Due to their significant value in both economy and ecology,Daphnia had long been employed to investigate in vivo response of cholinesterase(ChE) in anticholinesterase exposures,whereas the type constitution and proper...Due to their significant value in both economy and ecology,Daphnia had long been employed to investigate in vivo response of cholinesterase(ChE) in anticholinesterase exposures,whereas the type constitution and property of the enzyme remained unclear.A type of ChE was purified from Daphnia magna using a three-step procedure,i.e.,Triton X-100 extraction,ammonium sulfate precipitation,and diethylaminoethyl(DEAE)-Sepharose Fast-Flow chromatography.According to sodium dodecyl sulfate polyacrylamide gel electrophoresis(SDS-PAGE),molecular mass of the purified ChE was estimated to be 84 kDa.Based on substrate studies,the purified enzyme preferred butyrylthiocholine iodide(BTCh) [with maximum velocity(Vmax)/Michaelis constant(Km)=8.428 L/(min·mg protein)] to acetylthiocholine iodide(ATCh) [with V max /Km =5.346 L/(min·mg protein)] as its substrate.Activity of the purified enzyme was suppressed by high concentrations of either ATCh or BTCh.Inhibitor studies showed that the purified enzyme was more sensitive towards inhibition by tetraisopropylpyrophosphoramide(iso-OMPA) than by 1,5-bis(4-allyldimethylammoniumphenyl) pentan-3-one dibromide(BW284C51).Result of the study suggested that the purified ChE was more like a type of pseudocholinesterase,and it also suggested that Daphnia magna contained multiple types of ChE in their bodies.展开更多
Objective:To investigate the effect of Cannabis sativa resin and/or tramadol,two commonly drugs of abuse on acetylcholinesterase and butyrylcholinesterase activities as a possible cholinergic biomarkers of neurotoxici...Objective:To investigate the effect of Cannabis sativa resin and/or tramadol,two commonly drugs of abuse on acetylcholinesterase and butyrylcholinesterase activities as a possible cholinergic biomarkers of neurotoxicity induced by these agents.Methods:rats were treated with cannabis resin(5,10 or 20 mg/kg)(equivalent to the active constituent A'-tetrahydrocannabinol),tramadol(5,10 and 20 mg/kg) or tramadol(10 mg/kg)combined with cannabis resin(5,10 and 20 mg/kg) subcutaneously daily for 6 weeks.Acetylcholinesterase(AChE) and butyrylcholinesterase(BChE) activities were measured in brain and serum.We also measured the activity of paraoxonase-1(PONl) in serum of rats treated with these agents.Results:(i) AChE activity in brain increased after 10-20 mg/kg cannabis resin(by 16.3%-36.5%).AChE activity in brain did not change after treatment with 5-20 mg/kg tramadol.The administration of both cannabis resin(5,10 or 20 mg/kg) and tramadol(10 mg/kg) resulted in decreased brain AChE activity by 14.1%,12.9%and 13.6%,respectively;(ii) BChE activity in serum was markedly and dose-dependenlly inhibited by cannabis resin(by 60.9%-76.9%).BChE activity also decreased by 17.6%-36.5%by 10-20mg/kg tramadol and by 57.2%-63.9%by the cannabis resin/tramadol combined treatment;(iii)Cannabis resin at dose of 20 mg/kg increased serum PONl activity by 25.7%.In contrast,tramadol given at 5,10 and 20 mg/kg resulted in a dose-dependent decrease in serum PON1 activity by 19%,36.7%,and 46.1%,respectively.Meanwhile,treatment with cannabis resin plus tramadol resulted in 40.2%,35.8%,30.7%inhibition of PONl activity compared to the saline group.Conclusions:these data suggest that cannabis resin exerts different effects on AChE and BChE activities which could contribute to the memory problems and the decline in cognitive function in chronic users.展开更多
Objective: To assess and compare the clinical efficacy and safety of cognitive enhancers(donepezil, galantamine, rivastigmine, and memantine) on cognition, behavior, function, and global status in patients with vascul...Objective: To assess and compare the clinical efficacy and safety of cognitive enhancers(donepezil, galantamine, rivastigmine, and memantine) on cognition, behavior, function, and global status in patients with vascular cognitive impairment.Data sources: The initial literature search was performed with PubMed, EMBASE, the Cochrane Methodology Register, the Cochrane Central Register of Controlled Trials, and Cumulative Index to Nursing & Allied Health(CINAHL) from inception to January 2018 for studies regarding donepezil, galantamine, rivastigmine, and memantine for treatment of vascular cognitive impairment.Data selection: Randomized controlled trials on donepezil, galantamine, rivastigmine, and memantine as monotherapy in the treatment of vascular cognitive impairment were included. A Bayesian network meta-analysis was conducted. Outcome measures: Efficacy was assessed by changes in scores of the Alzheimer's Disease Assessment Scale, cognitive subscale, Mini-Mental State Examination, Neuropsychiatric Inventory scores and Clinician's Interview-Based Impression of Change Scale Plus Caregiver's Input, Activities of Daily Living, the Clinical Dementia Rating scale. Safety was evaluated by mortality, total adverse events(TAEs), serious adverse events(SAEs), nausea, vomiting. diarrhea, or cerebrovascular accidents(CVAs). Results: After screening 1717 citations, 12 randomized controlled trials were included. Donepezil and rivastigmine(mean difference(e) = –0.77, 95% confidence interval(CI): 0.25–1.32; MD = 1.05, 95% CI: 0.18–1.79) were significantly more effective than placebo in reducing Mini-Mental State Examination scores. Donepezil, galantamine, and memantine(MD = –1.30, 95% CI: –2.27 to –0.42; MD = –1.67, 95% CI: –3.36 to –0.06; MD = –2.27, 95% CI: –3.91 to –0.53) showed superior benefits on the Alzheimer's Disease Assessment Scale–cognitive scores compared with placebo. Memantine(MD = 2.71, 95% CI: 1.05–7.29) improved global status(Clinician's Interview-Based Impression of Change Scale Plus Caregiver's Input) more than the placebo. Safety results revealed that donepezil 10 mg(odds ratio(OR) = 3.04, 95% CI: 1.86–5.41) contributed to higer risk of adverse events than placebo. Galantamine(OR = 5.64, 95% CI: 1.31–26.71) increased the risk of nausea. Rivastigmine(OR = 16.80, 95% CI: 1.78–319.26) increased the risk of vomiting. No agents displayed a significant risk of serious adverse events, mortality, cerebrovascular accidents, or diarrhea.Conclusion: We found significant efficacy of donepezil, galantamine, and memantine on cognition. Memantine can provide significant efficacy in global status. They are all safe and well tolerated.展开更多
BACKGROUND: Paraoxonase 1(PON1) is an ester hydro- lase in serum and in the liver. Studies have suggested that PON1 measurement to the current battery of tests may im- prove the evaluation of chronic liver diseases. T...BACKGROUND: Paraoxonase 1(PON1) is an ester hydro- lase in serum and in the liver. Studies have suggested that PON1 measurement to the current battery of tests may im- prove the evaluation of chronic liver diseases. The aim of this study was to investigate the clinical significance of mo- nitoring the level of serum PON1 activity in liver transplan- tation patients. METHODS: A series of biochemical indexes were moni- tored in preoperative, operative and postoperative serum samples of 17 liver-transplanted patients. The change of se- rum PON1 level and its relations with other biochemical in- dexes were analyzed. RESULTS: PON1 was distributed normally in the healthy population and its reference value ranged from 45.5 to 265.8 U/mL. The PON1 level of all patients was lower than that of control group significantly (P<0.001); the level be- gan to elevate continuously 5 minutes after opening of the portal vein and was higher than that 90 minutes after open- ing of the portal vein ( P <0.05). Two days after operation it was still higher than the normal. The levels of serum ALT and AST elevated more significantly after opening of the portal vein than before operation and they were higher than the normal values till 2 days after the operation. CONCLUSIONS: The level of PON1 in serum may be taken as one of the effective indexes to assess whether the implant is alive and to monitor liver function of the patient together with other tests.展开更多
BACKGROUND:The aim of the present study is to describe the clinical correlates of hypotension and its associated outcomes in patients with acute organophosphorus poisoning(AOPP).METHODS:In this retrospective cohort st...BACKGROUND:The aim of the present study is to describe the clinical correlates of hypotension and its associated outcomes in patients with acute organophosphorus poisoning(AOPP).METHODS:In this retrospective cohort study,we analyzed data pertaining to 871 patients with AOPP who were treated at two hospitals.Data from hypotensive and non-hypotensive patients were compared to identify clinical correlates of hypotension.We also evaluated the association between clinical parameters(including hypotension)and in-hospital mortality.RESULTS:The incidence of hypotension in AOPP patients was 16.4%.Hypotensive patients showed signifi cantly higher in-hospital mortality(1.1%vs.39.9%,P<0.001).Advanced age(odds ratio[OR]1.25,95%confi dence interval[CI]1.08–1.44),history of diabetes(OR 2.65,95%CI 1.14–5.96),and increased white blood cell count(OR 1.06,95%CI 1.03–1.09),plasma cholinesterase(OR 0.91,95%CI 0.84–0.94),plasma albumin(OR 0.88,95%CI 0.85–0.92),serum amylase(OR 1.01,95%CI 1.01–1.02),and blood pH(OR 0.64,95%CI 0.54–0.75)were signifi cantly associated with hypotension.After adjusting for potential confounders,hypotension was associated with increased in-hospital mortality(hazard ratio 8.77–37.06,depending on the controlled variables).CONCLUSIONS:Hypotension is a common complication of AOPP and is associated with increased in-hospital mortality.Advanced age,history of diabetes,and changes in laboratory parameters were associated with hypotension in AOPP patients.展开更多
Objective:To evaluate the effect of different doses of lead acetate(1/20,1/40 and 1/60 of LD_(50))on body weight gain,blood picture,plasma prolein profile and the function of liver,kidney and thyroid gland.Methods:Mal...Objective:To evaluate the effect of different doses of lead acetate(1/20,1/40 and 1/60 of LD_(50))on body weight gain,blood picture,plasma prolein profile and the function of liver,kidney and thyroid gland.Methods:Male albino rats were divided into four groups,the first group represented the health control animals,while the second,third and fourth groups were ingested orally with sub lethal doses of load acetate(1/20,1/40 and 1/60)of the oral LD_(50),respectively.One dose was ingested every two days during the experimental period(14 weeks)including the adaptation time.Blood was collected and used for all analysis.Results:The results showed that,the ingestion of Pb^(2+)induced significant stimulation in glutamic-pyruvic transaminase(ALT)and glutamic-oxalacetic transaminease(AST)activity.Also,total soluble protein and albumin contents of plasma were significantly decreased,while the content of globulin was changed by the Pb^(2+)treatments.The cholinesteiase activity was inhibited,but the activities of alkaline and acid phosphates and lactate dehydrogenase were stimulated,while plasma glucose level was elevated as a result of lead acetate intoxication.In case of blood picture,Pb^(2+)ingestion reduced the contents of hemoglobin and RBCs count of intoxicated rat's blood and the plasma levels of T3,T4 and blood WBCs count were decreased.Conclusions:It can be concluded that lead acetate has harmful effect on experimental male albino rats.Therefore,the present work advises people to prevent exposure to the lead compound to avoid injurious hazard risk.展开更多
A novel quartz crystal microbalance (QCM) biosensor for the determination of organophosphorus pesticide,such as dichlorvos (DDVP),has been fabricated with poly (3,4-ethylenedioxythiophene)/Poly (4-styrenesulfonate) (P...A novel quartz crystal microbalance (QCM) biosensor for the determination of organophosphorus pesticide,such as dichlorvos (DDVP),has been fabricated with poly (3,4-ethylenedioxythiophene)/Poly (4-styrenesulfonate) (PEDOT/PSS) and cholinesterase butyl (BuChE).It is found that PEDOT/PSS coated sensor exhibits the highest sensitivity for DDVP among PEDOT,polyvinyl pyrrolidone,polyvinyl alcohol and polyacrylic acid sensor series.The conditions to prepare PEDOT/PSS coated sensor are optimized.The sensitivity of the PEDOT/PSS hiosensor with BuChE is higher than the others without BuChE The determination of dichlorvos in the range from 400μg/g to 2400μg/g used PEDOT/PSS with BuChE coated hiosensor was obtained.展开更多
The effects of bis(7) tacrine, a novel dimeric acetylcholinesterase (AChE) inhibitor, on glutamate induced cell injury were investigated in primary cerebral cortical neurons of rats. Exposure of cultured neurons (12 d...The effects of bis(7) tacrine, a novel dimeric acetylcholinesterase (AChE) inhibitor, on glutamate induced cell injury were investigated in primary cerebral cortical neurons of rats. Exposure of cultured neurons (12 days after plating) to 0.5 mmol/L glutamate for 30 min resulted in significant cell damage. Pretreatment with bis(7) tacrine (0.03 1.0 μmol/L) reduced the glutamate induced neurotoxicity in a concentration dependent manner and the maximal response was seen at 1 μmol/L with approximately 30% protection. A receptor binding assay showed that bis(7) tacrine can completely displace MK 801 binding to rat cortical membrane with an IC 50 of 0.57 μmol/L. These findings suggest that bis(7) tacrine can directly interact with N methyl D aspartate receptor channel complex, which may contribute to the inhibitor’s protective effects against glutamate induced excitotoxicity. Thus, it is possible that anti glutamate/anti AChE synergism is responsible for potentially better Alzheimer’s therapy of bis(7) tacrine relative to tacrine.展开更多
Objective: To study the effect of citric acid given alone or combined with atropine on brain oxidative stress, neuronal injury, liver damage, and DNA damage of peripheral blood lymphocytes induced in the rat by acute ...Objective: To study the effect of citric acid given alone or combined with atropine on brain oxidative stress, neuronal injury, liver damage, and DNA damage of peripheral blood lymphocytes induced in the rat by acute malathion exposure. Methods: Rats were received intraperitoneal(i.p.) injection of malathion 150 mg/kg along with citric acid(200 or 400 mg/kg, orally), atropine(1 mg/kg, i.p.) or citric acid 200 mg/kg+atropine 1 mg/kg and euthanized 4 h later. Results: Malathion resulted in increased lipid peroxidation(malondialdehyde) and nitric oxide concentrations accompanied with a decrease in brain reduced glutathione, glutathione peroxidase(GPx) activity, total antioxidant capacity(TAC) and glucose concentrations. Paraoxonase-1, acetylcholinesterase(ACh E) and butyrylcholinesterase activities decreased in brain as well. Liver aspartate aminotransferase and alanine aminotransferase activities were raised. The Comet assay showed increased DNA damage of peripheral blood lymphocytes. Histological damage and increased expression of inducible nitric oxide synthase(i NOS) were observed in brain and liver. Citric acid resulted in decreased brain lipid peroxidation and nitric oxide. Meanwhile, glutathione, GPx activity, TAC capacity and brain glucose level increased. Brain ACh E increased but PON1 and butyrylcholinesterase activities decreased by citric acid. Liver enzymes, the percentage of damaged blood lymphocytes, histopathological alterations and i NOS expression in brain and liver was decreased by citric acid. Meanwhile, rats treated with atropine showed decreased brain MDA, nitrite but increased GPx activity, TAC, ACh E and glucose. The drug also decreased DNA damage of peripheral blood lymphocytes, histopathological alterations and i NOS expression in brain and liver. Conclusions: The study demonstrates a beneficial effect for citric acid upon brain oxidative stress, neuronal injury, liver and DNA damage due to acute malathion exposure.展开更多
AIM To examine whether nizatidine stimulatesduodenal HCO<sub>3</sub><sup>-</sup> secretion in rats by inhibitingAChE activity.METHODS Under pentobarbital anesthesia,aproximal duodenal loop was ...AIM To examine whether nizatidine stimulatesduodenal HCO<sub>3</sub><sup>-</sup> secretion in rats by inhibitingAChE activity.METHODS Under pentobarbital anesthesia,aproximal duodenal loop was perfused withsaline,and the HCO<sub>3</sub> secretion was measuredat pH 7.0 using a pH-stat method and by adding10mM HCI.Nizatidine,neostigmine,carbacholor famotidine was administered i.v.as a singleinjection.RESULTS Intravenous administration ofnizatidine（3-30 mg/kg）dose-dependentlyincreased duodenal HCO<sub>3</sub><sup>-</sup> secretion,and theeffect at 10mg/kg was equivalent to thatobtained by carbachol at 0.01 mg/kg.Thisnizatidine action was observed at the same doserange that inhibited acid secretion and enhancedgastric motility,mimicked by i.v.injection ofneostigmine（0.03 mg/kg）,and significantlyattenuated by bilateral vagotomy and prior s.c.administration of atropine but not byindomethacin,a cyclooxygenase inhibitor,orN<sup>G</sup>-nitro-L-arginine methyl ester,a NO synthaseinhibitor.The HCO<sub>3</sub><sup>-</sup> secretory response toacetylcholine（0.001 mg/kg）was significantlypotentiated by the concurrent administration ofnizatidine（3mg/kg,i.v.）.The IC<sub>50</sub>of nizatidine for AChE of rat erythrocytes was1.4×10<sup>-6</sup>M,about 12 times higher than that ofneostigmine.Neither famotidine(】10<sup>-3</sup>M,30mg/kg,i.v.)nor cisapride(】 10<sup>-3</sup>M,3mg/kg,i.v.)had any influence on AChEactivity or duodenal HCO<sub>3</sub><sup>-</sup> secretion.Duodenaldamage induced by acid perfusion（100 mM HCIfor 4 h）in the presence of indomethacin wassignificantly prevented by nizatidine andneostigmine,at the doses that increased theHCO<sub>3</sub><sup>-</sup> secretion.CONCLUSION Nizatidine stimulates duodenalHCO<sub>3</sub><sup>-</sup> secretion,in both vagal-dependent andatropine-sensitive manners,and the action isassociated with the anti-AChE activity of thisagent.展开更多
Background: Although Alzheimer’s disease (AD) has been intensively investigated for many years, the effective treatments are largely missing. Commonly used conventional therapy, such as cholinesterase inhibitors (ChE...Background: Although Alzheimer’s disease (AD) has been intensively investigated for many years, the effective treatments are largely missing. Commonly used conventional therapy, such as cholinesterase inhibitors (ChEI) and N-methyl D-asparate receptor antagonist, have been generally considered as having symptom-relieving rather than disease-modifying effects. Thus, how to improve cognitive function beyond such effect & time limitations has become a serious challenge. Aim: In order to solve this challenge, a sequential therapy with the integration of conventional therapy and herbal therapy was applied to AD patients. Careful clinical observation was conducted in our outpatient setting. Case Presentation: A case of probable AD received the sequential therapy has achieved relative stable cognition and overall status in eight years. Conclusion: During the treatment of this AD case in eight years, sequential therapy showed great potential in stabilizing and improving cognition and overall status. Well designed preclinical and clinical studies are needed to investigate the efficacy of sequential therapy for AD and other type of dementia.展开更多
Introduction: Organ phosphorus (OP) toxicity has been studied extensively because of its world wide use. Toxicity of organophosphates is the result of inhibition of acetyl cholinesterase resulting in cholinergic signs...Introduction: Organ phosphorus (OP) toxicity has been studied extensively because of its world wide use. Toxicity of organophosphates is the result of inhibition of acetyl cholinesterase resulting in cholinergic signs. Aim of the Work: To evaluate initial indicators that can indicate prognosis of patients in OP poisoning. Materials and Methods: A retrospective study conducted in Zagazig university hospital over a year. OP poisoning was clinically diagnosed with history of OP compound exposure and confirmed by low pseudo cholinesterase levels. Results: In the present study, 76 patients were enrolled. Major cases were male. High mortality rates were in the youth and in prolonged ventilated patients. The mortality rate was proportionally related to lag time after exposure and plasma pseudo cholinesterase levels. Electrolyte disturbance did not affect clinical outcome. Conclusion: From this study, it could be concluded that mortality is directly proportionate to the lag time, amount of OP consumed, clinical severity, pseudo cholinesterase levels and duration of ventilator support. This study helps in rapid diagnosis, and rapid early and effective treatment, which may result in decreasing the morbidity and mortality rates. Recommendation: It is recommended to increase awareness regarding the rapid diagnosis, and rapid effective treatment of organ phosphorous.展开更多
Chronotoxicological studies were performed with dichlorphos (DDVP) and its timing toxic effects on mice and humans. The circadian rhythms were revealed in the blood cholinesterase (ChE) activity in intact mice and nor...Chronotoxicological studies were performed with dichlorphos (DDVP) and its timing toxic effects on mice and humans. The circadian rhythms were revealed in the blood cholinesterase (ChE) activity in intact mice and normal persons, as well as in mice mortality treated at different daily times. The inverse relationship of the two rhythm suggested that the risk of exposure to DDVP might be much higher at evening hours than in other clocks of the day, and the disappearance of the ChE rhythms in DDVP-treated mice and DDVP-exposed workers implicated a disturbing effect of DDVP on the maintenance and regulation of the rhythmic mechanisms.展开更多
Objective: To use structure-activity analysis to study the anti-Alzheimer's disease(anti-AD) activity of natural coumarins isolated from Angelica decursiva and Artemisia capillaries, along with one purchased couma...Objective: To use structure-activity analysis to study the anti-Alzheimer's disease(anti-AD) activity of natural coumarins isolated from Angelica decursiva and Artemisia capillaries, along with one purchased coumarin(daphnetin). Methods: Umbelliferone, umbelliferone 6-carboxylic acid, scopoletin, isoscopoletin, 7-methoxy coumarin, scoparone, scopolin, and esculetin have been previously isolated; however 2'-isopropyl psoralene was isolated from Angelica decursiva for the first time to evaluate their inhibitory effects against acetylcholinesterase(ACh E), butyrylcholinesterase(BCh E), and β-site amyloid precursor protein cleaving enzyme 1(BACE1) enzyme activity. We scrutinized the potentials of coumarins as cholinesterase and BACE1 inhibitors via enzyme kinetics and molecular docking simulation. Results: Among the test compounds, umbelliferone 6-carboxylic acid, esculetin and daphnetin exhibited potent inhibitory activity against ACh E, BCh E and BACE1. Both esculetin and daphnetin have a catechol group and exhibit significant anti-AD activity against ACh E and BCh E. In contrast, presence of a sugar moiety and methoxylation markedly reduced the anti-AD activity of the coumarins investigated in this study. With respect to BACE1 inhibition, umbelliferone 6-carboxylic acid, esculetin and daphnetin contained carboxyl or catechol groups, which significantly contributed to their antiAD activities. To further investigate these results, we generated a 3D structure of BACE1 using Autodock 4.2 and simulated binding of umbelliferone 6-carboxylic acid, esculetin and daphnetin. Docking simulations showed that different residues of BACE1 interacted with hydroxyl and carboxylic groups, and the binding energies of umbelliferone 6-carboxylic acid, esculetin and daphnetin were negative(-4.58,-6.25 and-6.37 kcal/mol respectively). Conclusions: Taken together, our results suggest that umbelliferone 6-carboxylic acid, esculetin and daphnetin have anti-AD effects by inhibiting ACh E, BCh E and BACE1, which might be useful against AD.展开更多
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.horizantal...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 butyrylcholinesterasc(BChE)inhibitory activity at 100μg/mL.Antioxidant activity of the extracts was tested using 2,2-diphenyl-1-picrylhydrazyl(DPPH)and N,N-dimethyl-p-phenylendiamine(DMPD)radical scavenging,nietal-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 metalchelation 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.展开更多
Experiments to investisate the effects of soman on lymphocyte proliferation werecarried out on balb/c mice,which were injected subcutaneously with soman in the doseof 154μg/kg (0.8 LD<sub>50</sub>),96μg/...Experiments to investisate the effects of soman on lymphocyte proliferation werecarried out on balb/c mice,which were injected subcutaneously with soman in the doseof 154μg/kg (0.8 LD<sub>50</sub>),96μg/kg (0.5 LD<sub>50</sub>) and 38.4μg/kg (0.2 LD<sub>50</sub>) respectively.Itwas found that from the 1st to the 7th day after poisoning with 154μg/kg soman,B-lymphocyte proliferation was severely inhibited （P【0.05）,and it returned to the controllevel on the 10th day.Con A-stimulated T-cell proliferation showed a diphasic change,increasing at first and then markedly decreasing thereafter,after soman poisoning.The re-sults imply that the mitogenic response of both B- and T- cells and the primary increaseof T- cell response are closely related to the dosage of soman but not with the changes ofwhole blood cholinesterase activity.展开更多
Two novel naphthol derivatives(1 and 2) were synthesized and characterized via IR,~1H NMR,and HRMS.The structure of compound 2 was verified by single-crystal X-ray crystallography.It crystallizes in monoclinic,space g...Two novel naphthol derivatives(1 and 2) were synthesized and characterized via IR,~1H NMR,and HRMS.The structure of compound 2 was verified by single-crystal X-ray crystallography.It crystallizes in monoclinic,space group C2/c with a = 21.6725(9),b = 6.0127(3),c = 25.5405(14) ?,β = 94.716(5)o,V = 3316.9(3) ?~3,Z = 8,F(000) = 1384,D_c = 1.511 Mg/m^3,M_r = 377.22 and μ = 2.487 mm^(-1).In addition,their cholinesterase inhibitory activities in vitro toward Electrophorus electricus acetylcholinesterase(eel ACh E) and horse serum butyrylcholinesterase(eq BCh E) were further determined.The results showed that compound 1 as a new acetylcholinesterase(ACh E) inhibitor displayed higher ACh E inhibitory activity(IC_(50) = 1.4 μM),which could be considered for Alzheimer's disease therapeutics.展开更多
Acetylcholine is an essential neurotransmitter found throughout the nervous system. Its action on postsynaptic receptors is regulated through hydrolysis by various carboxylesterases, especially cholinesterases (ChEs)....Acetylcholine is an essential neurotransmitter found throughout the nervous system. Its action on postsynaptic receptors is regulated through hydrolysis by various carboxylesterases, especially cholinesterases (ChEs). The acute toxicity of organophosphate (OP) compounds is directly linked to their action as inhibitors of ChE. One widely used assay for evaluating ChE activity is a spectrophotometric method developed by Ellman et al. When the enzyme source is from tissues or, in particular, blood, hemoglobin displays a spectrophotometric peak at the same wave-length used to analyze cholinergic activity. This creates a substantial background that interferes with the Ellman’s assay and must be overcome in order to accurately monitor cholinesterase activity. Herein, we directly compare blood processing methods: classical method (1.67 ± 0.30 U/mL) and HemogloBindTM treatment (1.51 ± 0.17 U/mL), and clearly demonstrate that pretreatment of blood samples with HemoglobindTM is both a sufficient and rapid sample preparation method for the assessment of ChE activity using the Ellman’s method.展开更多
Cholinergic dysfunction is common to Alzheimer’s dementia and Schizophrenia. The objective of this study is to undertake a systematic review and meta-analysis of the literature on the cognitive and clinical effects o...Cholinergic dysfunction is common to Alzheimer’s dementia and Schizophrenia. The objective of this study is to undertake a systematic review and meta-analysis of the literature on the cognitive and clinical effects of cholinesterase inhibitors administered to patients with schizophrenia and co-morbid Alzheimer’s disease dementia. A literature search of the MEDLINE, CINAHL, PubMed, PsycINFO, EMBASE, AMED, BNI, HMIC and Health Business Elite databases has been performed (up to January 2013) to investigate the use of cholinesterase inhibitors in patients with schizophrenia and dementia. The terms “schizophrenia”, “dementia”, “rivastigmine”, “donepezil”, “galantamine” and “cognitive deficit” have been searched, with a restriction for English language. Five published studies including 1 RCT have been included for the qualitative review. Treatments include Donepezil 5 mg and 10 mg as well as Rivastigmine 9 mg. The numbers of participants vary from 2 incase report to20 inthe RCT. Only 1 study qualifies for meta-analysis. There is a very limited evidence on the efficacy and safety of using acetylcholinesterase inhibitors in the management of dementia co-morbid with schizophrenia. The only randomised controlled study shows lack of evidence in terms of efficacy in using cholinesterase inhibitors in the management of dementia with schizophrenia. Future research projects will have to look at an adequate sample size to explore treatment on various cognitive and noncognitive domains and the sample should be selected by using definitive and internationally acceptable diagnostic criteria.展开更多
基金Project supported by the Zhejiang Provincial Natural Science Foundation of China(No.LY12B07008)the Department of Education of Zhejiang Province,China(No.20070138)
文摘Due to their significant value in both economy and ecology,Daphnia had long been employed to investigate in vivo response of cholinesterase(ChE) in anticholinesterase exposures,whereas the type constitution and property of the enzyme remained unclear.A type of ChE was purified from Daphnia magna using a three-step procedure,i.e.,Triton X-100 extraction,ammonium sulfate precipitation,and diethylaminoethyl(DEAE)-Sepharose Fast-Flow chromatography.According to sodium dodecyl sulfate polyacrylamide gel electrophoresis(SDS-PAGE),molecular mass of the purified ChE was estimated to be 84 kDa.Based on substrate studies,the purified enzyme preferred butyrylthiocholine iodide(BTCh) [with maximum velocity(Vmax)/Michaelis constant(Km)=8.428 L/(min·mg protein)] to acetylthiocholine iodide(ATCh) [with V max /Km =5.346 L/(min·mg protein)] as its substrate.Activity of the purified enzyme was suppressed by high concentrations of either ATCh or BTCh.Inhibitor studies showed that the purified enzyme was more sensitive towards inhibition by tetraisopropylpyrophosphoramide(iso-OMPA) than by 1,5-bis(4-allyldimethylammoniumphenyl) pentan-3-one dibromide(BW284C51).Result of the study suggested that the purified ChE was more like a type of pseudocholinesterase,and it also suggested that Daphnia magna contained multiple types of ChE in their bodies.
文摘Objective:To investigate the effect of Cannabis sativa resin and/or tramadol,two commonly drugs of abuse on acetylcholinesterase and butyrylcholinesterase activities as a possible cholinergic biomarkers of neurotoxicity induced by these agents.Methods:rats were treated with cannabis resin(5,10 or 20 mg/kg)(equivalent to the active constituent A'-tetrahydrocannabinol),tramadol(5,10 and 20 mg/kg) or tramadol(10 mg/kg)combined with cannabis resin(5,10 and 20 mg/kg) subcutaneously daily for 6 weeks.Acetylcholinesterase(AChE) and butyrylcholinesterase(BChE) activities were measured in brain and serum.We also measured the activity of paraoxonase-1(PONl) in serum of rats treated with these agents.Results:(i) AChE activity in brain increased after 10-20 mg/kg cannabis resin(by 16.3%-36.5%).AChE activity in brain did not change after treatment with 5-20 mg/kg tramadol.The administration of both cannabis resin(5,10 or 20 mg/kg) and tramadol(10 mg/kg) resulted in decreased brain AChE activity by 14.1%,12.9%and 13.6%,respectively;(ii) BChE activity in serum was markedly and dose-dependenlly inhibited by cannabis resin(by 60.9%-76.9%).BChE activity also decreased by 17.6%-36.5%by 10-20mg/kg tramadol and by 57.2%-63.9%by the cannabis resin/tramadol combined treatment;(iii)Cannabis resin at dose of 20 mg/kg increased serum PONl activity by 25.7%.In contrast,tramadol given at 5,10 and 20 mg/kg resulted in a dose-dependent decrease in serum PON1 activity by 19%,36.7%,and 46.1%,respectively.Meanwhile,treatment with cannabis resin plus tramadol resulted in 40.2%,35.8%,30.7%inhibition of PONl activity compared to the saline group.Conclusions:these data suggest that cannabis resin exerts different effects on AChE and BChE activities which could contribute to the memory problems and the decline in cognitive function in chronic users.
基金supported by the Natural Science Foundation of Liaoning Province of China,No.20170541036(to HYL)
文摘Objective: To assess and compare the clinical efficacy and safety of cognitive enhancers(donepezil, galantamine, rivastigmine, and memantine) on cognition, behavior, function, and global status in patients with vascular cognitive impairment.Data sources: The initial literature search was performed with PubMed, EMBASE, the Cochrane Methodology Register, the Cochrane Central Register of Controlled Trials, and Cumulative Index to Nursing & Allied Health(CINAHL) from inception to January 2018 for studies regarding donepezil, galantamine, rivastigmine, and memantine for treatment of vascular cognitive impairment.Data selection: Randomized controlled trials on donepezil, galantamine, rivastigmine, and memantine as monotherapy in the treatment of vascular cognitive impairment were included. A Bayesian network meta-analysis was conducted. Outcome measures: Efficacy was assessed by changes in scores of the Alzheimer's Disease Assessment Scale, cognitive subscale, Mini-Mental State Examination, Neuropsychiatric Inventory scores and Clinician's Interview-Based Impression of Change Scale Plus Caregiver's Input, Activities of Daily Living, the Clinical Dementia Rating scale. Safety was evaluated by mortality, total adverse events(TAEs), serious adverse events(SAEs), nausea, vomiting. diarrhea, or cerebrovascular accidents(CVAs). Results: After screening 1717 citations, 12 randomized controlled trials were included. Donepezil and rivastigmine(mean difference(e) = –0.77, 95% confidence interval(CI): 0.25–1.32; MD = 1.05, 95% CI: 0.18–1.79) were significantly more effective than placebo in reducing Mini-Mental State Examination scores. Donepezil, galantamine, and memantine(MD = –1.30, 95% CI: –2.27 to –0.42; MD = –1.67, 95% CI: –3.36 to –0.06; MD = –2.27, 95% CI: –3.91 to –0.53) showed superior benefits on the Alzheimer's Disease Assessment Scale–cognitive scores compared with placebo. Memantine(MD = 2.71, 95% CI: 1.05–7.29) improved global status(Clinician's Interview-Based Impression of Change Scale Plus Caregiver's Input) more than the placebo. Safety results revealed that donepezil 10 mg(odds ratio(OR) = 3.04, 95% CI: 1.86–5.41) contributed to higer risk of adverse events than placebo. Galantamine(OR = 5.64, 95% CI: 1.31–26.71) increased the risk of nausea. Rivastigmine(OR = 16.80, 95% CI: 1.78–319.26) increased the risk of vomiting. No agents displayed a significant risk of serious adverse events, mortality, cerebrovascular accidents, or diarrhea.Conclusion: We found significant efficacy of donepezil, galantamine, and memantine on cognition. Memantine can provide significant efficacy in global status. They are all safe and well tolerated.
文摘BACKGROUND: Paraoxonase 1(PON1) is an ester hydro- lase in serum and in the liver. Studies have suggested that PON1 measurement to the current battery of tests may im- prove the evaluation of chronic liver diseases. The aim of this study was to investigate the clinical significance of mo- nitoring the level of serum PON1 activity in liver transplan- tation patients. METHODS: A series of biochemical indexes were moni- tored in preoperative, operative and postoperative serum samples of 17 liver-transplanted patients. The change of se- rum PON1 level and its relations with other biochemical in- dexes were analyzed. RESULTS: PON1 was distributed normally in the healthy population and its reference value ranged from 45.5 to 265.8 U/mL. The PON1 level of all patients was lower than that of control group significantly (P<0.001); the level be- gan to elevate continuously 5 minutes after opening of the portal vein and was higher than that 90 minutes after open- ing of the portal vein ( P <0.05). Two days after operation it was still higher than the normal. The levels of serum ALT and AST elevated more significantly after opening of the portal vein than before operation and they were higher than the normal values till 2 days after the operation. CONCLUSIONS: The level of PON1 in serum may be taken as one of the effective indexes to assess whether the implant is alive and to monitor liver function of the patient together with other tests.
基金approved by the Medical Ethics Committee of the First Hospital of Jilin University(approval number:2018-146).
文摘BACKGROUND:The aim of the present study is to describe the clinical correlates of hypotension and its associated outcomes in patients with acute organophosphorus poisoning(AOPP).METHODS:In this retrospective cohort study,we analyzed data pertaining to 871 patients with AOPP who were treated at two hospitals.Data from hypotensive and non-hypotensive patients were compared to identify clinical correlates of hypotension.We also evaluated the association between clinical parameters(including hypotension)and in-hospital mortality.RESULTS:The incidence of hypotension in AOPP patients was 16.4%.Hypotensive patients showed signifi cantly higher in-hospital mortality(1.1%vs.39.9%,P<0.001).Advanced age(odds ratio[OR]1.25,95%confi dence interval[CI]1.08–1.44),history of diabetes(OR 2.65,95%CI 1.14–5.96),and increased white blood cell count(OR 1.06,95%CI 1.03–1.09),plasma cholinesterase(OR 0.91,95%CI 0.84–0.94),plasma albumin(OR 0.88,95%CI 0.85–0.92),serum amylase(OR 1.01,95%CI 1.01–1.02),and blood pH(OR 0.64,95%CI 0.54–0.75)were signifi cantly associated with hypotension.After adjusting for potential confounders,hypotension was associated with increased in-hospital mortality(hazard ratio 8.77–37.06,depending on the controlled variables).CONCLUSIONS:Hypotension is a common complication of AOPP and is associated with increased in-hospital mortality.Advanced age,history of diabetes,and changes in laboratory parameters were associated with hypotension in AOPP patients.
基金Supported by Management of Agriculture,Cario University
文摘Objective:To evaluate the effect of different doses of lead acetate(1/20,1/40 and 1/60 of LD_(50))on body weight gain,blood picture,plasma prolein profile and the function of liver,kidney and thyroid gland.Methods:Male albino rats were divided into four groups,the first group represented the health control animals,while the second,third and fourth groups were ingested orally with sub lethal doses of load acetate(1/20,1/40 and 1/60)of the oral LD_(50),respectively.One dose was ingested every two days during the experimental period(14 weeks)including the adaptation time.Blood was collected and used for all analysis.Results:The results showed that,the ingestion of Pb^(2+)induced significant stimulation in glutamic-pyruvic transaminase(ALT)and glutamic-oxalacetic transaminease(AST)activity.Also,total soluble protein and albumin contents of plasma were significantly decreased,while the content of globulin was changed by the Pb^(2+)treatments.The cholinesteiase activity was inhibited,but the activities of alkaline and acid phosphates and lactate dehydrogenase were stimulated,while plasma glucose level was elevated as a result of lead acetate intoxication.In case of blood picture,Pb^(2+)ingestion reduced the contents of hemoglobin and RBCs count of intoxicated rat's blood and the plasma levels of T3,T4 and blood WBCs count were decreased.Conclusions:It can be concluded that lead acetate has harmful effect on experimental male albino rats.Therefore,the present work advises people to prevent exposure to the lead compound to avoid injurious hazard risk.
文摘A novel quartz crystal microbalance (QCM) biosensor for the determination of organophosphorus pesticide,such as dichlorvos (DDVP),has been fabricated with poly (3,4-ethylenedioxythiophene)/Poly (4-styrenesulfonate) (PEDOT/PSS) and cholinesterase butyl (BuChE).It is found that PEDOT/PSS coated sensor exhibits the highest sensitivity for DDVP among PEDOT,polyvinyl pyrrolidone,polyvinyl alcohol and polyacrylic acid sensor series.The conditions to prepare PEDOT/PSS coated sensor are optimized.The sensitivity of the PEDOT/PSS hiosensor with BuChE is higher than the others without BuChE The determination of dichlorvos in the range from 400μg/g to 2400μg/g used PEDOT/PSS with BuChE coated hiosensor was obtained.
文摘The effects of bis(7) tacrine, a novel dimeric acetylcholinesterase (AChE) inhibitor, on glutamate induced cell injury were investigated in primary cerebral cortical neurons of rats. Exposure of cultured neurons (12 days after plating) to 0.5 mmol/L glutamate for 30 min resulted in significant cell damage. Pretreatment with bis(7) tacrine (0.03 1.0 μmol/L) reduced the glutamate induced neurotoxicity in a concentration dependent manner and the maximal response was seen at 1 μmol/L with approximately 30% protection. A receptor binding assay showed that bis(7) tacrine can completely displace MK 801 binding to rat cortical membrane with an IC 50 of 0.57 μmol/L. These findings suggest that bis(7) tacrine can directly interact with N methyl D aspartate receptor channel complex, which may contribute to the inhibitor’s protective effects against glutamate induced excitotoxicity. Thus, it is possible that anti glutamate/anti AChE synergism is responsible for potentially better Alzheimer’s therapy of bis(7) tacrine relative to tacrine.
文摘Objective: To study the effect of citric acid given alone or combined with atropine on brain oxidative stress, neuronal injury, liver damage, and DNA damage of peripheral blood lymphocytes induced in the rat by acute malathion exposure. Methods: Rats were received intraperitoneal(i.p.) injection of malathion 150 mg/kg along with citric acid(200 or 400 mg/kg, orally), atropine(1 mg/kg, i.p.) or citric acid 200 mg/kg+atropine 1 mg/kg and euthanized 4 h later. Results: Malathion resulted in increased lipid peroxidation(malondialdehyde) and nitric oxide concentrations accompanied with a decrease in brain reduced glutathione, glutathione peroxidase(GPx) activity, total antioxidant capacity(TAC) and glucose concentrations. Paraoxonase-1, acetylcholinesterase(ACh E) and butyrylcholinesterase activities decreased in brain as well. Liver aspartate aminotransferase and alanine aminotransferase activities were raised. The Comet assay showed increased DNA damage of peripheral blood lymphocytes. Histological damage and increased expression of inducible nitric oxide synthase(i NOS) were observed in brain and liver. Citric acid resulted in decreased brain lipid peroxidation and nitric oxide. Meanwhile, glutathione, GPx activity, TAC capacity and brain glucose level increased. Brain ACh E increased but PON1 and butyrylcholinesterase activities decreased by citric acid. Liver enzymes, the percentage of damaged blood lymphocytes, histopathological alterations and i NOS expression in brain and liver was decreased by citric acid. Meanwhile, rats treated with atropine showed decreased brain MDA, nitrite but increased GPx activity, TAC, ACh E and glucose. The drug also decreased DNA damage of peripheral blood lymphocytes, histopathological alterations and i NOS expression in brain and liver. Conclusions: The study demonstrates a beneficial effect for citric acid upon brain oxidative stress, neuronal injury, liver and DNA damage due to acute malathion exposure.
文摘AIM To examine whether nizatidine stimulatesduodenal HCO<sub>3</sub><sup>-</sup> secretion in rats by inhibitingAChE activity.METHODS Under pentobarbital anesthesia,aproximal duodenal loop was perfused withsaline,and the HCO<sub>3</sub> secretion was measuredat pH 7.0 using a pH-stat method and by adding10mM HCI.Nizatidine,neostigmine,carbacholor famotidine was administered i.v.as a singleinjection.RESULTS Intravenous administration ofnizatidine（3-30 mg/kg）dose-dependentlyincreased duodenal HCO<sub>3</sub><sup>-</sup> secretion,and theeffect at 10mg/kg was equivalent to thatobtained by carbachol at 0.01 mg/kg.Thisnizatidine action was observed at the same doserange that inhibited acid secretion and enhancedgastric motility,mimicked by i.v.injection ofneostigmine（0.03 mg/kg）,and significantlyattenuated by bilateral vagotomy and prior s.c.administration of atropine but not byindomethacin,a cyclooxygenase inhibitor,orN<sup>G</sup>-nitro-L-arginine methyl ester,a NO synthaseinhibitor.The HCO<sub>3</sub><sup>-</sup> secretory response toacetylcholine（0.001 mg/kg）was significantlypotentiated by the concurrent administration ofnizatidine（3mg/kg,i.v.）.The IC<sub>50</sub>of nizatidine for AChE of rat erythrocytes was1.4×10<sup>-6</sup>M,about 12 times higher than that ofneostigmine.Neither famotidine(】10<sup>-3</sup>M,30mg/kg,i.v.)nor cisapride(】 10<sup>-3</sup>M,3mg/kg,i.v.)had any influence on AChEactivity or duodenal HCO<sub>3</sub><sup>-</sup> secretion.Duodenaldamage induced by acid perfusion（100 mM HCIfor 4 h）in the presence of indomethacin wassignificantly prevented by nizatidine andneostigmine,at the doses that increased theHCO<sub>3</sub><sup>-</sup> secretion.CONCLUSION Nizatidine stimulates duodenalHCO<sub>3</sub><sup>-</sup> secretion,in both vagal-dependent andatropine-sensitive manners,and the action isassociated with the anti-AChE activity of thisagent.
文摘Background: Although Alzheimer’s disease (AD) has been intensively investigated for many years, the effective treatments are largely missing. Commonly used conventional therapy, such as cholinesterase inhibitors (ChEI) and N-methyl D-asparate receptor antagonist, have been generally considered as having symptom-relieving rather than disease-modifying effects. Thus, how to improve cognitive function beyond such effect & time limitations has become a serious challenge. Aim: In order to solve this challenge, a sequential therapy with the integration of conventional therapy and herbal therapy was applied to AD patients. Careful clinical observation was conducted in our outpatient setting. Case Presentation: A case of probable AD received the sequential therapy has achieved relative stable cognition and overall status in eight years. Conclusion: During the treatment of this AD case in eight years, sequential therapy showed great potential in stabilizing and improving cognition and overall status. Well designed preclinical and clinical studies are needed to investigate the efficacy of sequential therapy for AD and other type of dementia.
文摘Introduction: Organ phosphorus (OP) toxicity has been studied extensively because of its world wide use. Toxicity of organophosphates is the result of inhibition of acetyl cholinesterase resulting in cholinergic signs. Aim of the Work: To evaluate initial indicators that can indicate prognosis of patients in OP poisoning. Materials and Methods: A retrospective study conducted in Zagazig university hospital over a year. OP poisoning was clinically diagnosed with history of OP compound exposure and confirmed by low pseudo cholinesterase levels. Results: In the present study, 76 patients were enrolled. Major cases were male. High mortality rates were in the youth and in prolonged ventilated patients. The mortality rate was proportionally related to lag time after exposure and plasma pseudo cholinesterase levels. Electrolyte disturbance did not affect clinical outcome. Conclusion: From this study, it could be concluded that mortality is directly proportionate to the lag time, amount of OP consumed, clinical severity, pseudo cholinesterase levels and duration of ventilator support. This study helps in rapid diagnosis, and rapid early and effective treatment, which may result in decreasing the morbidity and mortality rates. Recommendation: It is recommended to increase awareness regarding the rapid diagnosis, and rapid effective treatment of organ phosphorous.
文摘Chronotoxicological studies were performed with dichlorphos (DDVP) and its timing toxic effects on mice and humans. The circadian rhythms were revealed in the blood cholinesterase (ChE) activity in intact mice and normal persons, as well as in mice mortality treated at different daily times. The inverse relationship of the two rhythm suggested that the risk of exposure to DDVP might be much higher at evening hours than in other clocks of the day, and the disappearance of the ChE rhythms in DDVP-treated mice and DDVP-exposed workers implicated a disturbing effect of DDVP on the maintenance and regulation of the rhythmic mechanisms.
基金supported by the Basic Science Research Program through the National Research Foundation of Koreafunded by the Ministry of Science,ICT&Future Planning(grant No.2014R1A1A3051684 and 2012R1A6A1028677)
文摘Objective: To use structure-activity analysis to study the anti-Alzheimer's disease(anti-AD) activity of natural coumarins isolated from Angelica decursiva and Artemisia capillaries, along with one purchased coumarin(daphnetin). Methods: Umbelliferone, umbelliferone 6-carboxylic acid, scopoletin, isoscopoletin, 7-methoxy coumarin, scoparone, scopolin, and esculetin have been previously isolated; however 2'-isopropyl psoralene was isolated from Angelica decursiva for the first time to evaluate their inhibitory effects against acetylcholinesterase(ACh E), butyrylcholinesterase(BCh E), and β-site amyloid precursor protein cleaving enzyme 1(BACE1) enzyme activity. We scrutinized the potentials of coumarins as cholinesterase and BACE1 inhibitors via enzyme kinetics and molecular docking simulation. Results: Among the test compounds, umbelliferone 6-carboxylic acid, esculetin and daphnetin exhibited potent inhibitory activity against ACh E, BCh E and BACE1. Both esculetin and daphnetin have a catechol group and exhibit significant anti-AD activity against ACh E and BCh E. In contrast, presence of a sugar moiety and methoxylation markedly reduced the anti-AD activity of the coumarins investigated in this study. With respect to BACE1 inhibition, umbelliferone 6-carboxylic acid, esculetin and daphnetin contained carboxyl or catechol groups, which significantly contributed to their antiAD activities. To further investigate these results, we generated a 3D structure of BACE1 using Autodock 4.2 and simulated binding of umbelliferone 6-carboxylic acid, esculetin and daphnetin. Docking simulations showed that different residues of BACE1 interacted with hydroxyl and carboxylic groups, and the binding energies of umbelliferone 6-carboxylic acid, esculetin and daphnetin were negative(-4.58,-6.25 and-6.37 kcal/mol respectively). Conclusions: Taken together, our results suggest that umbelliferone 6-carboxylic acid, esculetin and daphnetin have anti-AD effects by inhibiting ACh E, BCh E and BACE1, which might be useful against AD.
基金the Scientific and Technological Research Council of Turkey(TUBITAK)for the scholarship provided her for Ph.D.program
文摘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 butyrylcholinesterasc(BChE)inhibitory activity at 100μg/mL.Antioxidant activity of the extracts was tested using 2,2-diphenyl-1-picrylhydrazyl(DPPH)and N,N-dimethyl-p-phenylendiamine(DMPD)radical scavenging,nietal-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 metalchelation 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.
文摘Experiments to investisate the effects of soman on lymphocyte proliferation werecarried out on balb/c mice,which were injected subcutaneously with soman in the doseof 154μg/kg (0.8 LD<sub>50</sub>),96μg/kg (0.5 LD<sub>50</sub>) and 38.4μg/kg (0.2 LD<sub>50</sub>) respectively.Itwas found that from the 1st to the 7th day after poisoning with 154μg/kg soman,B-lymphocyte proliferation was severely inhibited （P【0.05）,and it returned to the controllevel on the 10th day.Con A-stimulated T-cell proliferation showed a diphasic change,increasing at first and then markedly decreasing thereafter,after soman poisoning.The re-sults imply that the mitogenic response of both B- and T- cells and the primary increaseof T- cell response are closely related to the dosage of soman but not with the changes ofwhole blood cholinesterase activity.
文摘Two novel naphthol derivatives(1 and 2) were synthesized and characterized via IR,~1H NMR,and HRMS.The structure of compound 2 was verified by single-crystal X-ray crystallography.It crystallizes in monoclinic,space group C2/c with a = 21.6725(9),b = 6.0127(3),c = 25.5405(14) ?,β = 94.716(5)o,V = 3316.9(3) ?~3,Z = 8,F(000) = 1384,D_c = 1.511 Mg/m^3,M_r = 377.22 and μ = 2.487 mm^(-1).In addition,their cholinesterase inhibitory activities in vitro toward Electrophorus electricus acetylcholinesterase(eel ACh E) and horse serum butyrylcholinesterase(eq BCh E) were further determined.The results showed that compound 1 as a new acetylcholinesterase(ACh E) inhibitor displayed higher ACh E inhibitory activity(IC_(50) = 1.4 μM),which could be considered for Alzheimer's disease therapeutics.
文摘Acetylcholine is an essential neurotransmitter found throughout the nervous system. Its action on postsynaptic receptors is regulated through hydrolysis by various carboxylesterases, especially cholinesterases (ChEs). The acute toxicity of organophosphate (OP) compounds is directly linked to their action as inhibitors of ChE. One widely used assay for evaluating ChE activity is a spectrophotometric method developed by Ellman et al. When the enzyme source is from tissues or, in particular, blood, hemoglobin displays a spectrophotometric peak at the same wave-length used to analyze cholinergic activity. This creates a substantial background that interferes with the Ellman’s assay and must be overcome in order to accurately monitor cholinesterase activity. Herein, we directly compare blood processing methods: classical method (1.67 ± 0.30 U/mL) and HemogloBindTM treatment (1.51 ± 0.17 U/mL), and clearly demonstrate that pretreatment of blood samples with HemoglobindTM is both a sufficient and rapid sample preparation method for the assessment of ChE activity using the Ellman’s method.
文摘Cholinergic dysfunction is common to Alzheimer’s dementia and Schizophrenia. The objective of this study is to undertake a systematic review and meta-analysis of the literature on the cognitive and clinical effects of cholinesterase inhibitors administered to patients with schizophrenia and co-morbid Alzheimer’s disease dementia. A literature search of the MEDLINE, CINAHL, PubMed, PsycINFO, EMBASE, AMED, BNI, HMIC and Health Business Elite databases has been performed (up to January 2013) to investigate the use of cholinesterase inhibitors in patients with schizophrenia and dementia. The terms “schizophrenia”, “dementia”, “rivastigmine”, “donepezil”, “galantamine” and “cognitive deficit” have been searched, with a restriction for English language. Five published studies including 1 RCT have been included for the qualitative review. Treatments include Donepezil 5 mg and 10 mg as well as Rivastigmine 9 mg. The numbers of participants vary from 2 incase report to20 inthe RCT. Only 1 study qualifies for meta-analysis. There is a very limited evidence on the efficacy and safety of using acetylcholinesterase inhibitors in the management of dementia co-morbid with schizophrenia. The only randomised controlled study shows lack of evidence in terms of efficacy in using cholinesterase inhibitors in the management of dementia with schizophrenia. Future research projects will have to look at an adequate sample size to explore treatment on various cognitive and noncognitive domains and the sample should be selected by using definitive and internationally acceptable diagnostic criteria.
