develop more efficient and cost-effective smKI formulation. Moreover, it may also be of help in the future design of the formulations of new smKIs.

  2. Use of proteasome inhibitors in anticancer therapy

    Directory of Open Access Journals (Sweden)

    Sara M. Schmitt

    2011-10-01

    Full Text Available The importance of the ubiquitin-proteasome pathway to cellular function has brought it to the forefront in the search for new anticancer therapies. The ubiquitin-proteasome pathway has proven promising in targeting various human cancers. The approval of the proteasome inhibitor bortezomib for clinical treatment of relapsed/refractory multiple myeloma and mantle cell lymphoma has validated the ubiquitin-proteasome as a rational target. Bortezomib has shown positive results in clinical use but some toxicity and side effects, as well as resistance, have been observed, indicating that further development of novel, less toxic drugs is necessary. Because less toxic drugs are necessary and drug development can be expensive and time-consuming, using existing drugs that can target the ubiquitin-proteasome pathway in new applications, such as cancer therapy, may be effective in expediting the regulatory process and bringing new drugs to the clinic. Toward this goal, previously approved drugs, such as disulfiram, as well as natural compounds found in common foods, such as green tea polyphenol (--EGCG and the flavonoid apigenin, have been investigated for their possible proteasome inhibitory and cell death inducing abilities. These compounds proved quite promising in preclinical studies and have now moved into clinical trials, with preliminary results that are encouraging. In addition to targeting the catalytic activity of the proteasome pathway, upstream regulators, such as the 19S regulatory cap, as well as E1, E2, and E3, are now being investigated as potential drug targets. This review outlines the development of novel proteasome inhibitors from preclinical to clinical studies, highlighting their abilities to inhibit the tumor proteasome and induce apoptosis in several human cancers.

  3. 多发伤患者血清胆碱酯酶与急性期蛋白的相关性%Relationship between serum cholinesterase and acute-phase proteins in patients with multiple trauma

    Institute of Scientific and Technical Information of China (English)

    巴立; 张茂; 沈凌炜; 吴定钱; 干建新; 徐少文

    2008-01-01

    和第7天显著低于存活组,CRP仅在第7天显著高于存活组,Logistic回归分析提示仅血清ChE和PAB是判断预后的独立因素. 结论 血清ChE可视为负急性期蛋白的一种,在反映多发伤病情严重度和预测患者转归中的综合价值要优于其他主要APP.%Objective To investigate the relationship between serum cholinesterase(ChE) and acute-phase proteins in patients with multiple trauma, then to evaluate their significance to judge prognosis. Method It's a prospective observation study. Patients with multiple trauma admitted to emergency intensive care unit,Second Af-filiated Hospital, Zhejiang Universieg, school of medicihe within 24 h after trauma from Oct. 2005 to Oct. 2007 were enrolled. And those with chronic liver disease, touching orgnaophosphorus, active tuberculosis, tumor, in-fection of major organ before trauma, liver injury or age < 18 year were excluded. Among 81 patients, 57 were male and24 female. The average age was (46±18) years, and the average injury severity score was (34.0±11.9).Seventy six healthy were selected as controls, 53 male and 23 female, with an average age of (44±16)years. The exclusion standards were the same as those in patients. Both groups had same gender proportion and age. Senum ChE and acute-phase proteins(APP) including albumin(ALB), prealbumin(PAB), transferrin(TRF),C-reactive protein(CRP) in patients were detected at 1, 3, 7 d after trauma. The acute physiology and chronic health evaluation Ⅲ (APACHEⅢ) was recorded simuhancously. Serum ChE, ALB, PAB, TRF, CRP in the controls were also detected. All of these indexes in the controls were compared with thoses in patients by t test or rank surn test. The dynamic changes of serum ChE and APPs in patients were analyzed by one way repeated mea-sures ANOVA. The relationships between serum ChE and those APPs and the relationships between APACHE Ⅲ and these indexes were analyzed by Pearson correlation analysis. We also compared these indexes

  4. Urea Transporter Inhibitors: En Route to New Diuretics

    Science.gov (United States)

    Sands, Jeff M.

    2013-01-01

    Summary A selective urea transporter UT-A1 inhibitor would be a novel type of diuretic, likely with less undesirable side-effects than conventional diureticssince it acts on the last portion of the nephron. Esteva-Font et al. (2013) develop suchan inhibitor by using a clever high-throughput screening assay, and document its selectivity. . PMID:24210002

  5. Calpains: attractive targets for the development of synthetic inhibitors.

    Science.gov (United States)

    Pietsch, Markus; Chua, Krystle C H; Abell, Andrew D

    2010-01-01

    The physiological roles of calpains are discussed, as are the associated pathological disorders that result from their over-activation. We also present practical information for establishing functional inhibition assays and an overview of X-ray crystal structures of calpain-inhibitor complexes to aid inhibitor design. These structures reveal the expected extended beta-strand conformation for the inhibitor backbone, a geometry that has been engineered into inhibitors with the introduction of either an N-terminal heterocycle or a macrocycle that links the P(1) and P(3) residues. The structure and function of all the main classes of inhibitors are reviewed, with most examples being classified according to the nature of the C-terminal reactive warhead group that reacts with the active site cysteine of calpains. These inhibitor classes include epoxysuccinate derivatives, aldehydes, aldehyde prodrugs (hemiacetals) and alpha-keto carbonyl compounds. Inhibitors derived from the endogenous inhibitor calpastatin and examples lacking a warhead, are now known and these are also discussed.

  6. Detecting and treating breast cancer resistance to EGFR inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Moonlee, Sun-Young; Bissell, Mina J.; Furuta, Saori; Meier, Roland; Kenny, Paraic A.

    2016-04-05

    The application describes therapeutic compositions and methods for treating cancer. For example, therapeutic compositions and methods related to inhibition of FAM83A (family with sequence similarity 83) are provided. The application also describes methods for diagnosing cancer resistance to EGFR inhibitors. For example, a method of diagnosing cancer resistance to EGFR inhibitors by detecting increased FAM83A levels is described.

  7. A new inhibitor of apoptosis from vaccinia virus and eukaryotes.

    NARCIS (Netherlands)

    Gubser, C.; Bergamaschi, D.; Hollinshead, M.; Lu, X.; Kuppeveld, F.J.M. van; Smith, G.L.

    2007-01-01

    A new apoptosis inhibitor is described from vaccinia virus, camelpox virus, and eukaryotic cells. The inhibitor is a hydrophobic, multiple transmembrane protein that is resident in the Golgi and is named GAAP (Golgi anti-apoptotic protein). Stable expression of both viral GAAP (v-GAAP) and human GAA

  8. Protein C Inhibitor-A Novel Antimicrobial Agent

    NARCIS (Netherlands)

    Malmström, E.; Mörgelin, M.; Malmsten, M.; Johansson, L.; Norrby-Teglund, A.; Shannon, O.; Schmidtchen, A.; Meijers, J.C.M.; Herwald, H.

    2009-01-01

    Protein C inhibitor (PCI) is a heparin-binding serine proteinase inhibitor belonging to the family of serpin proteins. Here we describe that PCI exerts broad antimicrobial activity against bacterial pathogens. This ability is mediated by the interaction of PCI with lipid membranes, which subsequentl

  9. Mammalian target of rapamycin inhibitor-associated stomatitis

    NARCIS (Netherlands)

    Boers-Doets, C.B.; Raber-Durlacher, J.E.; Treister, N.S.; Epstein, J.B.; Arends, A.B.P.; Wiersma, D.R.; Lalla, R.V.; Logan, R.M.; van Erp, N.R.P.; Gelderblom, H.

    2013-01-01

    With the recent introduction of inhibitors of mammalian target of rapamycin (mTOR) in oncology, distinct cutaneous and oral adverse events have been identified. In fact, stomatitis and rash are documented as the most frequent and potentially dose-limiting side effects. Clinically, mTOR inhibitor-ass

  10. Rational design of an organometallic glutathione transferase inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    Ang, W.H.; Parker, L.J.; De Luca, A.; Juillerat-Jeanneret, L.; Morton, C.J.; LoBello, M.; Parker, M.W.; Dyson, P.J.; (ISIC)

    2010-08-17

    A hybrid organic-inorganic (organometallic) inhibitor was designed to target glutathione transferases. The metal center is used to direct protein binding, while the organic moiety acts as the active-site inhibitor. The mechanism of inhibition was studied using a range of biophysical and biochemical methods.

  11. Corrosion inhibitors for solar-heating and cooling

    Science.gov (United States)

    Humphries, T. S.

    1979-01-01

    Report describes results of tests conducted to evaluate abilities of 12 candidate corrosion inhibitors to protect aluminum, steel, copper, or stainless steel at typical conditions encountered in solar heating and cooling systems. Inhibitors are based on sodium salts including nitrates, borates, silicates, and phosphates.

  12. Hydroxyapatite microparticles as feedback-active reservoirs of corrosion inhibitors.

    Science.gov (United States)

    Snihirova, D; Lamaka, S V; Taryba, M; Salak, A N; Kallip, S; Zheludkevich, M L; Ferreira, M G S; Montemor, M F

    2010-11-01

    This work contributes to the development of new feedback-active anticorrosion systems. Inhibitor-doped hydroxyapatite microparticles (HAP) are used as reservoirs, storing corrosion inhibitor to be released on demand. Release of the entrapped inhibitor is triggered by redox reactions associated with the corrosion process. HAP were used as reservoirs for several inhibiting species: cerium(III), lanthanum(III), salicylaldoxime, and 8-hydroxyquinoline. These species are effective corrosion inhibitors for a 2024 aluminum alloy (AA2024), used here as a model metallic substrate. Dissolution of the microparticles and release of the inhibitor are triggered by local acidification resulting from the anodic half-reaction during corrosion of AA2024. Calculated values and experimentally measured local acidification over the aluminum anode (down to pH = 3.65) are presented. The anticorrosion properties of inhibitor-doped HAP were assessed using electrochemical impedance spectroscopy. The microparticles impregnated with the corrosion inhibitors were introduced into a hybrid silica-zirconia sol-gel film, acting as a thin protective coating for AA2024, an alloy used for aeronautical applications. The protective properties of the sol-gel films were improved by the addition of HAP, proving their applicability as submicrometer-sized reservoirs of corrosion inhibitors for active anticorrosion coatings.

  13. Antiplatelet agents and proton pump inhibitors – personalizing treatment

    Directory of Open Access Journals (Sweden)

    Eugene Lin

    2010-06-01

    Full Text Available Eugene Lin, Rajiv Padmanabhan, Majaz MoonisDepartment of Neurology, University of Massachusetts Medical School and UMass Memorial Medical Center, Worcester, Massachusetts, USAIntroduction: Antiplatelet therapy remains one of the cornerstones in the management of noncardioembolic ischemic stroke. However, a significant percentage of patients have concomitant gastroesophageal reflux or peptic ulcer disease that requires acid-reducing medications, the most powerful and effective being the proton pump inhibitors (PPIs. Antiplatelet efficacy, at least in vivo, and particularly for clopidogrel, has been shown to be reduced with concomitant proton pump inhibitor use. Whether this is clinically relevant is not clear from the limited studies available.Methods: We conducted an extensive review of studies available on Medline related to pharmacodynamic interactions between the antiplatelet medications and proton pump inhibitors as well as clinical studies that addressed this potential interaction.Results: Based on the present pharmacodynamic and clinical studies we did not find a significant interaction that would reduce the efficacy of antiplatelet agents with concomitant user of proton pump inhibitors.Conclusions: Patients on antiplatelet agents after a transient ischemic attack or ischemic stroke can safely use aspirin, and extended release dipyridamole/aspirin with proton pump inhibitors. Patients on clopidogrel may use other acid-reducing drugs besides proton pump inhibitors. In rare cases where proton pump inhibitors and clopidogrel have to be used concurrently, careful close monitoring for recurrent vascular events is required.Keywords: proton pump inhibitors, antiplatelet medications, clopidogrel, ischemic stroke, cardiovascular events

  14. Nox Inhibitors & Therapies: Rational Design of Peptidic and Small Molecule Inhibitors

    Science.gov (United States)

    Cifuentes-Pagano, M. Eugenia; Meijles, Daniel N.; Pagano, Patrick J.

    2016-01-01

    Oxidative stress-related diseases underlie many if not all of the major leading causes of death in United States and the Western World. Thus, enormous interest from both academia and pharmaceutical industry has been placed on the development of agents which attenuate oxidative stress. With that in mind, great efforts have been placed in the development of inhibitors of NADPH oxidase (Nox), the major enzymatic source of reactive oxygen species and oxidative stress in many cells and tissue. The regulation of a catalytically active Nox enzyme involves numerous protein-protein interactions which, in turn, afford numerous targets for inhibition of its activity. In this review, we will provide an updated overview of the available Nox inhibitors, both peptidic and small molecules, and discuss the body of data related to their possible mechanisms of action and specificity towards each of the various isoforms of Nox. Indeed, there have been some very notable successes. However, despite great commitment by many in the field, the need for efficacious and well-characterized, isoform-specific Nox inhibitors, essential for the treatment of major diseases as well as for delineating the contribution of a given Nox in physiological redox signalling, continues to grow. PMID:26510437

  15. Characterization of inhibitor(s) of β-glucuronidase enzyme activity in GUS-transgenic wheat

    KAUST Repository

    Ramadan, Ahmed M Ali

    2011-06-26

    The uidA gene, encoding for β-glucuronidase (GUS), is the most frequently used reporter gene in plants. As a reporter enzyme, GUS can be assayed both qualitatively and quantitatively. In wheat, there are numerous reports of failure in detecting GUS enzyme activity in tissues of transgenic plants, while other reports have suggested presence of β-glucuronidase inhibitor(s) in wheat tissues. In the present study, we show that the β-glucuronidase enzyme activity is not only tissue-specific but also genotype-dependent. Our data demonstrate that the glucuronic acid could be the candidate inhibitor for β-glucuronidase enzyme activity in wheat leaves and roots. It should be noted that the assays to detect β-glucuronidase enzyme activity in wheat should be interpreted carefully. Based on the data of our present study, we recommend studying the chemical pathways, the unintended effects and the possible loss-of-function of any candidate transgene prior to transformation experiments. © 2011 Springer Science+Business Media B.V.

  16. Isolation and characterization of a proteinase inhibitor from marama beans.

    Science.gov (United States)

    Elfant, M; Bryant, L; Starcher, B

    1985-11-01

    A protease inhibitor was purified from the African marama bean (Tylosema esculenturm). The inhibitor is present in large amounts, representing about 10.5% of the total protein. The molecular weight is slightly larger than soybean trypsin inhibitor and was estimated at 23,000 by SDS-gel electrophoresis or 24,500 by amino acid analysis. The amino acid composition was atypical of most other plant inhibitors with a cysteine content of only one or possibly two residues/mole and a blocked amino terminus. Inhibition studies indicated virtually no inhibition of chymotrypsin activity. Elastase, however, was inhibited to the same extent as trypsin, requiring about 2 moles of inhibitor for complete inhibition of the enzyme.

  17. Synthesis and evaluation of indazole based analog sensitive Akt inhibitors.

    Science.gov (United States)

    Okuzumi, Tatsuya; Ducker, Gregory S; Zhang, Chao; Aizenstein, Brian; Hoffman, Randy; Shokat, Kevan M

    2010-08-01

    The kinase Akt is a key signaling node in regulating cellular growth and survival. It is implicated in cancer by mutation and its role in the downstream transmission of aberrant PI3K signaling. For these reasons, Akt has become an increasingly important target of drug development efforts and several inhibitors are now reaching clinical trials. Paradoxically it has been observed that active site kinase inhibitors of Akt lead to hyperphosphorylation of Akt itself. To investigate this phenomenon we here describe the application of a chemical genetics strategy that replaces native Akt with a mutant version containing an active site substitution that allows for the binding of an engineered inhibitor. This analog sensitive strategy allows for the selective inhibition of a single kinase. In order to create the inhibitor selective for the analog sensitive kinase, a diversity of synthetic approaches was required, finally resulting in the compound PrINZ, a 7-substituted version of the Abbott Labs Akt inhibitor A-443654.

  18. Skin problems and EGFR-tyrosine kinase inhibitor.

    Science.gov (United States)

    Kozuki, Toshiyuki

    2016-04-01

    Epidermal growth factor receptor inhibition is a good target for the treatment of lung, colon, pancreatic and head and neck cancers. Epidermal growth factor receptor-tyrosine kinase inhibitor was first approved for the treatment of advanced lung cancer in 2002. Epidermal growth factor receptor-tyrosine kinase inhibitor plays an essential role in the treatment of cancer, especially for patients harbouring epidermal growth factor receptor activating mutation. Hence, skin toxicity is the most concerning issue for the epidermal growth factor receptor-tyrosine kinase inhibitor treatment. Skin toxicity is bothersome and sometimes affects the quality of life and treatment compliance. Thus, it is important for physicians to understand the background and how to manage epidermal growth factor receptor-tyrosine kinase inhibitor-associated skin toxicity. Here, the author reviewed the mechanism and upfront preventive and reactive treatments for epidermal growth factor receptor inhibitor-associated skin toxicities.

  19. [Bifunctional inhibitor of alpha-amylase/trypsin from wheat grain].

    Science.gov (United States)

    Islamov, R A; Furusov, O V

    2007-01-01

    A trypsin inhibitor, isolated from whole-wheat grain (Triticum aestivum L.) by the method of bio-specific chromatography on trypsin-Sepharose, was potent in inhibiting human salivary alpha-amylase. The bi-functional alpha-amylase/trypsin inhibitor was characterized by a narrow specificity for other alpha-amylases and proteinases. The high thermostability of the inhibitor was lost in the presence of SH group-reducing agents. The inhibitor-trypsin complex retained its activity against alpha-amylase. The inhibitor-alpha-amylase complex was active against trypsin. Studies of the enzyme kinetics demonstrated that the inhibition of alpha-amylase and trypsin was noncompetitive. Our results suggest the existence of two independent active sites responsible for the interaction with the enzymes.

  20. Recent Natural Corrosion Inhibitors for Mild Steel: An Overview

    Directory of Open Access Journals (Sweden)

    Marko Chigondo

    2016-01-01

    Full Text Available Traditionally, reduction of corrosion has been managed by various methods including cathodic protection, process control, reduction of the metal impurity content, and application of surface treatment techniques, as well as incorporation of suitable alloys. However, the use of corrosion inhibitors has proven to be the easiest and cheapest method for corrosion protection and prevention in acidic media. These inhibitors slow down the corrosion rate and thus prevent monetary losses due to metallic corrosion on industrial vessels, equipment, or surfaces. Inorganic and organic inhibitors are toxic and costly and thus recent focus has been turned to develop environmentally benign methods for corrosion retardation. Many researchers have recently focused on corrosion prevention methods using green inhibitors for mild steel in acidic solutions to mimic industrial processes. This paper provides an overview of types of corrosion, corrosion process, and mainly recent work done on the application of natural plant extracts as corrosion inhibitors for mild steel.

  1. Classification of Cytochrome P450 1A2 Inhibitors and Non-Inhibitors by Machine Learning Techniques

    DEFF Research Database (Denmark)

    Vasanthanathan, Poongavanam; Taboureau, Olivier; Oostenbrink, Chris

    2009-01-01

    of CYP1A2 inhibitors and non-inhibitors. Training and test sets consisted of about 400 and 7000 compounds, respectively. Various machine learning techniques, like binary QSAR, support vector machine (SVM), random forest, kappa nearest neighbors (kNN), and decision tree methods were used to develop...

  2. Dissociable effects of acetylcholinesterase inhibitors and phosphodiesterase type 5 inhibitors on object recognition memory: acquisition versus consolidation

    NARCIS (Netherlands)

    Prickaerts, L.; Sik, A.; Staay, van der F.J.; Vente, de J.; Blokland, A.

    2005-01-01

    Rationale Phosphodiesterase enzyme type 5 (PDE5) inhibitors and acetylcholinesterase (AChE) inhibitors have cognition-enhancing properties. However, it is not known whether these drug classes affect the same memory processes. Objective We investigated the memory-enhancing effects of the PDE5 inhibit

  3. Nonnucleoside Reverse-transcriptase Inhibitor- vs Ritonavir-boosted Protease Inhibitor-based Regimens for Initial Treatment of HIV Infection

    DEFF Research Database (Denmark)

    Borges, Álvaro H; Lundh, Andreas; Tendal, Britta;

    2016-01-01

    BACKGROUND:  Previous studies suggest that nonnucleoside reverse-transcriptase inhibitors (NNRTIs) cause faster virologic suppression, while ritonavir-boosted protease inhibitors (PI/r) recover more CD4 cells. However, individual trials have not been powered to compare clinical outcomes. METHODS:...

  4. Discovery of novel AKT inhibitors with enhanced anti-tumor effects in combination with the MEK inhibitor.

    Directory of Open Access Journals (Sweden)

    Melissa Dumble

    Full Text Available Tumor cells upregulate many cell signaling pathways, with AKT being one of the key kinases to be activated in a variety of malignancies. GSK2110183 and GSK2141795 are orally bioavailable, potent inhibitors of the AKT kinases that have progressed to human clinical studies. Both compounds are selective, ATP-competitive inhibitors of AKT 1, 2 and 3. Cells treated with either compound show decreased phosphorylation of several substrates downstream of AKT. Both compounds have desirable pharmaceutical properties and daily oral dosing results in a sustained inhibition of AKT activity as well as inhibition of tumor growth in several mouse tumor models of various histologic origins. Improved kinase selectivity was associated with reduced effects on glucose homeostasis as compared to previously reported ATP-competitive AKT kinase inhibitors. In a diverse cell line proliferation screen, AKT inhibitors showed increased potency in cell lines with an activated AKT pathway (via PI3K/PTEN mutation or loss while cell lines with activating mutations in the MAPK pathway (KRAS/BRAF were less sensitive to AKT inhibition. Further investigation in mouse models of KRAS driven pancreatic cancer confirmed that combining the AKT inhibitor, GSK2141795 with a MEK inhibitor (GSK2110212; trametinib resulted in an enhanced anti-tumor effect accompanied with greater reduction in phospho-S6 levels. Taken together these results support clinical evaluation of the AKT inhibitors in cancer, especially in combination with MEK inhibitor.

  5. Discovery of novel AKT inhibitors with enhanced anti-tumor effects in combination with the MEK inhibitor.

    Science.gov (United States)

    Dumble, Melissa; Crouthamel, Ming-Chih; Zhang, Shu-Yun; Schaber, Michael; Levy, Dana; Robell, Kimberly; Liu, Qi; Figueroa, David J; Minthorn, Elisabeth A; Seefeld, Mark A; Rouse, Meagan B; Rabindran, Sridhar K; Heerding, Dirk A; Kumar, Rakesh

    2014-01-01

    Tumor cells upregulate many cell signaling pathways, with AKT being one of the key kinases to be activated in a variety of malignancies. GSK2110183 and GSK2141795 are orally bioavailable, potent inhibitors of the AKT kinases that have progressed to human clinical studies. Both compounds are selective, ATP-competitive inhibitors of AKT 1, 2 and 3. Cells treated with either compound show decreased phosphorylation of several substrates downstream of AKT. Both compounds have desirable pharmaceutical properties and daily oral dosing results in a sustained inhibition of AKT activity as well as inhibition of tumor growth in several mouse tumor models of various histologic origins. Improved kinase selectivity was associated with reduced effects on glucose homeostasis as compared to previously reported ATP-competitive AKT kinase inhibitors. In a diverse cell line proliferation screen, AKT inhibitors showed increased potency in cell lines with an activated AKT pathway (via PI3K/PTEN mutation or loss) while cell lines with activating mutations in the MAPK pathway (KRAS/BRAF) were less sensitive to AKT inhibition. Further investigation in mouse models of KRAS driven pancreatic cancer confirmed that combining the AKT inhibitor, GSK2141795 with a MEK inhibitor (GSK2110212; trametinib) resulted in an enhanced anti-tumor effect accompanied with greater reduction in phospho-S6 levels. Taken together these results support clinical evaluation of the AKT inhibitors in cancer, especially in combination with MEK inhibitor.

  6. Proteolytic Cleavage of Various Human Serum Proteinase Inhibitors by Candida albicans Aspartic Proteinase

    OpenAIRE

    Tsushima, Hirofumi; MINE, Hiroko

    2008-01-01

    The secreted Candida albicans aspartic proteinase (SAP) is presumed to be one of the putative Candida virulence factors, while serum proteinase inhibitors depend on host defense mechanisms. We examined the interaction between SAP and serum proteinase inhibitors, such as C1-inhibitor, α2 plasmin inhibitor, and antithrombin III. SAP progressively inactivated plasmin inhibitory activity of C1-inhibitor and α2 plasmin inhibitor. It also inactivated thrombin inhibitory activity of antithrombin III...

  7. Trypsin-chymotrypsin inhibitors from Vigna mungo seeds.

    Science.gov (United States)

    Cheung, Allen H K; Wong, Jack H; Ng, T B

    2009-01-01

    Three trypsin-chymotrypsin inhibitors were isolated from seeds of the black gram (Vigna mungo) with a procedure that entailed cation exchange chromatography on SP-Sepharose, anion exchange chromatography on Q-Sepharose, ion exchange chromatography by fast protein liquid chromatography (FPLC) on Mono Q and Mono S, and gel filtration by FPLC on Superdex 75. Two of the trypsin-chymotrypsin inhibitors were adsorbed on the first four types of chromatographic media. All three inhibitors have a molecular mass of 16 kDa as judged by gel filtration and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The trypsin inhibitory activity of the inhibitors was attenuated in the presence of the reducing agent dithiothreitol. The remaining inhibitor was unadsorbed on SP-Sepharose but adsorbed on Q-Sepharose, Mono Q and Mono S. The protease inhibitors did not exert any inhibitory effect on hepatoma (Hep G2) and breast cancer (MCF 7) cells or antifungal action toward Botrytis cinerea, Fusarium oxysporum and Mycosphaerella arachidicola. Two of the inhibitors slightly inhibited the activity of HIV-1 reverse transcriptase, with an IC50 in the millimolar range.

  8. A novel method for screening the glutathione transferase inhibitors

    Directory of Open Access Journals (Sweden)

    Węgrzyn Grzegorz

    2009-03-01

    Full Text Available Abstract Background Glutathione transferases (GSTs belong to the family of Phase II detoxification enzymes. GSTs catalyze the conjugation of glutathione to different endogenous and exogenous electrophilic compounds. Over-expression of GSTs was demonstrated in a number of different human cancer cells. It has been found that the resistance to many anticancer chemotherapeutics is directly correlated with the over-expression of GSTs. Therefore, it appears to be important to find new GST inhibitors to prevent the resistance of cells to anticancer drugs. In order to search for glutathione transferase (GST inhibitors, a novel method was designed. Results Our results showed that two fragments of GST, named F1 peptide (GYWKIKGLV and F2 peptide (KWRNKKFELGLEFPNL, can significantly inhibit the GST activity. When these two fragments were compared with several known potent GST inhibitors, the order of inhibition efficiency (measured in reactions with 2,4-dinitrochlorobenzene (CDNB and glutathione as substrates was determined as follows: tannic acid > cibacron blue > F2 peptide > hematin > F1 peptide > ethacrynic acid. Moreover, the F1 peptide appeared to be a noncompetitive inhibitor of the GST-catalyzed reaction, while the F2 peptide was determined as a competitive inhibitor of this reaction. Conclusion It appears that the F2 peptide can be used as a new potent specific GST inhibitor. It is proposed that the novel method, described in this report, might be useful for screening the inhibitors of not only GST but also other enzymes.

  9. Fucoidans as Potential Inhibitors of HIV-1

    Science.gov (United States)

    Prokofjeva, Maria M.; Imbs, Tatyana I.; Shevchenko, Natalya M.; Spirin, Pavel V.; Horn, Stefan; Fehse, Boris; Zvyagintseva, Tatyana N.; Prassolov, Vladimir S.

    2013-01-01

    The antiviral activity of different structure fucoidans (α-l-fucans and galactofucans) was studied using two model viral systems based on a lentiviral vectors and a replication competent Moloney murine leukemia virus (Mo-MuLV). It was found that investigated fucoidans have no cytotoxic effects on Jurkat and SC-1cell at the concentration range of 0.001–100 µg/mL. Fucoidans with different efficiency suppressed transduction of Jurkat cell line by pseudo-HIV-1 particles carrying the envelope protein of HIV-1 and infection of SC-1 cells by Mo-MuLV. According to our data, all natural fucoidans can be considered as potential anti-HIV agents regardless of their carbohydrate backbone and degree of sulfating, since their activity is shown at low concentrations (0.001–0.05 µg/mL). High molecular weight fucoidans isolated from Saccharina cichorioides (1.3-α-l-fucan), and S. japonica (galactofucan) were the most effective inhibitors. PMID:23966033

  10. Aromatase inhibitors in stimulated IVF cycles

    Directory of Open Access Journals (Sweden)

    Tournaye Herman

    2011-06-01

    Full Text Available Abstract Aromatase inhibitors have been introduced as a new treatment modality that could challenge clomiphene citrate as an ovulation induction regiment in patients with PCOS. Although several randomized trials have been conducted regarding their use as ovulation induction agents, only few trials are available regarding their efficacy in IVF stimulated cycles. Current available evidence support that letrozole may have a promising role in stimulated IVF cycles, either when administered during the follicular phase for ovarian stimulation. Especially for women with poor ovarian response, letrozole appears to have the potential to increase clinical pregnancy rates when combined with gonadotropins, whereas at the same time reduces the total gonadotropin dose required for ovarian stimulation. However, given that in all of the trials letrozole has been administered in GnRH antagonist cycles, it is intriguing to test in the future how it may perform when used in GnRH agonist cycles. Finally administration of letrozole during luteal phase in IVF cycles offers another treatment modality for patients at high risk for OHSS taking into account that it drastically reduces estradiol levels

  11. Inhibitors of Ras-SOS Interactions.

    Science.gov (United States)

    Lu, Shaoyong; Jang, Hyunbum; Zhang, Jian; Nussinov, Ruth

    2016-04-19

    Activating Ras mutations are found in about 30 % of human cancers. Ras activation is regulated by guanine nucleotide exchange factors, such as the son of sevenless (SOS), which form protein-protein interactions (PPIs) with Ras and catalyze the exchange of GDP by GTP. This is the rate-limiting step in Ras activation. However, Ras surfaces lack any evident suitable pockets where a molecule might bind tightly, rendering Ras proteins still 'undruggable' for over 30 years. Among the alternative approaches is the design of inhibitors that target the Ras-SOS PPI interface, a strategy that is gaining increasing recognition for treating Ras mutant cancers. Herein we focus on data that has accumulated over the past few years pertaining to the design of small-molecule modulators or peptide mimetics aimed at the interface of the Ras-SOS PPI. We emphasize, however, that even if such Ras-SOS therapeutics are potent, drug resistance may emerge. To counteract this development, we propose "pathway drug cocktails", that is, drug combinations aimed at parallel (or compensatory) pathways. A repertoire of classified cancer, cell/tissue, and pathway/protein combinations would be beneficial toward this goal.

  12. Evolution of cyclic peptide protease inhibitors.

    Science.gov (United States)

    Young, Travis S; Young, Douglas D; Ahmad, Insha; Louis, John M; Benkovic, Stephen J; Schultz, Peter G

    2011-07-05

    We report a bacterial system for the evolution of cyclic peptides that makes use of an expanded set of amino acid building blocks. Orthogonal aminoacyl-tRNA synthetase/tRNA(CUA) pairs, together with a split intein system were used to biosynthesize a library of ribosomal peptides containing amino acids with unique structures and reactivities. This peptide library was subsequently used to evolve an inhibitor of HIV protease using a selection based on cellular viability. Two of three cyclic peptides isolated after two rounds of selection contained the keto amino acid p-benzoylphenylalanine (pBzF). The most potent peptide (G12: GIXVSL; X=pBzF) inhibited HIV protease through the formation of a covalent Schiff base adduct of the pBzF residue with the ε-amino group of Lys 14 on the protease. This result suggests that an expanded genetic code can confer an evolutionary advantage in response to selective pressure. Moreover, the combination of natural evolutionary processes with chemically biased building blocks provides another strategy for the generation of biologically active peptides using microbial systems.

  13. α-Glucosidase Inhibitors from Vauquelinia corymbosa

    Directory of Open Access Journals (Sweden)

    Laura Flores-Bocanegra

    2015-08-01

    Full Text Available The α-glucosidase inhibitory activity of an aqueous extract and compounds from the aerial parts of V. corymbosa was demonstrated with yeast and rat small intestinal α-glucosidases. The aqueous extract inhibited yeast α-glucosidase with a half maximal inhibitory concentration (IC50 of 28.6 μg/mL. Bioassay-guided fractionation of the extract led to the isolation of several compounds, including one cyanogenic glycoside [prunasin (1], five flavonoids [(−-epi-catechin (2, hyperoside (3, isoquercetin (4, quercitrin (5 and quercetin-3-O-(6′′-benzoyl-β-galactoside (6] and two simple aromatic compounds [picein (7 and methylarbutin (8]. The most active compound was 6 with IC50 values of 30 μM in the case of yeast α-glucosidase, and 437 μM in the case of the mammalian enzyme. According to the kinetic analyses performed with rat and yeast enzymes, this compound behaved as mixed-type inhibitor; the calculated inhibition constants (Ki were 212 and 50 μM, respectively. Molecular docking analyses with yeast and mammalian α-glucosidases revealed that compound 6 bind differently to these enzymes. Altogether, the results of this work suggest that preparations of V. corymbosa might delay glucose absorption in vivo.

  14. Acquired Factor VIII Inhibitors: Three Cases

    Directory of Open Access Journals (Sweden)

    Tay Za Kyaw

    2013-03-01

    Full Text Available Acquired hemophilia A is a rare, but devastating bleeding disorder caused by spontaneous development of autoantibodies directed against coagulation factor VIII. In 40%-50% of patients it is associated with such conditions as the postpartum period, malignancy, use of medications, and autoimmune diseases; however, its cause is unknown in most cases. Acquired hemophilia A should be suspected in patients that present with a coagulation abnormality, and a negative personal and family history of bleeding. Herein we report 3 patients with acquired hemophilia A that had different underlying pathologies, clinical presentations, and therapeutic responses. Factor VIII inhibitor formation in case 1 occurred 6 months after giving birth; underlying disorders were not identified in cases 2 or 3. The bleeding phenotype in these patients’ ranged from no bleeding tendency with isolated prolongation of APTT (activated partial thromboplastin time to severe intramuscular hematoma and hemarthrosis necessitating recombinant activated factor VII infusion and blood components transfusion. Variable responses to immunosuppressive treatment were also observed.

  15. Small molecule phagocytosis inhibitors for immune cytopenias.

    Science.gov (United States)

    Neschadim, Anton; Kotra, Lakshmi P; Branch, Donald R

    2016-08-01

    Immune cytopenias are conditions characterized by low blood cell counts, such as platelets in immune thrombocytopenia (ITP) and red blood cells in autoimmune hemolytic anemia (AIHA). Chronic ITP affects approximately 4 in 100,000 adults annually while AIHA is much less common. Extravascular phagocytosis and massive destruction of autoantibody-opsonized blood cells by macrophages in the spleen and liver are the hallmark of these conditions. Current treatment modalities for ITP and AIHA include the first-line use of corticosteroids; whereas, IVIg shows efficacy in ITP but not AIHA. One main mechanism of action by which IVIg treatment leads to the reduction in platelet destruction rates in ITP is thought to involve Fcγ receptor (FcγR) blockade, ultimately leading to the inhibition of extravascular platelet phagocytosis. IVIg, which is manufactured from the human plasma of thousands of donors, is a limited resource, and alternative treatments, particularly those based on bioavailable small molecules, are needed. In this review, we overview the pathophysiology of ITP, the role of Fcγ receptors, and the mechanisms of action of IVIg in treating ITP, and outline the efforts and progress towards developing novel, first-in-class inhibitors of phagocytosis as synthetic, small molecule substitutes for IVIg in ITP and other conditions where the pathobiology of the disease involves phagocytosis.

  16. The Azadirachtins: potent insect growth inhibitors

    Directory of Open Access Journals (Sweden)

    Heinz Rembold

    1987-01-01

    Full Text Available In the course of their coevolution with insects, plants have learnt to protect themselves by chemical means. Semiochemical act as antifeedants or deterrents, others by disrupting growth and development. By use of the Epilachna varivestis bioassay we isolated from Azadirachta indica seed a group of triterpenoids which interfee with larval growth and development in ppm range. Main components are the azadirachtins A and B with identical biological activity. Various other azadirachtins were obtained, either as minor seed components or by chemical modification of the naturally occuring compounds. Structure vs. activity relation studies enabled us to postulate a basic structural element that should still be biologically active and with much simpler chemical structure than natural compounds. What underlies the biological activity of these insect growth inhibitors? Their interference with the hormonal regulation of development and reproduction has been studied in Locusta migratoria and Rhodnius prolixus. In addition, tritiated dihydroazadirachtin A was used. With this approach, a precise correlation between administered dose, resulting effects, and retention of the compound was established. The azadirachtins either interrupt, delay, or deviate whole developmental programs. Results from these studies provide another chemical probe for studies in insect endocrinology and physiology.

  17. Antiplatelet drug interactions with proton pump inhibitors

    Science.gov (United States)

    Scott, Stuart A; Obeng, Aniwaa Owusu; Hulot, Jean-Sébastien

    2014-01-01

    Introduction Non-aspirin antiplatelet agents (e.g., clopidogrel, prasugrel, ticagrelor) are commonly prescribed for the prevention of recurrent cardiovascular events among patients with acute coronary syndromes (ACS) and/or those undergoing percutaneous coronary intervention (PCI). In addition, combination therapy with proton pump inhibitors (PPIs) is often recommended to attenuate gastrointestinal bleeding risk, particularly during dual antiplatelet therapy (DAPT) with clopidogrel and aspirin. Importantly, a pharmacological interaction between clopidogrel and some PPIs has been proposed based on mutual CYP450-dependent metabolism, but available evidence is inconsistent. Areas covered This article provides an overview of the currently approved antiplatelet agents and PPIs, including their metabolic pathways. Additionally, the CYP450 isoenzyme at the center of the drug interaction, CYP2C19, is described in detail, and the available evidence on both the potential pharmacological interaction and influence on clinical outcomes are summarized and evaluated. Expert opinion Although concomitant DAPT and PPI use reduces clopidogrel active metabolite levels and ex vivo-measured platelet inhibition, the influence of the drug interaction on clinical outcomes has been conflicting and largely reported from non-randomized observational studies. Despite this inconsistency, a clinically important interaction cannot be definitively excluded, particularly among patient subgroups with higher overall cardiovascular risk and potentially among CYP2C19 loss-of-function allele carriers. PMID:24205916

  18. Ceruloplasmin is an endogenous inhibitor of myeloperoxidase.

    Science.gov (United States)

    Chapman, Anna L P; Mocatta, Tessa J; Shiva, Sruti; Seidel, Antonia; Chen, Brian; Khalilova, Irada; Paumann-Page, Martina E; Jameson, Guy N L; Winterbourn, Christine C; Kettle, Anthony J

    2013-03-01

    Myeloperoxidase is a neutrophil enzyme that promotes oxidative stress in numerous inflammatory pathologies. It uses hydrogen peroxide to catalyze the production of strong oxidants including chlorine bleach and free radicals. A physiological defense against the inappropriate action of this enzyme has yet to be identified. We found that myeloperoxidase oxidized 75% of the ascorbate in plasma from ceruloplasmin knock-out mice, but there was no significant loss in plasma from wild type animals. When myeloperoxidase was added to human plasma it became bound to other proteins and was reversibly inhibited. Ceruloplasmin was the predominant protein associated with myeloperoxidase. When the purified proteins were mixed, they became strongly but reversibly associated. Ceruloplasmin was a potent inhibitor of purified myeloperoxidase, inhibiting production of hypochlorous acid by 50% at 25 nm. Ceruloplasmin rapidly reduced Compound I, the Fe(V) redox intermediate of myeloperoxidase, to Compound II, which has Fe(IV) in its heme prosthetic groups. It also prevented the fast reduction of Compound II by tyrosine. In the presence of chloride and hydrogen peroxide, ceruloplasmin converted myeloperoxidase to Compound II and slowed its conversion back to the ferric enzyme. Collectively, our results indicate that ceruloplasmin inhibits myeloperoxidase by reducing Compound I and then trapping the enzyme as inactive Compound II. We propose that ceruloplasmin should provide a protective shield against inadvertent oxidant production by myeloperoxidase during inflammation.

  19. Cystatin protease inhibitors and immune functions.

    Science.gov (United States)

    Zavasnik-Bergant, Tina

    2008-05-01

    Cystatins are natural tight-binding reversible inhibitors of cysteine proteases. They are wide spread in all living organisms (mammals, nematodes, arthropods etc.) and are involved in various biological processes where they regulate normal proteolysis and also take part in disease pathology. Many cystatins show changes in expression and/or localization, as well as changes in secretion, following certain stimuli acting on immune cells. In immune cells, cystatins interfere with antigen processing and presentation, phagocytosis, expression of cytokines and nitric oxide and these ways modify the immune response. Further, it has been suggested that cystatin-type molecules secreted from parasites down-modulate the host immune response. Precise understanding of the regulatory roles on proteolytic enzymes of endogenous and exogenous cystatins, such as those from parasites, will provide us with valuable insight into how immune response could be modulated to treat a specific disease. This review covers some specific functions of individual cystatins, with a particular focus on the relevance of cystatins to the immune response.

  20. Antimetastatic Integrin as Inhibitors of Snake Venoms

    Directory of Open Access Journals (Sweden)

    Felix Rosenow

    2008-02-01

    Full Text Available Metastasis comprises several subsequent steps including local invasion and intravasation at the primary site, then their adhesion/arrest within the vessels of host organs followed by their extravasation and infiltration into the target organ stroma. In contrast to previous studies which have used aspartate-glycine-arginine (RGD peptides and antibodies against integrins, we used rare collagen- and laminin-antagonizing integrin inhibitors from snake venoms to analyze the colonization of the liver by tumor cells both by intravital microscopy and in vitro. Adhesion of liver-targeting tumor cells to the sinusoid wall components, laminin-1 and fibronectin, is essential for liver metastasis. This step is inhibited by lebein-1, but not by lebein-2 or rhodocetin. Both lebeins from the Vipera lebetina venom block integrin interactions with laminins in an RGD-independent manner. Rhodocetin is an antagonist of α2β1 integrin, a collagen receptor on many tumor cells. Subsequent to tumor cell arrest, extravasation into the liver stroma and micrometastasis are efficiently delayed by rhodocetin. This underlines the importance of α2β1 integrin interaction with the reticular collagen I-rich fibers in liver stroma. Antagonists of laminin- and collagen-binding integrins could be valuable tools to individually block the direct interactions of tumor cells with distinct matrix components of the Disse space, thereby reducing liver metastasis.

  1. Inhibitor of apoptosis proteins and apoptosis

    Institute of Scientific and Technical Information of China (English)

    Yunbo Wei; Tingjun Fan; Miaomiao Yu

    2008-01-01

    Apoptosis is a physiological cell death process that plays a critical role in development, homeostasis, and immune defense of multicellular animals. Inhibitor of apoptosis proteins (IAPs) constitute a family of proteins that possess between one and three baculovirus IAP repeats. Some of them also have a really interesting new gene finger domain, and can prevent cell death by binding and inhibiting active caspases, but are regulated by IAP antagonists. Some evidence also indicates that IAP can modulate the cell cycle and signal transduction. The three main factors, IAPs, IAP antagonists, and caspases, are involved in regulating the progress of apoptosis in many species. Many studies and assumptions have been focused on the anfractuous interactions between these three main factors to explore their real functional model in order to develop potential anticancer drugs.In this review, we describe the classification, molecular structures, and properties of IAPs and discuss the mechanisms of apoptosis. We also discuss the promising significance of clinical applications of IAPs in the diagnosis and treatment of malignancy.

  2. Multikinase inhibitors use in differentiated thyroid carcinoma

    Directory of Open Access Journals (Sweden)

    Jasim S

    2014-12-01

    Full Text Available Sina Jasim,1,* Levent Ozsari,2,* Mouhammed Amir Habra2 1Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN, USA; 2Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA *These authors contributed equally in this work Abstract: Thyroid cancer is the most common endocrine malignancy, and its incidence is increasing. Standard therapy for most patients with localized differentiated thyroid cancer (DTC includes surgery, radioactive iodine, and thyroid hormone replacement. A minority of thyroid cancer patients requires systemic therapy for metastatic disease. Patients with metastatic DTC do not usually benefit from traditional cytotoxic chemotherapy. In this review, we describe newly developed small-molecule tyrosine kinase inhibitors (TKIs that are being actively tested and used in the management of advanced thyroid cancer. The use of TKIs as a form of molecular targeted therapy is evolving based on understanding of the pathways involved in DTC. Disrupting tumor vascular supply by targeting vascular endothelial growth factor receptor signaling is the most commonly used approach to treat advanced/metastatic DTC. Other mechanisms include targeting BRAF, MAPK/ERK kinase, or mammalian target of rapamycin signaling. Although TKIs appear to have superior efficacy compared to cytotoxic chemotherapy, they can cause substantial adverse effects; symptomatic management of adverse effects, dose adjustment, or cessation of therapy may be required. Keywords: differentiated thyroid cancer, progression-free survival, adverse effects, targeted therapy, sorafenib, lenvatinib

  3. Progeria, the nucleolus and farnesyltransferase inhibitors.

    Science.gov (United States)

    Mehta, Ishita S; Bridger, Joanna M; Kill, Ian R

    2010-02-01

    HGPS (Hutchinson-Gilford progeria syndrome) is a rare genetic disease affecting children causing them to age and die prematurely. The disease is typically due to a point mutation in the coding sequence for the nuclear intermediate-type filament protein lamin A and gives rise to a dominant-negative splice variant named progerin. Accumulation of progerin within nuclei causes disruption to nuclear structure, causes and premature replicative senescence and increases apoptosis. Now it appears that accumulation of progerin may have more widespread effects than previously thought since the demonstration that the presence and distribution of some nucleolar proteins are also adversely affected in progeria cells. One of the major breakthroughs both in the lamin field and for this syndrome is that many of the cellular defects observed in HGPS patient cells and model systems can be restored after treatment with a class of compounds known as FTIs (farnesyltransferase inhibitors). Indeed, it is demonstrated that FTI-277 is able to completely restore nucleolar antigen localization in treated progeria cells. This is encouraging news for the HGPS patients who are currently undergoing clinical trials with FTI treatment.

  4. Metal-based antimicrobial protease inhibitors.

    Science.gov (United States)

    Kellett, A; Prisecaru, A; Slator, C; Molphy, Z; McCann, M

    2013-01-01

    Limitations associated with the production cost, metabolic instability, side-effects, resistance and poor pharmacokinetics of organic protease inhibitors (PIs), which form an essential component of the front line HAART treatment for HIV, have fuelled efforts into finding novel, transition metal-based alternatives. Some of the attractive features of metalbased therapeutics include synthetic simplicity, solubility control, redox capability, expansion of coordination number and topography matching of the complex to the protein's active site. Building asymmetry into the complex, which may offer better discrimination between host and rogue cell, can readily be achieved through coordination of chiral ligands to the metal centre. Although the scope of this review has been limited to metal-based agents that have been reported to bind/inhibit HIV-1 and parasitic proteases, some desirables, such as high activity, low dosage, minimal toxicity, crossinhibition, unique binding modes and selectivity, have already been delivered. The variability of the d-block metals, coupled with the availability of designer organic ligands, augers well for the future development of clinical metallo-drugs for deployment against protease-associated, fatal diseases.

  5. Suppression of Coronavirus Replication by Cyclophilin Inhibitors

    Directory of Open Access Journals (Sweden)

    Takashi Sasaki

    2013-05-01

    Full Text Available Coronaviruses infect a variety of mammalian and avian species and cause serious diseases in humans, cats, mice, and birds in the form of severe acute respiratory syndrome (SARS, feline infectious peritonitis (FIP, mouse hepatitis, and avian infectious bronchitis, respectively. No effective vaccine or treatment has been developed for SARS-coronavirus or FIP virus, both of which cause lethal diseases. It has been reported that a cyclophilin inhibitor, cyclosporin A (CsA, could inhibit the replication of coronaviruses. CsA is a well-known immunosuppressive drug that binds to cellular cyclophilins to inhibit calcineurin, a calcium-calmodulin-activated serine/threonine-specific phosphatase. The inhibition of calcineurin blocks the translocation of nuclear factor of activated T cells from the cytosol into the nucleus, thus preventing the transcription of genes encoding cytokines such as interleukin-2. Cyclophilins are peptidyl-prolyl isomerases with physiological functions that have been described for many years to include chaperone and foldase activities. Also, many viruses require cyclophilins for replication; these include human immunodeficiency virus, vesicular stomatitis virus, and hepatitis C virus. However, the molecular mechanisms leading to the suppression of viral replication differ for different viruses. This review describes the suppressive effects of CsA on coronavirus replication.

  6. The dawn of hedgehog inhibitors: Vismodegib

    Directory of Open Access Journals (Sweden)

    Selvarajan Sandhiya

    2013-01-01

    Full Text Available Cancer, one of the leading causes of death worldwide is estimated to increase to approximately 13.1 million by 2030. This has amplified the research in oncology towards the exploration of novel targets. Recently there has been lots of interest regarding the hedgehog (Hh pathway, which plays a significant role in the development of organs and tissues during embryonic and postnatal periods. In a normal person, the Hh signaling pathway is under inhibition and gets activated upon the binding of Hh ligand to a transmembrane receptor called Patched (PTCH1 thus allowing the transmembrane protein, smoothened (SMO to transfer signals through various proteins. One of the newer drugs namely vismodegib involves the inhibition of Hh pathway and has shown promising results in the treatment of advanced basal-cell carcinoma as well as medulloblastoma. It has been granted approval by US Food and Drug Administration′s (US FDA priority review program on January 30, 2012 for the treatment of advanced basal-cell carcinoma. The drug is also being evaluated in malignancies like medulloblastoma, pancreatic cancer, multiple myeloma, chondrosarcoma and prostate cancer. Moreover various Hh inhibitors namely LDE 225, saridegib, BMS 833923, LEQ 506, PF- 04449913 and TAK-441 are also undergoing phase I and II trials for different neoplasms. Hence this review will describe briefly the Hh pathway and the novel drug vismodegib.

  7. Fucoidans as Potential Inhibitors of HIV-1

    Directory of Open Access Journals (Sweden)

    Vladimir S. Prassolov

    2013-08-01

    Full Text Available The antiviral activity of different structure fucoidans (α-l-fucans and galactofucans was studied using two model viral systems based on a lentiviral vectors and a replication competent Moloney murine leukemia virus (Mo-MuLV. It was found that investigated fucoidans have no cytotoxic effects on Jurkat and SC-1cell at the concentration range of 0.001–100 µg/mL. Fucoidans with different efficiency suppressed transduction of Jurkat cell line by pseudo-HIV-1 particles carrying the envelope protein of HIV-1 and infection of SC-1 cells by Mo-MuLV. According to our data, all natural fucoidans can be considered as potential anti-HIV agents regardless of their carbohydrate backbone and degree of sulfating, since their activity is shown at low concentrations (0.001–0.05 µg/mL. High molecular weight fucoidans isolated from Saccharina cichorioides (1.3-α-l-fucan, and S. japonica (galactofucan were the most effective inhibitors.

  8. Fucoidans as potential inhibitors of HIV-1.

    Science.gov (United States)

    Prokofjeva, Maria M; Imbs, Tatyana I; Shevchenko, Natalya M; Spirin, Pavel V; Horn, Stefan; Fehse, Boris; Zvyagintseva, Tatyana N; Prassolov, Vladimir S

    2013-08-19

    The antiviral activity of different structure fucoidans (α-l-fucans and galactofucans) was studied using two model viral systems based on a lentiviral vectors and a replication competent Moloney murine leukemia virus (Mo-MuLV). It was found that investigated fucoidans have no cytotoxic effects on Jurkat and SC-1cell at the concentration range of 0.001-100 µg/mL. Fucoidans with different efficiency suppressed transduction of Jurkat cell line by pseudo-HIV-1 particles carrying the envelope protein of HIV-1 and infection of SC-1 cells by Mo-MuLV. According to our data, all natural fucoidans can be considered as potential anti-HIV agents regardless of their carbohydrate backbone and degree of sulfating, since their activity is shown at low concentrations (0.001-0.05 µg/mL). High molecular weight fucoidans isolated from Saccharina cichorioides (1.3-α-l-fucan), and S. japonica (galactofucan) were the most effective inhibitors.

  9. Corrosion inhibitor mechanisms on reinforcing steel in Portland cement pastes

    Science.gov (United States)

    Martin, Farrel James

    2001-07-01

    The mechanisms of corrosion inhibitor interaction with reinforcing steel are investigated in the present work, with particular emphasis on effects associated with corrosion inhibitors admixed into Portland cement paste. The principal objective in reinforcing steel corrosion inhibition for Portland cement concrete is observed to be preservation of the naturally passive steel surface condition established by the alkaline environment. Introduction of chloride ions to the steel surface accelerates damage to the passive film. Excessive damage to the passive film leads to loss of passivity and a destabilization of conditions that facilitate repair of the passive film. Passive film preservation in presence of chloride ions is achieved either through stabilization of the passive film or by modification of the chemical environment near the steel surface. Availability of inhibitors to the steel surface and their tendency to stabilize passive film defects are observed to be of critical importance. Availability of admixed corrosion inhibitors to the passive film is affected by binding of inhibitors during cement paste hydration. It is determined that pore solution concentrations of inorganic admixed inhibitors tend to be lower than the admixed concentration, while pore solution concentrations of organic admixed inhibitors tend to be higher than the admixed concentration. A fundamental difference of inhibitor function is observed between film-forming and defect stabilizing corrosion inhibitors. Experiments are conducted using coupons of reinforcing steel that are exposed to environments simulating chloride-contaminated Portland cement concrete. A study of the steel/cement paste interface is also performed, and compounds forming at this interface are identified using X-Ray diffraction.

  10. Discovery of potent imidazole and cyanophenyl containing farnesyltransferase inhibitors with improved oral bioavailability.

    Science.gov (United States)

    Tong, Yunsong; Lin, Nan-Horng; Wang, Le; Hasvold, Lisa; Wang, Weibo; Leonard, Nicholas; Li, Tongmei; Li, Qun; Cohen, Jerry; Gu, Wen-Zhen; Zhang, Haiying; Stoll, Vincent; Bauch, Joy; Marsh, Kennan; Rosenberg, Saul H; Sham, Hing L

    2003-05-05

    A pyridyl moiety was introduced into a previously developed series of farnesyltransferase inhibitors containing imidazole and cyanophenyl (such as 4), resulting in potent inhibitors with improved pharmacokinetics.

  11. Acalabrutinib (ACP-196: a selective second-generation BTK inhibitor

    Directory of Open Access Journals (Sweden)

    Jingjing Wu

    2016-03-01

    Full Text Available Abstract More and more targeted agents become available for B cell malignancies with increasing precision and potency. The first-in-class Bruton’s tyrosine kinase (BTK inhibitor, ibrutinib, has been in clinical use for the treatment of chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom’s macroglobulinemia. More selective BTK inhibitors (ACP-196, ONO/GS-4059, BGB-3111, CC-292 are being explored. Acalabrutinib (ACP-196 is a novel irreversible second-generation BTK inhibitor that was shown to be more potent and selective than ibrutinib. This review summarized the preclinical research and clinical data of acalabrutinib.

  12. Measurement of enzyme kinetics and inhibitor constants using enthalpy arrays.

    Science.gov (United States)

    Recht, Michael I; Torres, Frank E; De Bruyker, Dirk; Bell, Alan G; Klumpp, Martin; Bruce, Richard H

    2009-05-15

    Enthalpy arrays enable label-free, solution-based calorimetric detection of molecular interactions in a 96-detector array format. Compared with conventional calorimetry, enthalpy arrays achieve a significant reduction of sample volume and measurement time through the combination of the small size of the detectors and ability to perform measurements in parallel. The current capabilities of the technology for studying enzyme-catalyzed reactions are demonstrated by determining the kinetic parameters for reactions with three model enzymes. In addition, the technology has been used with two classes of enzymes to determine accurate inhibitor constants for competitive inhibitors from measurements at a single inhibitor concentration.

  13. The safety of proton pump inhibitors in pregnancy

    DEFF Research Database (Denmark)

    Nielsen, Gunnar Lauge; Sørensen, Henrik Toft; Thulstrup, Ane Marie;

    1999-01-01

    on The Pharmaco-Epidemiological Prescription Database of North Jutland and the Danish Hospital Discharge Registry. RESULTS: Three babies with malformations were found among 38 women exposed to proton pump inhibitors from 30 days before conception to the end of the first trimester. No cases of stillbirth were...... birth weight or number of preterm deliveries in pregnancies exposed to proton pump inhibitors. However, further monitoring is warranted in order to establish or rule out a potential association between the use of proton pump inhibitors and increased risk of either cardiac malformations or preterm birth....

  14. Metalloprotein Inhibitors for the Treatment of Human Diseases.

    Science.gov (United States)

    Yang, Yang; Hu, Xue-Qin; Li, Qing-Shan; Zhang, Xing-Xing; Ruan, Ban-Feng; Xu, Jun; Liao, Chenzhong

    2016-01-01

    Metalloproteins have attracted momentous attentions for the treatment of many human diseases, including cancer, HIV, hypertension, etc. This article reviews the progresses that have been made in the field of drug development of metalloprotein inhibitors, putting emphasis on the targets of carbonic anhydrase, histone deacetylase, angiotensin converting enzyme, and HIV-1 integrase. Many other important metalloproteins are also briefly discussed. The binding and coordination modes of different marketed metalloprotein inhibitors are stated, providing insights to design novel metal binding groups and further novel inhibitors for metalloproteins.

  15. Inhibitors of snake venoms and development of new therapeutics.

    Science.gov (United States)

    Sánchez, Elda E; Rodríguez-Acosta, Alexis

    2008-01-01

    Natural inhibitors of snake venoms play a significant role in the ability to neutralize the degradation effects induced by venom toxins. It has been known for many years that animal sera and some plant extracts are competent in neutralizing snake venoms. The purpose of this review is to highlight the recent work that has been accomplished with natural inhibitors of snake venoms as well as revisiting the past research including those found in plants. The biomedical value of these natural inhibitors can lead to the development of new therapeutics for an assortment of diseases as well as contributing to efficient antivenoms for the treatment of ophidic accidents.

  16. Structure based design of 11β-HSD1 inhibitors.

    Science.gov (United States)

    Singh, Suresh; Tice, Colin

    2010-11-01

    Controlling elevated tissue-specific levels of cortisol may provide a novel therapeutic approach for treating metabolic syndrome. This concept has spurred large scale medicinal chemistry efforts in the pharmaceutical industry for the design of 11β-HSD1 inhibitors. High resolution X-ray crystal structures of inhibitors in complex with the enzyme have facilitated the structure-based design of diverse classes of molecules. A summary of binding modes, trends in structure-activity relationships, and the pharmacodynamic data of inhibitors from each class is presented.

  17. Natural plant enzyme inhibitors. Characterization of an unusual alpha-amylase/trypsin inhibitor from ragi (Eleusine coracana Geartn.).

    Science.gov (United States)

    Shivaraj, B; Pattabiraman, T N

    1981-01-01

    An inhibitor I-1, capable of acting on both alpha-amylase and trypsin, was purified to homogeneity from ragi (finger-millet) grains. The factor was found to be stable to heat treatment at 100 degrees C for 1 h in the presence of NaCl and also was stable over the wide pH range 1-10. Pepsin and Pronase treatment of inhibitor I-1 resulted in gradual loss of both the inhibitory activities. Formation of trypsin-inhibitor I-1 complex, amylase-inhibitor I-1 complex and trypsin-inhibitor I-1-amylase trimer complex was demonstrated by chromatography on a Bio-Gel P-200 column. This indicated that the inhibitor is 'double-headed' in nature. The inhibitor was retained on a trypsin-Sepharose 4B column at pH 7.0. Elution at acidic pH resulted in almost complete recovery of amylase-inhibitory and trypsin-inhibitory activities. alpha-Amylase was retained on a trypsin-Sepharose column to which inhibitor I-1 was bound, but not on trypsin-Sepharose alone. Modification of amino groups of the inhibitor with 2,4,6-trinitrobenzenesulphonic acid resulted in complete loss of amylase-inhibitory activity but only 40% loss in antitryptic activity. Modification of arginine residues by cyclohexane-1,2-dione led to 85% loss of antitryptic activity after 5 h, but no effect on amylase-inhibitory activity. The results show that a single bifunctional protein factor is responsible for both amylase-inhibitory and trypsin-inhibitory activities with two different reactive sites.

  18. Chelation: a fundamental mechanism of action of AGE inhibitors, AGE breakers, and other inhibitors of diabetes complications.

    Science.gov (United States)

    Nagai, Ryoji; Murray, David B; Metz, Thomas O; Baynes, John W

    2012-03-01

    This article outlines evidence that advanced glycation end product (AGE) inhibitors and breakers act primarily as chelators, inhibiting metal-catalyzed oxidation reactions that catalyze AGE formation. We then present evidence that chelation is the most likely mechanism by which ACE inhibitors, angiotensin receptor blockers, and aldose reductase inhibitors inhibit AGE formation in diabetes. Finally, we note several recent studies demonstrating therapeutic benefits of chelators for diabetic cardiovascular and renal disease. We conclude that chronic, low-dose chelation therapy deserves serious consideration as a clinical tool for prevention and treatment of diabetes complications.

  19. Antitumor Activity of Cytotoxic Cyclooxygenase-2 Inhibitors

    Science.gov (United States)

    Uddin, Md. Jashim; Crews, Brenda C.; Xu, Shu; Ghebreselasie, Kebreab; Daniel, Cristina K.; Kingsley, Philip J.; Banerjee, Surajit; Marnett, Lawrence J.

    2017-01-01

    Targeted delivery of chemotherapeutic agents to tumors has been explored as a means to increase the selectivity and potency of cytotoxicity. Most efforts in this area have exploited the molecular recognition of proteins highly expressed on the surface of cancer cells followed by internalization. A related approach that has received less attention is the targeting of intracellular proteins by ligands conjugated to anti-cancer drugs. An attractive target for this approach is the enzyme cyclooxygenase-2 (COX-2), which is highly expressed in a range of malignant tumors. Herein, we describe the synthesis and evaluation of a series of chemotherapeutic agents targeted to COX-2 by conjugation to indomethacin. Detailed characterization of compound 12, a conjugate of indomethacin with podophyllotoxin, revealed highly potent and selective COX-2 inhibition in vitro and in intact cells. Kinetics and X-ray crystallographic studies demonstrated that compound 12 is a slow, tight-binding inhibitor that likely binds to COX-2’s allosteric site with its indomethacin moiety in a conformation similar to that of indomethacin. Compound 12 exhibited cytotoxicity in cell culture similar to that of podophyllotoxin with no evidence of COX-2-dependent selectivity. However, in vivo, compound 12 accumulated selectively in and more effectively inhibited the growth of a COX-2-expressing xenograft compared to a xenograft that did not express COX-2. Compound 12, which we have named chemocoxib A, provides proof-of-concept for the in vivo targeting of chemotherapeutic agents to COX-2, but suggests that COX-2-dependent selectivity may not be evident in cell culture-based assays. PMID:27588346

  20. XIMELAGATRAN: A NEW DIRECT THROMBIN INHIBITOR

    Directory of Open Access Journals (Sweden)

    Mehta Hiren R

    2011-04-01

    Full Text Available Venous thromboembolism is a serious illness that affects patient morbidity and mortality and presents a significant management challenge to healthcare providers world-wide. Despite major achievements in the significant reduction of thromboembolic complications, the most common therapies currently used for prevention and treatment of venous thromboembolism – heparins and vitamin K antagonists such as warfarin – have several limitations. Warfarin sodium is an effective oral anticoagulant drug. However, warfarin has a narrow therapeutic window with significant risks of hemorrhage at therapeutic concentrations. Dosing is difficult and requires frequent monitoring. New oral anticoagulant agents are required to improve current anticoagulant therapy. Furthermore, while warfarin is effective in venous disease, it does not provide more than 60% risk reduction compared with placebo in venous thrombosis prophylaxis and considerably lower risk reduction in terms of arterial thrombosis. Unlike warfarin and heparin, these direct thrombin inhibitors are able to inhibit fibrin-bound thrombin and so produce more effective inhibition of coagulation. Importantly, some members of this class of drugs have been developed for oral administration. Ximelagatran is an oral pro-drug of melagatran, a synthetic small peptidomimetic with direct thrombin inhibitory actions and anticoagulant activity. As an oral agent, ximelagatran has a number of desirable properties including a rapid onset of action, fixed dosing, stable absorption, apparent low potential for medication interactions, and no requirement for monitoring of drug levels or dose adjustment. It has a short plasma elimination half-life of about 4 hours in cases of unexpected hemorrhage or need for reversal.

  1. Do proton pump inhibitors decrease calcium absorption?

    Science.gov (United States)

    Hansen, Karen E; Jones, Andrea N; Lindstrom, Mary J; Davis, Lisa A; Ziegler, Toni E; Penniston, Kristina L; Alvig, Amy L; Shafer, Martin M

    2010-12-01

    Proton pump inhibitors (PPIs) increase osteoporotic fracture risk presumably via hypochlorhydria and consequent reduced fractional calcium absorption (FCA). Existing studies provide conflicting information regarding the direct effects of PPIs on FCA. We evaluated the effect of PPI therapy on FCA. We recruited women at least 5 years past menopause who were not taking acid suppressants. Participants underwent three 24-hour inpatient FCA studies using the dual stable isotope method. Two FCA studies were performed 1 month apart to establish baseline calcium absorption. The third study occurred after taking omeprazole (40 mg/day) for 30 days. Each participant consumed the same foods during all FCA studies; study meals replicated subjects' dietary habits based on 7-day diet diaries. Twenty-one postmenopausal women ages 58 ± 7 years (mean ± SD) completed all study visits. Seventeen women were white, and 2 each were black and Hispanic. FCA (mean ± SD) was 20% ± 10% at visit 1, 18% ± 10% at visit 2, and 23% ± 10% following 30 ± 3 days of daily omeprazole (p = .07, ANOVA). Multiple linear regression revealed that age, gastric pH, serum omeprazole levels, adherence to omeprazole, and 25-hydroxyvitamin D levels were unrelated to changes in FCA between study visits 2 and 3. The 1,25-dihydroxyvitamin D(3) level at visit 2 was the only variable (p = .049) associated with the change in FCA between visits 2 and 3. PPI-associated hypochlorhydria does not decrease FCA following 30 days of continuous use. Future studies should focus on identifying mechanisms by which PPIs increase the risk of osteoporotic fracture.

  2. ETORICOXIB IS A NEW SELECTIVE CYCLOOXYGENASE-2 INHIBITOR

    Directory of Open Access Journals (Sweden)

    A E Karateev

    2009-01-01

    Full Text Available The paper provides the clinical characteristics of etoricoxib (Arcoxia, a new selective cyclooxygenase-2 inhibitor having unique properties, which permits it to be distinguished among other nonsteroidal anti-inflammatory agents.

  3. Committee Opinion No. 663 Summary: Aromatase Inhibitors in Gynecologic Practice.

    Science.gov (United States)

    2016-06-01

    Aromatase inhibitors have been used for the treatment of breast cancer, ovulation induction, endometriosis, and other estrogen-modulated conditions. For women with breast cancer, bone mineral density screening is recommended with long-term aromatase inhibitor use because of risk of osteoporosis due to estrogen deficiency. Based on long-term adverse effects and complication safety data, when compared with tamoxifen, aromatase inhibitors are associated with a reduced incidence of thrombosis, endometrial cancer, and vaginal bleeding. For women with polycystic ovary syndrome and a body mass index greater than 30, letrozole should be considered as first-line therapy for ovulation induction because of the increased live birth rate compared with clomiphene citrate. Lifestyle changes that result in weight loss should be strongly encouraged. Aromatase inhibitors are a promising therapeutic option that may be helpful for the management of endometriosis-associated pain in combination therapy with progestins.

  4. Committee Opinion No. 663: Aromatase Inhibitors in Gynecologic Practice.

    Science.gov (United States)

    2016-06-01

    Aromatase inhibitors have been used for the treatment of breast cancer, ovulation induction, endometriosis, and other estrogen-modulated conditions. For women with breast cancer, bone mineral density screening is recommended with long-term aromatase inhibitor use because of risk of osteoporosis due to estrogen deficiency. Based on long-term adverse effects and complication safety data, when compared with tamoxifen, aromatase inhibitors are associated with a reduced incidence of thrombosis, endometrial cancer, and vaginal bleeding. For women with polycystic ovary syndrome and a body mass index greater than 30, letrozole should be considered as first-line therapy for ovulation induction because of the increased live birth rate compared with clomiphene citrate. Lifestyle changes that result in weight loss should be strongly encouraged. Aromatase inhibitors are a promising therapeutic option that may be helpful for the management of endometriosis-associated pain in combination therapy with progestins.

  5. ETORICOXIB IS A NEW SELECTIVE CYCLOOXYGENASE-2 INHIBITOR

    Directory of Open Access Journals (Sweden)

    A E Karateev

    2009-06-01

    Full Text Available The paper provides the clinical characteristics of etoricoxib (Arcoxia, a new selective cyclooxygenase-2 inhibitor having unique properties, which permits it to be distinguished among other nonsteroidal anti-inflammatory agents.

  6. Highlights of the Latest Advances in Research on CDK Inhibitors

    Directory of Open Access Journals (Sweden)

    Jonas Cicenas

    2014-10-01

    Full Text Available Uncontrolled proliferation is the hallmark of cancer and other proliferative disorders and abnormal cell cycle regulation is, therefore, common in these diseases. Cyclin-dependent kinases (CDKs play a crucial role in the control of the cell cycle and proliferation. These kinases are frequently deregulated in various cancers, viral infections, neurodegenerative diseases, ischemia and some proliferative disorders. This led to a rigorous pursuit for small-molecule CDK inhibitors for therapeutic uses. Early efforts to block CDKs with nonselective CDK inhibitors led to little specificity and efficacy but apparent toxicity, but the recent advance of selective CDK inhibitors allowed the first successful efforts to target these kinases for the therapies of several diseases. Major ongoing efforts are to develop CDK inhibitors as monotherapies and rational combinations with chemotherapy and other targeted drugs.

  7. Rational Design of Calpain Inhibitors Based on Calpastatin Peptidomimetics.

    Science.gov (United States)

    Low, Kristin E; Ler, Spencer; Chen, Kevin J; Campbell, Robert L; Hickey, Jennifer L; Tan, Joanne; Scully, Conor C G; Davies, Peter L; Yudin, Andrei K; Zaretsky, Serge

    2016-06-01

    Our previously reported structures of calpain bound to its endogenous inhibitor calpastatin have motivated the use of aziridine aldehyde-mediated peptide macrocyclization toward the design of cyclic peptides and peptidomimetics as calpain inhibitors. Inspired by nature's hint that a β-turn loop within calpastatin forms a broad interaction around calpain's active site cysteine, we have constructed and tested a library of 45 peptidic compounds based on this loop sequence. Four molecules have shown reproducibly low micromolar inhibition of calpain-2. Further systematic sequence changes led to the development of probes that displayed increased potency and specificity of inhibition against calpain over other cysteine proteases. Calculated Ki values were in the low micromolar range, rivaling other peptidomimetic calpain inhibitors and presenting an improved selectivity profile against other therapeutically relevant proteases. Competitive and mixed inhibition against calpain-2 was observed, and an allosteric inhibition site on the enzyme was identified for a noncompetitive inhibitor.

  8. Azorhodanine derivatives as inhibitors for acidic corrosion of nickel.

    Science.gov (United States)

    Fouda, Abd El-Aziz S; Al-Sarawy, Ahmed A; Omar, Tark M

    2005-01-01

    Azorhodanine derivatives (HL1-HL5) were tested as corrosion inhibitors for nickel in 2M HNO3 solution using weight loss and galvanostatic polarization techniques. The results showed that these derivatives act as inhibitors for nickel in this medium. The inhibition was assumed to occur via adsorption of the inhibitor molecule on the metal surface. Polarization measurements indicated that these compounds act as mixed-type inhibitors, but the cathode is more polarized when an external current was applied. This means that these compounds retard the rate of hydrogen evolution and the rate of dissolution of the metal. Results showed that azorhodanine derivatives are adsorbed on the nickel surface following Temkin's adsorption isotherm. The activation energy and thermodynamic parameters were calculated and discussed at different temperatures (30-45 degrees C).

  9. Discovery of Phenylglycine Lactams as Potent Neutral Factor VIIa Inhibitors.

    Science.gov (United States)

    Wurtz, Nicholas R; Parkhurst, Brandon L; Jiang, Wen; DeLucca, Indawati; Zhang, Xiaojun; Ladziata, Vladimir; Cheney, Daniel L; Bozarth, Jeffrey R; Rendina, Alan R; Wei, Anzhi; Luettgen, Joseph M; Wu, Yiming; Wong, Pancras C; Seiffert, Dietmar A; Wexler, Ruth R; Priestley, E Scott

    2016-12-08

    Inhibitors of Factor VIIa (FVIIa), a serine protease in the clotting cascade, have shown strong antithrombotic efficacy in preclinical thrombosis models with minimal bleeding liabilities. Discovery of potent, orally active FVIIa inhibitors has been largely unsuccessful because known chemotypes have required a highly basic group in the S1 binding pocket for high affinity. A recently reported fragment screening effort resulted in the discovery of a neutral heterocycle, 7-chloro-3,4-dihydroisoquinolin-1(2H)-one, that binds in the S1 pocket of FVIIa and can be incorporated into a phenylglycine FVIIa inhibitor. Optimization of this P1 binding group led to the first series of neutral, permeable FVIIa inhibitors with low nanomolar potency.

  10. Design of second generation HIV-1 integrase inhibitors.

    Science.gov (United States)

    Deng, Jinxia; Dayam, Raveendra; Al-Mawsawi, Laith Q; Neamati, Nouri

    2007-01-01

    The prospect of HIV-1 integrase (IN) as a therapeutically viable retroviral drug target is on the verge of realization. The observed preclinical and clinical performance of beta-diketo containing and naphthyridine carboxamide compounds provides direct proof for the clinical application of IN inhibition. These validated lead compounds are useful in the design and development of second generation IN inhibitors. The results from preclinical and clinical studies on the first generation IN inhibitors reiterate a demand for novel second generation inhibitors with improved pharmacokinetic and metabolic properties. Pharmacophore-based drug design techniques facilitate the discovery of novel compounds on the basis of validated lead compounds specific for a drug target. In this article we have comprehensively reviewed the application of pharmacophore-based drug design methods in the field of IN inhibitor discovery.

  11. Refined homology model of monoacylglycerol lipase: toward a selective inhibitor

    Science.gov (United States)

    Bowman, Anna L.; Makriyannis, Alexandros

    2009-11-01

    Monoacylglycerol lipase (MGL) is primarily responsible for the hydrolysis of 2-arachidonoylglycerol (2-AG), an endocannabinoid with full agonist activity at both cannabinoid receptors. Increased tissue 2-AG levels consequent to MGL inhibition are considered therapeutic against pain, inflammation, and neurodegenerative disorders. However, the lack of MGL structural information has hindered the development of MGL-selective inhibitors. Here, we detail a fully refined homology model of MGL which preferentially identifies MGL inhibitors over druglike noninhibitors. We include for the first time insight into the active-site geometry and potential hydrogen-bonding interactions along with molecular dynamics simulations describing the opening and closing of the MGL helical-domain lid. Docked poses of both the natural substrate and known inhibitors are detailed. A comparison of the MGL active-site to that of the other principal endocannabinoid metabolizing enzyme, fatty acid amide hydrolase, demonstrates key differences which provide crucial insight toward the design of selective MGL inhibitors as potential drugs.

  12. Angioedema Due to use of ACE-Inhibitor

    Directory of Open Access Journals (Sweden)

    Hulya Eyigor

    2014-03-01

    Full Text Available       Angioedema; which may be hereditary or non-hereditary, is defined as a sudden, severe, often in awkward, temporary swelling of skin, subcutaneous and mucous membranes of the face, tongue, lip, larynx, and gastrointestinal areas. Angiotensin Converting Enzyme (ACE inhibitor drugs are widely used in essential hypertension and congestive heart diseases and effective and safe drugs. Angioedema is quite rare due to the use of ACE inhibitors, the rate changes from 0.1 to 0.7% reported in the literature. The pathophysiology of angioedema induced by ACE inhibitors are not completely understood, this situation has been tought to be associated with an increased activity of bradykinin related vasodilatation, increased vascular permeability and interstitial edema. In this study, a case of 65-year-old male patient presented angioedema induced by lisinopril was presented and a very rare side effect of ACE inhibitor drugs was reviewed with the relevant literature.

  13. Optimization of Cyclic Plasmin Inhibitors: From Benzamidines to Benzylamines.

    Science.gov (United States)

    Hinkes, Stefan; Wuttke, André; Saupe, Sebastian M; Ivanova, Teodora; Wagner, Sebastian; Knörlein, Anna; Heine, Andreas; Klebe, Gerhard; Steinmetzer, Torsten

    2016-07-14

    New macrocyclic plasmin inhibitors based on our previously optimized P2-P3 core segment have been developed. In the first series, the P4 residue was modified, whereas the 4-amidinobenzylamide in P1 position was maintained. The originally used P4 benzylsulfonyl residue could be replaced by various sulfonyl- or urethane-like protecting groups. In the second series, the P1 benzamidine was modified and a strong potency and excellent selectivity was retained by incorporation of p-xylenediamine. Several analogues inhibit plasmin in the subnanomolar range, and their potency against related trypsin-like serine proteases including trypsin itself could be further reduced. Selected derivatives have been tested in a plasma fibrinolysis assay and are more effective than the reference inhibitor aprotinin. The crystal structure of one inhibitor was determined in complex with trypsin. The binding mode reveals a sterical clash of the inhibitor's linker segment with the 99-hairpin loop of trypsin, which is absent in plasmin.

  14. Pyridoxine hydroxamic acids as novel HIV-integrase inhibitors.

    Science.gov (United States)

    Stranix, Brent R; Wu, Jinzi J; Milot, Guy; Beaulieu, Françis; Bouchard, Jean-Emanuel; Gouveia, Kristine; Forte, André; Garde, Seema; Wang, Zhigang; Mouscadet, Jean-François; Delelis, Olivier; Xiao, Yong

    2016-02-15

    A series of pyridoxine hydroxamic acid analog bearing a 5-aryl-spacers were synthesized. Evaluation of these novel HIV integrase complex inhibitors revealed compounds with high potency against wild-type HIV virus.

  15. Tetrahydrobenzothiophene inhibitors of hepatitis C virus NS5B polymerase.

    Science.gov (United States)

    Laporte, M G; Lessen, T A; Leister, L; Cebzanov, D; Amparo, E; Faust, C; Ortlip, D; Bailey, T R; Nitz, T J; Chunduru, S K; Young, D C; Burns, C J

    2006-01-01

    A novel series of selective HCV NS5B RNA dependent RNA polymerase inhibitors has been disclosed. These compounds contain an appropriately substituted tetrahydrobenzothiophene scaffold. This communication will detail the SAR and activities of this series.

  16. The biology and clinical development of MEK inhibitors for cancer.

    Science.gov (United States)

    Luke, Jason J; Ott, Patrick A; Shapiro, Geoffrey I

    2014-12-01

    The mitogen-activated protein kinase kinases (MAPKK) MEK1 and MEK2 are integral members of the MAPK/ERK signaling pathway and are of interest in the development of anti-cancer therapeutics. The MAPK/ERK pathway is dysregulated in more than 30 % of cancers, predominately by mutations in RAS and BRAF proteins, and MEK serves as a potential downstream target for both of these. The biology of MEK inhibition is complex, as the molecule is differentially regulated by upstream RAS or RAF. This has impacted on the past development of MEK inhibitors as treatments for cancer and may be exploited in more rational, molecularly selected drug development plans in the future. The role of MEK in cancer and the mechanism of action of MEK inhibitors is reviewed. Furthermore, MEK inhibitors that are available in standard practice, as well as those most advanced in clinical development, are discussed. Finally, next steps in the development of MEK inhibitors are considered.

  17. Physical and psychosocial challenges in adult hemophilia patients with inhibitors

    Directory of Open Access Journals (Sweden)

    duTreil S

    2014-07-01

    Full Text Available Sue duTreil Louisiana Center for Bleeding and Clotting Disorders, Tulane University Health Sciences Center, New Orleans, LA, USA Abstract: Numerous challenges confront adult hemophilia patients with inhibitors, including difficulty in controlling bleeding episodes, deterioration of joints, arthritic pain, physical disability, emotional turmoil, and social issues. High-intensity treatment regimens often used in the treatment of patients with inhibitors also impose significant scheduling, economic, and emotional demands on patients and their families or primary caregivers. A comprehensive multidisciplinary assessment of the physical, emotional, and social status of adult hemophilia patients with inhibitors is essential for the development of treatment strategies that can be individualized to address the complex needs of these patients. Keywords: adult hemophilia patients with inhibitors, adherence, physical challenges, psychosocial challenges, health-related quality of life

  18. The design of inhibitors for medicinally relevant metalloproteins.

    Science.gov (United States)

    Jacobsen, Faith E; Lewis, Jana A; Cohen, Seth M

    2007-02-01

    A number of metalloproteins are important medicinal targets for conditions ranging from pathogenic infections to cancer. Many but not all of these metalloproteins contain a zinc(II) ion in the protein active site. Small-molecule inhibitors of these metalloproteins are designed to bind directly to the active site metal ions. In this review several metalloproteins of interest are discussed, including matrix metalloproteinases (MMPs), histone deacetylases (HDACs), anthrax lethal factor (LF), and others. Different strategies that have been employed to design effective inhibitors against these proteins are described, with an effort to highlight the strengths and drawbacks of each approach. An emphasis is placed on examining the bioinorganic chemistry of these metal active sites and how a better understanding of the coordination chemistry in these systems may lead to improved inhibitors. It is hoped that this review will help inspire medicinal, biological, and inorganic chemists to tackle this important problem by considering all aspects of metalloprotein inhibitor design.

  19. Aromatase Inhibitors and Other Compounds for Lowering Breast Cancer Risk

    Science.gov (United States)

    ... to have broken bones. Aromatase inhibitors may raise cholesterol. Women with pre-existing coronary ... and master’s-prepared nurses with deep knowledge of cancer care as well as journalists, editors, ...

  20. Towards isozyme-selective HDAC inhibitors for interrogating disease.

    Science.gov (United States)

    Gupta, Praveer; Reid, Robert C; Iyer, Abishek; Sweet, Matthew J; Fairlie, David P

    2012-01-01

    Histone deacetylase (HDAC) enzymes have emerged as promising targets for the treatment of a wide range of human diseases, including cancers, inflammatory and metabolic disorders, immunological, cardiovascular, and infectious diseases. At present, such applications are limited by the lack of selective inhibitors available for each of the eighteen HDAC enzymes, with most currently available HDAC inhibitors having broad-spectrum activity against multiple HDAC enzymes. Such broad-spectrum activity maybe useful in treating some diseases like cancers, but can be detrimental due to cytotoxic side effects that accompany prolonged treatment of chronic diseased states. Here we summarize progress towards the design and discovery of HDAC inhibitors that are selective for some of the eleven zinc-containing classical HDAC enzymes, and identify opportunities to use such isozyme-selective inhibitors as chemical probes for interrogating the biological roles of individual HDAC enzymes in diseases.

  1. Effect of inhibitors on macroscopical oxidation kinetics of calcium sulfite

    Institute of Scientific and Technical Information of China (English)

    ZHAO Yi; WANG Li-dong; WANG Xiao-ming; LI Qiang-wei; XU Pei-yao

    2005-01-01

    In the presence of inhibitors, the macroscopical oxidation kinetics of calcium sulfite, the main byproduct in wet limestone scrubbing, was studied for the first time by adding different inhibitors and varying pH, concentration of calcium sulfite, oxygen partial pressure, concentration of inhibitors and temperature. The mathematical model about the general oxidation reaction was established,which was controlled by three steps involving dissolution of calcium sulfite, mass transfer of oxygen and chemical reaction in the solution.It was concluded that the general reaction was controlled by mass transfer of oxygen under uncatalyzed conditions, while it was controlled by dissolution of calcium sulfite after adding three kinds of inhibitors. Thus, the theory was provided for investigating the mechanism and oxidation kinetics of sulfite. The beneficial references were also supplied for design of oxidation technics in the wet limestone scrubbing.

  2. Effect of Mixed Corrosion Inhibitors in Cooling Water System

    Directory of Open Access Journals (Sweden)

    Dina Raheem

    2011-01-01

    Full Text Available The effect of mixed corrosion inhibitors in cooling system was evaluated by using carbon steel specimens and weight loss analysis. The carbon steel specimens immersed in mixture of sodium phosphate (Na2 HPO4 used as corrosion inhibitor and sodium glocunate (C6 H11 NaO7 as a scale dispersant at different concentrations (20,40, 60, 80 ppm and at different temperature (25,50,75 and 100ºC for (1-5 days. The corrosion inhibitors efficiency was calculated by using uninhibited and inhibited water to give 98.1%. The result of these investigations indicate that the corrosion rate decreases with the increase the corrosion inhibitors concentration at 80 ppm and at 100ºC for 5 days, (i.e, corrosion rate= 0.014gmd.

  3. Assessment of Synthetic Matrix Metalloproteinase Inhibitors by Fluorogenic Substrate Assay.

    Science.gov (United States)

    Lively, Ty J; Bosco, Dale B; Khamis, Zahraa I; Sang, Qing-Xiang Amy

    2016-01-01

    Matrix metalloproteinases (MMPs) are a family of metzincin enzymes that act as the principal regulators and remodelers of the extracellular matrix (ECM). While MMPs are involved in many normal biological processes, unregulated MMP activity has been linked to many detrimental diseases, including cancer, neurodegenerative diseases, stroke, and cardiovascular disease. Developed as tools to investigate MMP function and as potential new therapeutics, matrix metalloproteinase inhibitors (MMPIs) have been designed, synthesized, and tested to regulate MMP activity. This chapter focuses on the use of enzyme kinetics to characterize inhibitors of MMPs. MMP activity is measured via fluorescence spectroscopy using a fluorogenic substrate that contains a 7-methoxycoumarin-4-acetic acid N-succinimidyl ester (Mca) fluorophore and a 2,4-dinitrophenyl (Dpa) quencher separated by a scissile bond. MMP inhibitor (MMPI) potency can be determined from the reduction in fluorescent intensity when compared to the absence of the inhibitor. This chapter describes a technique to characterize a variety of MMPs through enzyme inhibition assays.

  4. Refractory Epistaxis due to Severe Factor V Deficiency with Inhibitor

    Directory of Open Access Journals (Sweden)

    Elizabeth S. John

    2015-01-01

    Full Text Available Factor V deficiency secondary to inhibitors is extremely rare and can be caused by a wide collection of exposures such as bovine thrombin and beta lactamase antibiotics. The management of factor V deficiency with inhibitor is a condition treated based on case reports due to the rarity of this condition. We describe a complicated case of an elderly patient with severe factor V deficiency with high inhibitor titer refractory to FEIBA (anti-inhibitor coagulation complex treated with NovoSeven concurrently with cyclosporine immunosuppression and Rituxan. Given that there are no consensus guidelines on treatment, this case offers important insight into the therapeutic approaches that can be used to treat such patients.

  5. Corrosion Inhibition of a Green Scale Inhibitor Polyepoxysuccinic Acid

    Institute of Scientific and Technical Information of China (English)

    Rong Chun XIONG; Qing ZHOU; Gang WEI

    2003-01-01

    The corrosion inhibition of a green scale inhibitor, polyepoxysuccinic acid (PESA) wasstudied based on dynamic tests. It is found that when PESA is used alone, it had good corrosioninhibition. So, PESA should be included in the category of corrosion inhibitors. It is not only akind of green scale inhibitor, but also a green corrosion inhibitor. The synergistic effect betweenPESA and Zn2+ or sodium gluconate is poor. However, the synergistic effect among PESA, Zn2+and sodium gluconate is excellent, and the corrosion inhibition efficiency for carbon steel is higherthan 99%. Further study of corrosion inhibition mechanism reveals that corrosion inhibition ofPESA is not affected by carboxyl group, but by the oxygen atom inserted The existence ofoxygen atom in PESA molecular structure makes it easy to form stable chelate with pentacyclicstructure.

  6. Synthesis and anti-HIV activity of some [Nucleoside Reverse Transcriptase Inhibitor]-C5'-linker-[Integrase Inhibitor] heterodimers as inhibitors of HIV replication.

    Science.gov (United States)

    Sugeac, Elena; Fossey, Christine; Ladurée, Daniel; Schmidt, Sylvie; Laumond, Geraldine; Aubertin, Anne-Marie

    2004-12-01

    Selected for their expected ability to inhibit HIV replication, a series of eight heterodimers containing a Nucleoside Reverse Transcriptase Inhibitor (NRTI) and an Integrase Inhibitor (INI), bound by a linker, were designed and synthesized. For the NRTIs, d4U, d2U and d4T were chosen. For the INIs, 4-[1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid (6) and 4-(3,5-dibenzyloxyphenyl)-2,4-dioxobutyric acid (9) (belonging to the beta-diketo acids class) were chosen. The conjugation of the two different inhibitors (NRTI and INI) was performed using an amino acid (glycine or beta-alanine) as a cleavable linker.

  7. Pyrrole-3-carboxamides as potent and selective JAK2 inhibitors.

    Science.gov (United States)

    Brasca, Maria Gabriella; Nesi, Marcella; Avanzi, Nilla; Ballinari, Dario; Bandiera, Tiziano; Bertrand, Jay; Bindi, Simona; Canevari, Giulia; Carenzi, Davide; Casero, Daniele; Ceriani, Lucio; Ciomei, Marina; Cirla, Alessandra; Colombo, Maristella; Cribioli, Sabrina; Cristiani, Cinzia; Della Vedova, Franco; Fachin, Gabriele; Fasolini, Marina; Felder, Eduard R; Galvani, Arturo; Isacchi, Antonella; Mirizzi, Danilo; Motto, Ilaria; Panzeri, Achille; Pesenti, Enrico; Vianello, Paola; Gnocchi, Paola; Donati, Daniele

    2014-09-01

    We report herein the discovery, structure guided design, synthesis and biological evaluation of a novel class of JAK2 inhibitors. Optimization of the series led to the identification of the potent and orally bioavailable JAK2 inhibitor 28 (NMS-P953). Compound 28 displayed significant tumour growth inhibition in SET-2 xenograft tumour model, with a mechanism of action confirmed in vivo by typical modulation of known biomarkers, and with a favourable pharmacokinetic and safety profile.

  8. Identification of catechols as histone-lysine demethylase inhibitors

    DEFF Research Database (Denmark)

    Nielsen, Anders L; Kristensen, Line H; Stephansen, Karen B;

    2012-01-01

    in the low µM range (1, a catechol), a subset of structurally related compounds was selected and tested against a panel of HDMs. In this subset, two inhibitors (2 and 10) had comparable affinities towards KDM4C and KDM6A but no effect on PHF8. One inhibitor restored H3K9me3 levels in KDM4C transfected U2-OS...

  9. A New Method to Quickly Assess the Inhibitor Efficiency

    Institute of Scientific and Technical Information of China (English)

    GENG Chunlei; XU Yongmo; WENG Duan

    2008-01-01

    A new method to quickly assess the efficiency of corrosion inhibitor was developed by electrically accelerating chloride ions diffusing onto the surface of the embedded steel bar in concrete and inducing corrosion.Potentiodynamic polarization scanning and linear polarization method were used to evaluate the corrosion states which were compared with the direct observation of the bar surface by breaking the sample.The test duration was about two days and the results clearly show the differences in efficiency of the inhibitors tested.

  10. Clinical stage EGFR inhibitors irreversibly alkylate Bmx kinase.

    Science.gov (United States)

    Hur, Wooyoung; Velentza, Anastasia; Kim, Sungjoon; Flatauer, Laura; Jiang, Xinnong; Valente, David; Mason, Daniel E; Suzuki, Melissa; Larson, Brad; Zhang, Jianming; Zagorska, Anna; Didonato, Michael; Nagle, Advait; Warmuth, Markus; Balk, Steven P; Peters, Eric C; Gray, Nathanael S

    2008-11-15

    Irreversible HER/erbB inhibitors selectively inhibit HER-family kinases by targeting a unique cysteine residue located within the ATP-binding pocket. Sequence alignment reveals that this rare cysteine is also present in ten other protein kinases including all five Tec-family members. We demonstrate that the Tec-family kinase Bmx is potently inhibited by irreversible modification at Cys496 by clinical stage EGFR inhibitors such as CI-1033. This cross-reactivity may have significant clinical implications.

  11. Recent Natural Corrosion Inhibitors for Mild Steel: An Overview

    OpenAIRE

    Marko Chigondo; Fidelis Chigondo

    2016-01-01

    Traditionally, reduction of corrosion has been managed by various methods including cathodic protection, process control, reduction of the metal impurity content, and application of surface treatment techniques, as well as incorporation of suitable alloys. However, the use of corrosion inhibitors has proven to be the easiest and cheapest method for corrosion protection and prevention in acidic media. These inhibitors slow down the corrosion rate and thus prevent monetary losses due to metalli...

  12. Waste of cleaning emulsion sewage as inhibitors of steel corrosion

    Science.gov (United States)

    Fazullin, D. D.; Mavrin, G. V.; Shaikhiev, I. G.

    2016-06-01

    The article describes the corrosion test of steel of the brand 20 in the stratal water. To increase corrosion resistance as a corrosion inhibitor the concentrate waste emulsion of the mark "Incam- 1" was provided. The article presents studies of the corrosion rate with different dosages of corrosion inhibitor in the stratal water. Based on these research results are revealed that the degree of protection of steel is 27% at a dosage of 3.8 g / dm3.

  13. Safety of TNF-alpha inhibitors during IBD pregnancy

    DEFF Research Database (Denmark)

    Nielsen, Ole Haagen; Loftus, Edward V; Jess, Tine

    2013-01-01

    Tumor necrosis factor (TNF)-alpha inhibitors are increasingly being used in inflammatory bowel disease (IBD). Because this chronic intestinal disorder often affects women of fertile age, it is essential to assess the effect of biologics on pregnancy outcome.......Tumor necrosis factor (TNF)-alpha inhibitors are increasingly being used in inflammatory bowel disease (IBD). Because this chronic intestinal disorder often affects women of fertile age, it is essential to assess the effect of biologics on pregnancy outcome....

  14. Morphological effects of MMPs inhibitors on the dentin bonding

    OpenAIRE

    Li, He; Li, Tianbo; LI, XIUYING; Zhang, Zhimin; Li, Penglian; Li, Zhenling

    2015-01-01

    Matrix metalloproteinases (MMPs) have been studied extensively, and MMP inhibitors have been used as dental pretreatment agents prior to dentin bonding because they reduce collagen fiber degradation and improve bonding strength. However, morphologic characteristics of the collagen network after etching and of the post-adhesive dentin hybrid layers (DHL) after MMP inhibitors pretreatment have not been evaluated. Thus, we investigated demineralized dentin pretreated with chlorhexidine (CHX) and...

  15. Identifying Epigenetic Modulators of Resistance to ERK Signaling Inhibitors

    Science.gov (United States)

    2015-08-01

    AWARD NUMBER: WSlXWH-14-1-0230 TITLE: Identifying Epigenetic Modulators of Resistance to ERK Signaling Inhibitors PRINCIPAL INVESTIGATOR: Emily...5a. CONTRACT NUMBER Identifying Epigenetic Modulators of Resistance to ERK Signaling Inhibitors 5b. GRANT NUMBER W8 1XWH- 1 4 - 1 - 0230 5c...response to targeted therapies in cancer. However, a global and unbiased approach to decipher the epigenetic mechanisms underlying melanoma drug

  16. Inhibitors of Hedgehog acyltransferase block Sonic Hedgehog signaling.

    Science.gov (United States)

    Petrova, Elissaveta; Rios-Esteves, Jessica; Ouerfelli, Ouathek; Glickman, J Fraser; Resh, Marilyn D

    2013-04-01

    Inhibition of Sonic hedgehog (Shh) signaling is of great clinical interest. Here we exploit Hedgehog acyltransferase (Hhat)-mediated Shh palmitoylation, a modification critical for Shh signaling, as a new target for Shh pathway inhibition. A target-oriented high-throughput screen was used to identify small-molecule inhibitors of Hhat. In cells, these Hhat inhibitors specifically block Shh palmitoylation and inhibit autocrine and paracrine Shh signaling.

  17. Unexpected Activity of a Novel Kunitz-type Inhibitor

    Science.gov (United States)

    Smith, David; Tikhonova, Irina G.; Jewhurst, Heather L.; Drysdale, Orla C.; Dvořák, Jan; Robinson, Mark W.; Cwiklinski, Krystyna; Dalton, John P.

    2016-01-01

    Kunitz-type (KT) protease inhibitors are low molecular weight proteins classically defined as serine protease inhibitors. We identified a novel secreted KT inhibitor associated with the gut and parenchymal tissues of the infective juvenile stage of Fasciola hepatica, a helminth parasite of medical and veterinary importance. Unexpectedly, recombinant KT inhibitor (rFhKT1) exhibited no inhibitory activity toward serine proteases but was a potent inhibitor of the major secreted cathepsin L cysteine proteases of F. hepatica, FhCL1 and FhCL2, and of human cathepsins L and K (Ki = 0.4-27 nm). FhKT1 prevented the auto-catalytic activation of FhCL1 and FhCL2 and formed stable complexes with the mature enzymes. Pulldown experiments from adult parasite culture medium showed that rFhKT1 interacts specifically with native secreted FhCL1, FhCL2, and FhCL5. Substitution of the unusual P1 Leu15 within the exposed reactive loop of FhKT1 for the more commonly found Arg (FhKT1Leu15/Arg15) had modest adverse effects on the cysteine protease inhibition but conferred potent activity against the serine protease trypsin (Ki = 1.5 nm). Computational docking and sequence analysis provided hypotheses for the exclusive binding of FhKT1 to cysteine proteases, the importance of the Leu15 in anchoring the inhibitor into the S2 active site pocket, and the inhibitor's selectivity toward FhCL1, FhCL2, and human cathepsins L and K. FhKT1 represents a novel evolutionary adaptation of KT protease inhibitors by F. hepatica, with its prime purpose likely in the regulation of the major parasite-secreted proteases and/or cathepsin L-like proteases of its host. PMID:27422822

  18. Primary structural analysis of sulfhydryl protease inhibitors from pineapple stem.

    Science.gov (United States)

    Reddy, M N; Keim, P S; Heinrikson, R L; Kezdy, F J

    1975-03-10

    Pineapple stem acetone powder provides a rich source of the sulfhydryl protease bromelain and of a family of compositionally similar but chromatographically distinct polypeptide inihibtors of this enzyme. The isoinhibitors have molecular weights of 5600, and they contain five disulfide bonds and about 50 amino acids each (Perlstein, S. H., AND Kezdy, F.J. (1973) J. Supramol. Struct. 1, 249-254). Primary structural analysis of one of the seven inhibitor fractions (VII) revealed extensive microheterogeneity. Each of the inhibitor molecules in Fraction VII was shown to be composed of two peptide chains joined by disulfide bonds. These chains, designated A and B on the basis of size, comprise 41 and 10-11 residues, respectively, and the amino acid sequence of one of each are given below: (see article for formular). On the basis of ionization properties and yields of the A and B chains, it would appear that one of the major inhibitor species in Fraction VII is the covalently linked complex of the two chains shown, namely [A-1, B-2]. The second major inhibitor component of Fraction VII is identical in structure with [A-1, B-2i1 except that residues 1 and 8 in the A chain are pyroglutamate and threonine, respectively, and in the B chain glutamine 11 is replaced by arginine. The third inhibitor in Fraction VII is a minor constituent identical with the second, except that residue 1 in the A chain is glutamate rather than pyroglutamate. This microheterogeneity in the inhibitors of Fraction VII is further increased by the fact that B chains may lack threonine 1, in which case they are decapeptides beginning with alanine. On the basis of the striking homology of the cysteine residues with those of other protease inhibitors, it is proposed that the bromelain inhibitors are generated enzymatically from single chain precursors by excision of a "bridge" paptide which links the NH-2 termal A chain to the COOH-terminal B chain.

  19. 2-Arylbenzoxazoles as CETP inhibitors: Substitution of the benzoxazole moiety.

    Science.gov (United States)

    Smith, Cameron J; Ali, Amjad; Chen, Liya; Hammond, Milton L; Anderson, Matt S; Chen, Ying; Eveland, Suzanne S; Guo, Qiu; Hyland, Sheryl A; Milot, Denise P; Sparrow, Carl P; Wright, Samuel D; Sinclair, Peter J

    2010-01-01

    A series of 2-arylbenzoxazole inhibitors of the cholesterol ester transfer protein (CETP) is described. Structure-activity studies focused on variation of the substitution of the benzoxazole moiety. Substitution at the 5- and 7-positions of the benzoxazole moiety was found to be beneficial for CETP inhibition. Compound 47 was found to be the most potent inhibitor in this series and inhibited CETP with an IC(50) of 28nM.

  20. Structure of human cytidine deaminase bound to a potent inhibitor.

    Science.gov (United States)

    Chung, Sang J; Fromme, J Christopher; Verdine, Gregory L

    2005-02-10

    Human cytidine deaminase (CDA) is an enzyme prominent for its role in catalyzing metabolic processing of nucleoside-type anticancer and antiviral agents. It is thus a promising target for the development of small molecule therapeutic adjuvants. We report the first crystal structure of human CDA as a complex with a tight-binding inhibitor, diazepinone riboside 1. The structure reveals that inhibitor 1 is able to establish a canonical pi/pi-interaction with a key active site residue, Phe 137.