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1.
Toxicol Lett ; 314: 153-163, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31408696

RESUMO

Eye exposure to organophosphate (OP) chemical warfare irreversible acetylcholinesterase inhibitors, results in long-term miosis and impaired visual function. In contrast to the well-documented miotic and ciliary muscle spasm observed following chemical warfare, OP ocular exposure, little is known regarding the ocular surface histopathological insult. The aim of the present study was to determine the degree of the ocular surface insult following sarin or VX ocular exposure and to evaluate potential anti-cholinergic treatments in counteracting this insult. Rats that were whole body exposed to various sarin concentrations (0.049-43 µg/L; 5 min exposure), showed a dose-dependent miotic response and light reflex impairment. Following whole body sarin exposure, a dose dependent ocular surface histopathological insult was developed. A week following exposure to a low concentration of 0.05 µg/L, conjunctival pathology was observed, while corneal insult was noticed only following exposure to a concentration of 0.5 µg/L and above. Both tissues presented poorer outcomes when exposed to higher sarin concentrations. In contrast, eyes topically exposed to 1 µg sarin demonstrated no ocular insult a week following exposure. On the contrary, topical exposure to 1 µg VX resulted in a significant corneal insult. Anticholinergic treatments such as 0.1% atropine or 2% homatropine, given shortly following VX exposure, counteracted this insult. The results of this study show that not only do anti-cholinergic treatments counteract the miotic response, but also prevent the histopathological insult observed when given shortly following OP exposure.


Assuntos
Antídotos/farmacologia , Piscadela/efeitos dos fármacos , Substâncias para a Guerra Química/toxicidade , Inibidores da Colinesterase/toxicidade , Olho/efeitos dos fármacos , Miose/prevenção & controle , Antagonistas Muscarínicos/farmacologia , Compostos Organotiofosforados/toxicidade , Sarina/toxicidade , Acetilcolinesterase/metabolismo , Animais , Citoproteção , Relação Dose-Resposta a Droga , Olho/enzimologia , Olho/patologia , Olho/fisiopatologia , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/metabolismo , Masculino , Miose/induzido quimicamente , Miose/patologia , Miose/fisiopatologia , Ratos Long-Evans , Fatores de Tempo
2.
Pestic Biochem Physiol ; 158: 101-111, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31378344

RESUMO

Standard chemical insecticides present mainly neurotoxic effects and are becoming less and less effective due to insects developing resistance to them. One of the innovative strategies to control insects pests is to find a way to increase the sensitivity of the target sites in the insect nervous system to the applied insecticides. In the presented research, we proposed menthol, a component of essential oils, as a factor increasing the effectiveness of bendiocarb, a carbamate insecticide. The aim of our study was to evaluate the potentiation of the bendiocarb effect by menthol. In toxicity tests performed on Periplaneta americana, menthol (0.1 µM) accelerated the lethal effect of bendiocarb, primarily in its low concentrations (lower than 0.05 mM). In the presence of menthol (1 and 0.1 µM), the ability of insects to turn back from its dorsal to the normal ventral side was significantly lower than with bendiocarb (1 µM) alone. We also evaluated the effectiveness of chemicals on the activity of the ventral nerve cord of the cockroach. In this preparation, bendiocarb (1 µM and higher concentrations) caused an irregular, spontaneous bursts of action potentials. The total nerve activity (including the response to stimulation and spontaneous firing) was much higher when bendiocarb was applied in the presence of menthol (1 µM). The effect of menthol was similar to the octopamine effect and was abolished by phentolamine, the octopamine receptor antagonist. Our results clearly indicated a strengthening effect of menthol on bendiocarb effectiveness; potentiation occurred through octopamine receptors activation.


Assuntos
Carbamatos/farmacologia , Baratas/efeitos dos fármacos , Inseticidas/farmacologia , Mentol/farmacologia , Óleos Voláteis/química , Fenilcarbamatos/farmacologia , Acetilcolinesterase/metabolismo , Animais , Interações de Medicamentos , Resistência a Inseticidas
3.
J Agric Food Chem ; 67(33): 9210-9219, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31390203

RESUMO

The insecticidal and antifeedant activities of five 7-chloro-4-(1H-1,2,3-triazol-1-yl)quinoline derivatives were evaluated against the maize armyworm, Spodoptera frugiperda (J.E. Smith). These hybrids were prepared through a copper-catalyzed azide alkyne cycloaddition (CuAAC, known as a click reaction) and displayed larvicidal properties with LD50 values below 3 mg/g insect, and triazolyl-quinoline hybrid 6 showed an LD50 of 0.65 mg/g insect, making it 2-fold less potent than methomyl, which was used as a reference insecticide (LD50 = 0.34 mg/g insect). Compound 4 was the most active antifeedant derivative (CE50 = 162.1 µg/mL) with a good antifeedant index (56-79%) at concentrations of 250-1000 µg/mL. Additionally, triazolyl-quinoline hybrids 4-8 exhibited weak inhibitory activity against commercial acetylcholinesterase from Electrophorus electricus (electric-eel AChE) (IC50 = 27.7 µg/mL) as well as low anti-ChE activity on S. frugiperda larvae homogenate (IC50 = 68.4 µg/mL). Finally, molecular docking simulations suggested that hybrid 7 binds to the catalytic active site (CAS) of this enzyme and around the rim of the enzyme cavity, acting as a mixed (competitive and noncompetitive) inhibitor like methomyl. Triazolyl-quinolines 4-6 and 8 inhibit AChE by binding over the perimeter of the enzyme cavity, functioning as noncompetitive inhibitors. The results described in this work can help to identify lead triazole structures from click chemistry for the development of insecticide and deterrent products against S. frugiperda and related insect pests.


Assuntos
Inseticidas/síntese química , Inseticidas/farmacologia , Larva/efeitos dos fármacos , Quinolinas/química , Quinolinas/farmacologia , Spodoptera/efeitos dos fármacos , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Animais , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Química Click , Simulação por Computador , Proteínas de Insetos/antagonistas & inibidores , Proteínas de Insetos/química , Proteínas de Insetos/metabolismo , Inseticidas/química , Larva/enzimologia , Larva/crescimento & desenvolvimento , Simulação de Acoplamento Molecular , Doenças das Plantas/parasitologia , Spodoptera/enzimologia , Spodoptera/crescimento & desenvolvimento , Zea mays/parasitologia
4.
Chem Biodivers ; 16(8): e1900318, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31364803

RESUMO

Sponges from freshwater environments, unlike marine's, are poorly known producers of natural compounds with medicinal purposes. Amazonian sponges produce massive large specimens and are widely spread, taxonomically diverse and their metabolites could represent a new frontier on unusual natural products to treat diseases such as Alzheimer's and Malaria. Species of Metania and Drulia (Metaniidae) genera are major contributors to the fauna of Amazonian freshwater sponges. Methanolic extracts from several species from these genera had their inhibitory activities evaluated in vitro, for parasite Plasmodium falciparum and acetyl and butyrylcholinesterase enzymes (AChE and BChE). All extracts were able to inhibit AChE, although no activity was observed towards BChE. Drulia uruguayensis extract was the most potent, inhibiting AChE with IC50 =1.04 mg/mL. For antiplasmodial activity, all species showed inhibition to P. falciparum, but Metania reticulata being the most efficient with IC50 =2.7 µg/mL. Mass spectrometry analyses evidenced the presence of fatty acids and sterols in active extracts.


Assuntos
Antiprotozoários/química , Inibidores da Colinesterase/química , Poríferos/química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Animais , Antiprotozoários/isolamento & purificação , Antiprotozoários/farmacologia , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/metabolismo , Ácidos Graxos/análise , Ácidos Graxos/química , Plasmodium falciparum/efeitos dos fármacos , Poríferos/metabolismo , Espectrometria de Massas por Ionização por Electrospray , Esteróis/química
5.
Phytochemistry ; 165: 112055, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31261031

RESUMO

Twenty-one known Amaryllidaceae alkaloids of various structural types and one undescribed alkaloid, named narcimatuline, have been isolated from fresh bulbs of Narcissus pseudonarcissus L. cv. Dutch Master. The chemical structures were elucidated by combination of MS, HRMS, 1D and 2D NMR spectroscopic techniques, and by comparison with literature data. Narcimatuline amalgamates two basic scaffolds of Amaryllidaceae alkaloids in its core, namely galanthamine and galanthindole. All isolated compounds were evaluated for their in vitro acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), prolyl oligopeptidase (POP), and glycogen synthase kinase-3ß (GSK-3ß) inhibitory activities. The most interesting biological profile was demonstrated by newly isolated alkaloid narcimatuline.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Alcaloides de Amaryllidaceae/farmacologia , Inibidores da Colinesterase/farmacologia , Narcissus/química , Fármacos Neuroprotetores/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Alcaloides de Amaryllidaceae/química , Alcaloides de Amaryllidaceae/isolamento & purificação , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/isolamento & purificação , Relação Dose-Resposta a Droga , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Estrutura Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Serina Endopeptidases/metabolismo , Relação Estrutura-Atividade
6.
An Acad Bras Cienc ; 91(2): e20180419, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31269106

RESUMO

The aim of this study was to evaluate the effect of spray-dried porcine plasma (SDPP) supplementation on cholinesterase enzymes and its relationship with animal behavior of weaning piglets exposed to mycotoxin contaminated diets. To achieve these objectives, two experimental design approaches were used. Male piglets (7.15±0.61kg) were allocated in four groups: CTL group received a regular diet; SDPP group received a regular diet and 6% SDPP; MYC group received a diet containing desired contamination of 210 µg/kg aflatoxins and 6.690 µg/kg fumonisins; group MYC+SDPP received 253 µg/kg aflatoxins, 6930 µg/kg fumonisins and 6% SDPP. The animals treated with mycotoxin co-contaminated diets showed an increase in AChE and BChE activities in peripheral system (MYC) when compared to control (CTL). Furthermore, supplementation with SDPP (MYC+SDPP group) prevented the mycotoxin-related reduction of AChE in blood and brain. Behavioral tests showed that sleeping and resting behaviors were more often observed in the MYC group; this group also fed fewer times when compared to the other groups, characterizing the deleterious effect of mycotoxins. Taken together, the data suggest changes in AChE and BChE activities may indicate alterations in cholinergic neurotransmission and consequently in the behavior of piglets.


Assuntos
Acetilcolinesterase/metabolismo , Ração Animal/microbiologia , Comportamento Animal , Suplementos Nutricionais/microbiologia , Contaminação de Alimentos , Micotoxinas/efeitos adversos , Suínos/fisiologia , Animais , Inibidores da Colinesterase , Masculino
7.
Toxicol Lett ; 314: 124-132, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31362050

RESUMO

Organophosphates are chemical pollutants that are existed widely in the environment, but the reactions of these agents with blood proteins are still not fully clarified. The current story was to analyze the static and dynamic interactions between human serum albumin (HSA) and phenthoate and then uncover the impact of the conjugations on the acetylcholinesterase (AChE) activity at the microscopic scale. Experimental results revealed clearly that the bioconjugate of the HSA-phenthoate was yielded and the conformation of HSA can produce autoregulation during the reaction. Dynamic reaction processes suggested that the conformational flexibility of the specific protein domain was changed significantly in equilibrium, and the electrostatic interaction energy played a major role in total energy of the biosystems, which matches the results of wet experiment and molecular docking. We also found that the modes of homologous proteins-phenthoate have obvious distinctions, and this point is related closely to the local dynamic flexibility of biomolecular structures. Additionally, the degree of bioconjugation of the HSA-phenthoate is positively associated with the enzymatic activity of target AChE, which may be attributed to the competitive reactions between HSA and AChE. Evidently, this scenario could provide useful molecular information for the systematic exploration of the toxicokinetics of organophosphorus compounds.


Assuntos
Inibidores da Colinesterase/sangue , Inseticidas/sangue , Modelos Biológicos , Simulação de Acoplamento Molecular , Compostos Organotiofosforados/sangue , Albumina Sérica Humana/metabolismo , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Sítios de Ligação , Ligação Competitiva , Inibidores da Colinesterase/química , Inibidores da Colinesterase/toxicidade , Humanos , Inseticidas/química , Inseticidas/toxicidade , Compostos Organotiofosforados/química , Compostos Organotiofosforados/toxicidade , Ligação Proteica , Conformação Proteica , Domínios Proteicos , Albumina Sérica Humana/química
8.
Ecotoxicol Environ Saf ; 182: 109311, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31272021

RESUMO

Effects of sub-lethal concentrations (0 (control), 0.009, 0.014, and 0.023 ppm) of the organophosphate insecticide "malathion" to rainbow trout (Oncorhynchus mykiss) after the determination of LC50-96 h value (0.093 ppm) were evaluated. Changes in biomarkers of neurotoxicity (acetylcholinesterase (AChE) activity), genotoxicity (DNA damage), and hematological parameters (red (RBC) and white (WBC) blood cell count, hemoglobin (Hb), hematocrit (Hct), mean cell hemoglobin (MCH), mean cell volume (MCV), and mean cell hemoglobin concentration (MCHC)) were assessed for a 15-day exposure. A significant time- and dose-dependent reduction in AChE activities of gill, muscle, brain, and liver tissues was found. However, the AChE activity was less affected by malathion concentration than by exposure time. DNA damage of erythrocytes at different malathion concentrations increased by increasing the experimental time up to the fourth day. A decrease in the count of WBC, RBC, and Hct and an increase in the number of MCH and MCV were observed by increasing malathion exposure dose and time (p < 0.05). An increase in the malathion concentration and exposure time significantly resulted in a decrease in Hb and an increase in MCHC. A significant improvement in AChE activity; DNA damage; and RBC, Hb, Hct, MCV, and MCH indices was detected during a 30-day recovery period, but the WBC count changed insignificantly. The recovery pattern based on 100% water exchange with clean water could be a successful strategy to improve the biomarker responses of rainbow trout habituating in contaminated aquatic environments.


Assuntos
Acetilcolinesterase/metabolismo , Malation/toxicidade , Oncorhynchus mykiss/fisiologia , Poluentes Químicos da Água/toxicidade , Animais , Dano ao DNA , Índices de Eritrócitos , Eritrócitos/efeitos dos fármacos , Hematócrito , Hemoglobinas/análise , Dose Letal Mediana , Contagem de Leucócitos
9.
Clin Exp Rheumatol ; 37 Suppl 117(2): 20-25, 2019 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31162030

RESUMO

OBJECTIVES: To investigate the in-situ expression of acetylcholinesterase (AChE) in the inflamed vessel wall of patients with biopsy-positive giant cell arteritis (GCA) as compared to biopsy-negative non-GCA patients, and to evaluate the in-vivo expression of AChE in patients with large-vessel GCA (LVGCA) by 11C-donepezil (AChE inhibitor) positron emission tomography/computed tomography (PET/CT). METHODS: Twenty-four biopsy-positive GCA and 44 biopsy-negative non-GCA patients were included for AChE histology. Immunohistochemical methods were used to determine the AChE expression. The histological inflammation and the AChE expression were assessed by an experienced pathologist on a 3-point scale. Two patients with newly diagnosed 18F-fluorodeoxyglucose (18F-FDG) PET/CT verified LVGCA were included for 11C-donepezil PET/CT. PET images were assessed by an experienced nuclear medicine physician. RESULTS: AChE was expressed in all 24 positive temporal artery biopsies, 10/24 showed high AChE expression (grade 2) and 14/24 showed moderate AChE expression (grade 1). No AChE expression was observed outside the media smooth muscle cells (grade 0) in any of the biopsy-negative non-GCA patients. The AChE expression was in 86% agreement with the histological inflammation. The AChE expression was not associated with any clinical or biochemical findings. In both LV-GCA patients, PET/CT revealed extensive vascular FDG uptake but no 11C-donepezil uptake. CONCLUSIONS: AChE is highly expressed in the inflamed vessel wall of patients with GCA. Although, 11C-donepezil PET/CT showed no vascular uptake in the FDG PET/CT verified LV-GCA patients, histological findings raise the possibility that AChE can be used in the development of new diagnostic and disease monitoring tools for GCA.


Assuntos
Acetilcolinesterase/metabolismo , Arterite de Células Gigantes , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Radioisótopos de Carbono , Donepezila , Fluordesoxiglucose F18 , Arterite de Células Gigantes/diagnóstico por imagem , Arterite de Células Gigantes/enzimologia , Arterite de Células Gigantes/patologia , Humanos , Inflamação , Compostos Radiofarmacêuticos
10.
Pestic Biochem Physiol ; 157: 122-137, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31153459

RESUMO

Novel phospho guanidine and phospho pyrazine derivatives were synthesized and characterized by 31P, 13C, 1HNMR and IR spectroscopy to obtain novel and human-safe insecticides. Compound 35 [(C4H4N2NH)2P(O)(C6H6)] was investigated by X-ray crystallography. The inhibitory effects of synthesized compounds were evaluated on human and insect acetylcholinesterase (AChE) using in vitro Ellman method. A few of these compounds, which had low human toxicity, were selected for assessing the killing effects (in vivo) on the elm leaf beetle (X.luteola). The in vitro and in vivo results indicated that compounds bearing both phosphoryl groups and aromatic systems were found to possess a good selectivity for the inhibition of insect AChE over human AChE; up to 550-fold selectivity was achieved for compound 19. Docking studies were performed to explain reasons for the selective behavior of AChE inhibitors. Additionally, the quantitative structure-activity relationship (QSAR) and density functional theory (DFT) results of AChEs demonstrated that the size, shape, dipole moment, and ability to form hydrogen bond played the main role in both models. In addition, the aromatic π - π interactions and charge of the amide nitrogen had a major effect on insecticidal activity of the compounds. The present research can be helpful to gain a better understanding of the interactions between the insect AChE and its inhibitors and introduces compounds which are capable of becoming human-safe insecticides.


Assuntos
Inibidores da Colinesterase/química , Inibidores da Colinesterase/síntese química , Guanidinas/química , Pirazinas/química , Acetilcolinesterase/metabolismo , Animais , Inibidores da Colinesterase/farmacologia , Besouros/efeitos dos fármacos , Humanos , Inseticidas/síntese química , Inseticidas/química , Inseticidas/farmacologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Quantitativa Estrutura-Atividade , Relação Estrutura-Atividade
11.
Sci Total Environ ; 683: 624-637, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31150883

RESUMO

The non-steroidal anti-inflammatory drug diclofenac (DCF) threatens the health of aquatic animals and ecosystems. In the present study, different biological endpoints (mortality, development and growth, abnormalities, cardiotoxicity, neurotoxicity and antioxidant system) were used to characterize the acute and chronic effects of DCF (at concentrations ranging between 125 and 4000 µg L-1) on two amphibian species from Argentina (Trachycephalus typhonius and Physalaemus albonotatus). Results showed that the larval developmental, growth rates, and body condition of DCF-exposed individuals of both species were significantly reduced. DCF-exposed individuals also showed several morphological abnormalities, including significantly altered body axis, chondrocranium and hyobranchial skeleton, and organ and visceral abnormalities including cardiac hypoplasia, malrotated guts, asymmetrically inverted guts, and cholecystitis. DCF also had a significant effect on the swimming performance of both species: at low concentrations (125 and 250 µg L-1), swimming distance, velocity and global activity decreased, whereas, at high concentrations (1000 and 2000 µg L-1), these behavioral responses increased. Regarding cardiac function and rhythm, at DCF concentrations higher than 1000 µg L-1, the heart frequency and ventricular systole interval of both species were significantly reduced. Regarding the antioxidant system, the activity of acetylcholinesterase indicated that DCF is neurotoxic and thus related to the changes in behavioral performance. The DCF concentrations studied produced a biochemical imbalance between radical oxygen species production and antioxidant systems. The sensitivities to sublethal and chronic DCF exposure in both anuran species were similar, thus indicating the inherent complexity involved in understanding the biotoxic effects of DCF.


Assuntos
Anti-Inflamatórios não Esteroides/toxicidade , Anuros/fisiologia , Diclofenaco/toxicidade , Coração/fisiologia , Poluentes Químicos da Água/toxicidade , Acetilcolinesterase/metabolismo , Animais , Coração/efeitos dos fármacos , Larva/efeitos dos fármacos , Testes de Toxicidade
12.
Chem Biol Interact ; 308: 317-322, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31170385

RESUMO

Acetylcholinesterase (AChE) hydrolyzes acetylcholine at cholinergic synapses, and which has various isoforms of AChE, i.e. AChER, AChEH and AChET, deriving from single gene. AChEH exists as a glycophosphatidylinositol (GPI)-linked dimer (G2), presents mainly in plasma membrane of mammalian erythrocyte. Transgenic mice with ACHE gene depletion were employed here to investigate the possible role of AChE in blood cell formation. ACHE knock-out mice were found to suffer normocytic anemia. In erythrocyte of ACHE-/- mice, the amount of hemoglobin, especially α-globin, was found to be markedly reduced. In addition, the number of erythrocyte and hematocrit of ACHE-/- mice were significantly lowered. To probe the role of AChE isoforms in erythroid differentiation, erythroblast-like cells (TF-1) over-expressed with different AChE isoforms were induced to differentiate by erythropoietin (EPO): this differentiation induced the expression of each AChE isoform. Only in the TF-1 cells over-expressed with AChEH, the EPO-induced transcriptions and protein expressions of α- and ß-globins could be significantly enhanced, which therefore suggested that AChEH might regulate the responsiveness of TF-1 cells to EPO. The alternation of EPO-induced downstream signaling might be accounted by association of AChE with EPO receptor in cell surface. The findings indicated the significance of AChE in erythroblast maturation, which provided an insight in elucidating possible mechanisms in regulating erythropoiesis.


Assuntos
Acetilcolinesterase/metabolismo , Receptores da Eritropoetina/metabolismo , Acetilcolinesterase/química , Acetilcolinesterase/imunologia , Animais , Anticorpos/imunologia , Diferenciação Celular , Linhagem Celular , Dimerização , Eritroblastos/citologia , Eritroblastos/metabolismo , Eritropoetina/farmacologia , Expressão Gênica/efeitos dos fármacos , Hemoglobinas/metabolismo , Humanos , Camundongos , Camundongos Knockout , Receptores da Eritropoetina/imunologia
13.
Chem Biol Interact ; 308: 392-395, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31175846

RESUMO

Carbamates are esters of substituted carbamic acids that react with acetylcholinesterase (AChE) by initially transferring the carbamoyl group to a serine residue in the enzyme active site accompanied by loss of the carbamate leaving group followed by hydrolysis of the carbamoyl enzyme. This hydrolysis, or decarbamoylation, is relatively slow, and half-lives of carbamoylated AChEs range from 4 min to more than 30 days. Therefore, carbamates are effective AChE inhibitors that have been developed as insecticides and as therapeutic agents. In this report, we review recent data showing that decarbamoylation rate constants are independent of the ester leaving group for a series of carbamic acid esters with the same carbamoyl group and that decarbamoylation rate constants decreased by 800-fold when the alkyl substituents on the carbamoyl group increased in size from N-monomethyl- to N,N-diethyl-. We also review data showing that solvent deuterium oxide isotope effects for decarbamoylation decreased from 2.8 for N-monomethylcarbamoyl AChE to 1.1 for N,N-diethylcarbamoyl AChE, indicating a shift in the rate-limiting step from general acid-base catalysis to a likely conformational change in the distorted active site in N,N-diethylcarbamoyl AChE. The nature of such a conformational change is suggested from X-ray crystal structures of AChE phosphorylated by paraoxon.


Assuntos
Acetilcolinesterase/metabolismo , Carbamatos/metabolismo , Acetilcolinesterase/química , Carbamatos/química , Domínio Catalítico , Cristalografia por Raios X , Cinética , Paraoxon/química , Paraoxon/metabolismo
14.
Mar Pollut Bull ; 142: 178-182, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31232292

RESUMO

The main objective of the present study was to explore the potential link between acetylcholinesterase (AChE) activity and burrowing behaviour of the ragworm Hediste diversicolor, which may have consequences at higher levels of biological organisation. Two complementary studies were conducted. AChE activity, at the sub-individual level, and behavioural responses, at the individual level, were evaluated in worms from the Loire estuary (France), whereas density and biomass of H. diversicolor were determined at the population level. A Spearman positive correlation between both biomarkers (AChE and burrowing) suggested that inhibition of AChE activity was linked to behaviour impairments. At the population level, lower AChE and behaviour activities were detected in worms corresponding to lower population density and biomass. These results provide direct empirical field evidence demonstrating the sensitivity of behaviour of H. diversicolor as a biomonitor of estuarine health status assessment.


Assuntos
Acetilcolinesterase/metabolismo , Poliquetos/fisiologia , Animais , Comportamento Animal/fisiologia , Biomarcadores/metabolismo , Ecotoxicologia/métodos , Estuários , França , Densidade Demográfica
15.
Chem Biol Interact ; 309: 108686, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31152735

RESUMO

Acetylcholinesterase (EC3.1.1.7; AChE) is a key enzyme in the cholinergic system. Emerging evidence has shown that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a typical persistent organic pollutant, suppressed neuronal AChE activity via dysregulation of different biosynthesis processes in human and rat neuronal cells. In the nervous system, astrocytes protect neurons from environmental pollutants. As a known target cell of TCDD, the astrocyte might be involved in TCDD effects on neuronal AChE. Therefore, in the present study, we found astrocyte-derived conditioned medium (ACM) could induce AChE activity preferentially in mature neurons in the absence of TCDD. The enzymatic activity of AChE was generally decreased in cultured cortical neurons upon direct treatment with TCDD (0.003-0.01 nM). This trend of changes in AChE activity was not significantly altered in immature neurons exposed to ACM produced in the presence of TCDD (TACM group), but reversed in mature neurons. Compared with effects of treatment with ACM plus TCDD (ACMT), a significant differential effect on AChE activity was found in the TACM group in response to TCDD treatment specifically in immature neurons, suggesting the presence of a TCDD-specific active component derived from the astrocyte. Inconsistent alterations in expression and enzymatic activities of the AChE T subunit (AChET) and the proline-rich membrane anchor (PRiMA) were found, suggesting that a mechanism of action beyond the transcriptional level might be involved. These data indicate that the astrocyte might play a protective role in TCDD-induced alterations of neuronal AChE in certain stages of differentiation.


Assuntos
Acetilcolinesterase/metabolismo , Meios de Cultivo Condicionados/química , Expressão Gênica/efeitos dos fármacos , Dibenzodioxinas Policloradas/farmacologia , Acetilcolinesterase/genética , Animais , Astrócitos/citologia , Astrócitos/metabolismo , Células Cultivadas , Meios de Cultivo Condicionados/farmacologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Dibenzodioxinas Policloradas/química , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley
16.
Chem Biodivers ; 16(7): e1900144, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31155827

RESUMO

A new series of coumarin-3-carboxamide-N-morpholine hybrids 5a-5l was designed and synthesized as cholinesterases inhibitors. The synthetic approach for title compounds was started from the reaction between 2-hydroxybenzaldehyde derivatives and Meldrum's acid to afford corresponding coumarin-3-carboxylic acids. Then, amidation of the latter compounds with 2-morpholinoethylamine or N-(3-aminopropyl)morpholine led to the formation of the compounds 5a-5l. The in vitro inhibition screen against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) revealed that most of the synthesized compounds had potent AChE inhibitory while their BuChE inhibitions are moderate to weak. Among them, propylmorpholine derivative 5g (N-[3-(morpholin-4-yl)propyl]-2-oxo-2H-chromene-3-carboxamide) bearing an unsubstituted coumarin moiety and ethylmorpholine derivative 5d (6-bromo-N-[2-(morpholin-4-yl)ethyl]-2-oxo-2H-chromene-3-carboxamide) bearing a 6-bromocoumarin moiety showed the most activity against AChE and BuChE, respectively. The inhibitory activity of compound 5g against AChE was 1.78 times more than that of rivastigmine and anti-BuChE activity of compound 5d is approximately same as rivastigmine. Kinetic and docking studies confirmed the dual binding site ability of compound 5g to inhibit AChE.


Assuntos
Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Desenho de Drogas , Morfolinas/farmacologia , Doença de Alzheimer/metabolismo , Animais , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Electrophorus , Cavalos , Cinética , Simulação de Acoplamento Molecular , Estrutura Molecular , Morfolinas/síntese química , Morfolinas/química
17.
Chem Biol Interact ; 309: 108682, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31163137

RESUMO

Casualties caused by nerve agents, potent acetylcholinesterase inhibitors, have attracted attention from media recently. Poisoning with these chemicals may be fatal if not correctly addressed. Therefore, research on novel antidotes is clearly warranted. Pyridinium oximes are the only clinically available compounds, but poor penetration into the blood-brain barrier hampers efficient enzyme reactivation at the central nervous system. In searching for structural factors that may be explored in SAR studies, we synthesized and evaluated neutral aryloximes as reactivators for acetylcholinesterase inhibited by NEMP, a VX surrogate. Although few tested compounds reached comparable reactivation results with clinical standards, they may be considered as leads for further optimization.


Assuntos
Acetilcolinesterase/metabolismo , Reativadores da Colinesterase/síntese química , Oximas/química , Pirrolidinas/química , Acetilcolinesterase/química , Animais , Antídotos/síntese química , Antídotos/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Reativadores da Colinesterase/metabolismo , Enguias , Compostos Organotiofosforados/química , Compostos Organotiofosforados/metabolismo , Oximas/metabolismo , Pirrolidinas/metabolismo , Relação Estrutura-Atividade
18.
Chem Biol Interact ; 309: 108707, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31194956

RESUMO

Alzheimer's disease (AD) is a slow but progressive neurodegenerative disease. One of the pathological hallmarks of AD is the progressive accumulation of ß-amyloid (Aß) in the form of senile plaques, and Aß insult to neuronal cells has been identified as one of the major causes of AD onset. In the present study, we investigated the anti-AD potential of four flavonoids, naringenin, didymin, prunin, and poncirin, by evaluating their ability to inhibit acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and ß-site amyloid precursor protein cleaving enzyme 1 (BACE1). All four flavonoids displayed promising inhibitory activity against AChE, BChE, and BACE1. Structure-activity relationships suggested that glycosylation of naringenin at sugar moieties, and at different positions of the glycosidic linkage, might be closely associated with anti-AD potential. Kinetic and docking studies showed the lowest binding energy and highest affinity for the mixed, competitive, and non-competitive type inhibitors didymin, prunin, and poncirin. Hydrophobic interactions and the number of hydrogen bonds determined the strength of the protein-inhibitor interaction. We also examined the neuroprotective mechanisms by which flavonoids act against Aß25-35-induced toxicity in PC12 cells. Exposure of PC12 cells to 10 µM Aß25-35 for 24 h resulted in a significant decrease in cell viability. In addition, pretreatment of PC12 cells with different concentrations of flavonoids for 1 h significantly reversed the effects of Aß. Furthermore, treatment with the most active flavonoid, didymin, significantly reduced BACE1, APPsß, and C99 expression levels in a dose-dependent manner, without affecting amyloid precursor protein (APP) levels in the amyloidogenic pathway. Together, our results indicate that flavonoids, and in particular didymin, exhibit inhibitory activity in vitro, and may be useful in the development of therapeutic modalities for the treatment of AD.


Assuntos
Acetilcolinesterase/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Butirilcolinesterase/metabolismo , Flavanonas/química , Glicosídeos/farmacologia , Agregados Proteicos/efeitos dos fármacos , Acetilcolinesterase/química , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/farmacologia , Animais , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Sítios de Ligação , Butirilcolinesterase/química , Domínio Catalítico , Sobrevivência Celular/efeitos dos fármacos , Glicosídeos/química , Cinética , Simulação de Acoplamento Molecular , Células PC12 , Fragmentos de Peptídeos/farmacologia , Substâncias Protetoras/química , Substâncias Protetoras/farmacologia , Ratos , Relação Estrutura-Atividade
19.
Chem Biol Interact ; 309: 108699, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31202688

RESUMO

The crystal structures of truncated forms of cholinesterases provide good models for assessing the role of non-covalent interactions in dimer assembly in the absence of cross-linking disulfide bonds. These structures identify the four-helix bundle that serves as the interface for formation of acetylcholinesterase and butyrylcholinesterase dimers. Here we performed a theoretical comparison of the structural and energetic factors governing dimerization. This included identification of inter-subunit and intra-subunit hydrogen bonds and hydrophobic interactions, evaluation of solvent-accessible surfaces, and estimation of electrostatic contributions to dimerization. To reveal the contribution to dimerization of individual amino acids within the contact area, free energy perturbation alanine screening was performed. Markov state modelling shows that the loop between the α13 and α14 helices in BChE is unstable, and occupies 4 macro-states. The order of magnitude of mean first passage times between these macrostates is ~10-8 s. Replica exchange molecular dynamics umbrella sampling calculations revealed that the free energy of human BChE dimerization is -15.5 kcal/mol, while that for human AChE is -26.4 kcal/mol. Thus, the C-terminally truncated human butyrylcholinesterase dimer is substantially less stable than that of human acetylcholinesterase. An animated Interactive 3D Complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:CHEMBIOINT:1.


Assuntos
Acetilcolinesterase/química , Butirilcolinesterase/química , Acetilcolinesterase/metabolismo , Sequência de Aminoácidos , Butirilcolinesterase/metabolismo , Dimerização , Humanos , Interações Hidrofóbicas e Hidrofílicas , Cadeias de Markov , Simulação de Dinâmica Molecular , Conformação Proteica em alfa-Hélice , Alinhamento de Sequência , Eletricidade Estática , Termodinâmica
20.
Chem Biol Interact ; 309: 108671, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31207225

RESUMO

Studies with oximes have been extensively developed to design new reactivators with better efficiency, and greater spectrum of action. In this study, we aimed to analyze the influence of the Carbamoyl group position change in two isomeric oximes, K203 and K206, on the reactivation percentage of Mus musculus Acetylcholinesterase (MmAChE), inhibited by different nerve agents. Theoretical calculations were performed to assess the difference for the oxime activity with inhibited AChE-complexes and the factors that govern this difference. Comparing theoretical and experimental data, it is possible to observe that this change between the oximes results in different reactivation percentage for the same nerve agent, due to the different interaction modes and activation energy for the studied systems.


Assuntos
Acetilcolinesterase/metabolismo , Reativadores da Colinesterase/química , Compostos Organofosforados/química , Oximas/química , Acetilcolinesterase/química , Animais , Sítios de Ligação , Reativadores da Colinesterase/metabolismo , Desenho de Drogas , Camundongos , Simulação de Acoplamento Molecular , Agentes Neurotóxicos/química , Agentes Neurotóxicos/metabolismo , Compostos Organofosforados/metabolismo , Compostos Organotiofosforados/química , Compostos Organotiofosforados/metabolismo , Teoria Quântica , Termodinâmica
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