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1.
J Agric Food Chem ; 67(44): 12182-12190, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31609606

RESUMO

In continuation of our program to develop natural-product-based pesticidal candidates, matrinic/oxymatrinic amides were obtained through structural optimization of matrine. N'-(4-Fluoro)phenyl-N-(4-bromo)phenylsulfonyloxymatrinic amide (IIm) showed potent insecticidal activity against Mythimna separata. N-(Un)substituted phenylsulfonylmatrinic acids (3a-c) exhibited promising acaricidal activity against Tetranychus cinnabarinus. By qRT-PCR analysis of nAChR subunits and AChE genes and determination of AChE activity of (un)treated T. cinnabarinus, it suggested that the open lactam ring of matrine and carboxyl group and (4-methyl)phenylsulfonyl of N-(4-methyl)phenylsulfonylmatrinic acid (3b) were necessary for action with α2, α4, α5, and ß3 nAChR subunits; compound 3b was an inhibitor of AChE in T. cinnabarinus, and AChE was one possible target of action in T. cinnabarinus against 3b; and compound 3b may be an antagonist of nAChR and AChE in T. cinnabarinus.


Assuntos
Acaricidas/química , Alcaloides/química , Amidas/química , Inseticidas/química , Quinolizinas/química , Acaricidas/síntese química , Acaricidas/farmacologia , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Alcaloides/farmacologia , Amidas/farmacologia , Animais , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Feminino , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Inseticidas/síntese química , Inseticidas/farmacologia , Estrutura Molecular , Mariposas/efeitos dos fármacos , Mariposas/genética , Mariposas/crescimento & desenvolvimento , Mariposas/metabolismo , Quinolizinas/farmacologia , Relação Estrutura-Atividade , Tetranychidae/efeitos dos fármacos , Tetranychidae/genética , Tetranychidae/crescimento & desenvolvimento , Tetranychidae/metabolismo
2.
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
3.
Gene ; 711: 143924, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31212050

RESUMO

The MnSOD Ala16Val single nucleotide polymorphism (SNP) has shown to be associated to inflammatory pathways and many metabolic disorders, such as obesity and dyslipidemia. Metabolic syndrome (MetS) is an emergent problem among patients with epilepsy. However, little is known about interaction between MnSOD Ala16Val SNP and metabolic comorbities in epilepsy. Thus, we investigated the relationship between MnSOD Ala16Val SNP with epilepsy and its influence on MetS, inflammation, apoptosis and DNA damage parameters. Ninety subjects were evaluated (47 epilepsy patients and 43 healthy controls) by questionnaires and laboratorial exams. Levels of inflammatory, apoptotic and DNA damage markers, as well as MnSOD polymorphism were assessed. An increased proportion of VV genotype in epilepsy group when compared to control group was observed. Tumor Necrosis Factor-α (TNF-α), Acetylcholinesterase, caspase-8, and Picogreen levels were increased in VV epilepsy group. An important correlation between TNF-α vs caspase-8, and Cholesterol vs. Triglycerides was observed in the epilepsy group with VV genotype. Our findings suggest that the MnSOD Ala16Val SNP might have an important role in epilepsy, mainly in patients with generalized seizures and particularly with VV genotype. The metabolic parameters also presented significant results in epilepsy group with VV genotype, which applying attention in view of further consequences and disorders that could be developed.


Assuntos
Substituição de Aminoácidos , Colesterol/metabolismo , Convulsões/genética , Superóxido Dismutase/genética , Triglicerídeos/metabolismo , Acetilcolinesterase/genética , Adulto , Estudos de Casos e Controles , Caspase 8/genética , Dano ao DNA , Feminino , Proteínas Ligadas por GPI/genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Estresse Oxidativo , Fator de Necrose Tumoral alfa/genética
4.
Chem Biol Interact ; 309: 108698, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31176713

RESUMO

Structure-guided design of novel pharmacologically active molecules relies at least in part on functionally relevant accuracy of macromolecular structures for template based drug design. Currently, about 95% of all macromolecular X-ray structures available in the PDB (Protein Data Bank) were obtained from diffraction experiments at low, cryogenic temperatures. However, it is known that functionally relevant conformations of both macromolecules and pharmacological ligands can differ at higher, physiological temperatures. We describe in this article development and properties of new human acetylcholinesterase (AChE) crystals of space group P31 and a new unit cell, amenable for room-temperature X-ray diffraction studies. We co-crystallized hAChE in P31 unit cell with the reversible inhibitor 9-aminoacridine that binds at the base of the active center gorge in addition to inhibitors that span the full length of the gorge, donepezil (Aricept, E2020) and AChE specific inhibitor BW284c51. Their new low temperature P31 space group structures appear similar to those previously obtained in the different P3121 unit cell. Successful solution of the new room temperature 3.2 Å resolution structure of BW284c51*hAChE complex from large P31 crystals enables us to proceed with studying room temperature structures of lower affinity complexes, such as oxime reactivators bound to hAChE, where temperature-related conformational diversity could be expected in both oxime and hAChE, which could lead to better informed structure-based design under conditions approaching physiological temperature.


Assuntos
Acetilcolinesterase/química , Cristalografia por Raios X , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Aminacrina/química , Aminacrina/metabolismo , Sítios de Ligação , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Dimerização , Humanos , Simulação de Dinâmica Molecular , Estrutura Quaternária de Proteína , Estrutura Terciária de Proteína , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Temperatura Ambiente
5.
Nat Rev Dis Primers ; 5(1): 30, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-31048702

RESUMO

Myasthenia gravis (MG) is an autoimmune disease caused by antibodies against the acetylcholine receptor (AChR), muscle-specific kinase (MuSK) or other AChR-related proteins in the postsynaptic muscle membrane. Localized or general muscle weakness is the predominant symptom and is induced by the antibodies. Patients are grouped according to the presence of antibodies, symptoms, age at onset and thymus pathology. Diagnosis is straightforward in most patients with typical symptoms and a positive antibody test, although a detailed clinical and neurophysiological examination is important in antibody-negative patients. MG therapy should be ambitious and aim for clinical remission or only mild symptoms with near-normal function and quality of life. Treatment should be based on MG subgroup and includes symptomatic treatment using acetylcholinesterase inhibitors, thymectomy and immunotherapy. Intravenous immunoglobulin and plasma exchange are fast-acting treatments used for disease exacerbations, and intensive care is necessary during exacerbations with respiratory failure. Comorbidity is frequent, particularly in elderly patients. Active physical training should be encouraged.


Assuntos
Miastenia Gravis/diagnóstico , Miastenia Gravis/terapia , Acetilcolinesterase/genética , Acetilcolinesterase/fisiologia , Corticosteroides/uso terapêutico , Agrina/genética , Agrina/fisiologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Autoanticorpos/análise , Autoanticorpos/sangue , Biomarcadores/análise , Biomarcadores/sangue , Blefaroptose/etiologia , Colágeno/genética , Colágeno/fisiologia , Cortactina/genética , Cortactina/fisiologia , Eletromiografia/métodos , Humanos , Canal de Potássio Kv1.4/genética , Canal de Potássio Kv1.4/fisiologia , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas Relacionadas a Receptor de LDL/fisiologia , Proteínas Musculares/genética , Proteínas Musculares/fisiologia , Miastenia Gravis/fisiopatologia , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/fisiologia , Receptores Colinérgicos/genética , Receptores Colinérgicos/fisiologia , Receptores Nicotínicos/genética , Fatores de Risco , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/fisiologia
6.
Fa Yi Xue Za Zhi ; 35(2): 143-148, 2019 Apr.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-31135106

RESUMO

Abstract: Objective To study the time-dependent expression and distribution of acetylcholinesterase (AChE) during skin incised wound healing in mice, and discuss its effect in wound healing as well as the feasibility of using it as a reference index for wound age estimation. Methods A total of 45 C57BL/KsJ mice were randomly divided into one control group and eight incised groups. The skin incised wound model was established in the incised groups with samples of skin wounds taken at 6 h, 12 h, 1 d, 3 d, 5 d, 7 d, 10 d and 14 d post-injury respectively, while the uninjured skin tissue was extracted in the control group. Expression and distribution of AChE in skin samples were detected by immunohistochemistry, double immunofluorescence and Western blotting. Results Immunohistochemistry results indicated that AChE was mainly detected in infiltrating polymorphonuclear cells (PMNs) 6 to 12 h post-injury. A large number of AChE-positive mononuclear cells (MNCs) were observed 1 to 3 d post-injury. The AChE-positive cells were mainly fibroblastic cells (FBCs) 5 to 14 d post-injury. The ratio of the AChE-positive cells increased initially 6 h post-injury, and reached the peak at 1 d post-injury. Double immunofluorescent staining showed that the majority of AChE-positive MNCs and FBCs expressed macrophage marker and myofibroblast marker, respectively. Western blotting results showed that the relative expression level of AChE in the incised group was higher than that in the control group averagely, reached the peak at 1 d post-injury, then reached a second peak at 7 d post-injury. Conclusion The expression of AChE is found in PMNs, macrophages and myofibroblast during skin wound healing, which indicates it might be involved in the adjustment of inflammatory response and fibrotic repair after injury. Moreover, combined use of various methods for the detection of the expression of AChE would provide reference for skin wound age estimation.


Assuntos
Acetilcolinesterase/metabolismo , Pele/lesões , Pele/metabolismo , Cicatrização/fisiologia , Acetilcolinesterase/genética , Animais , Camundongos , Camundongos Endogâmicos C57BL , Pele/patologia , Fatores de Tempo
7.
Chem Biol Interact ; 308: 101-109, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31100281

RESUMO

Eight derivatives of 4-aminoquinolines differing in the substituents attached to the C(4)-amino group and C(7) were synthesised and tested as inhibitors of human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Both enzymes were inhibited by all of the compounds with inhibition constants (Ki) ranging from 0.50 to 50 µM exhibiting slight selectivity toward AChE over BChE. The most potent inhibitors of AChE were compounds with an n-octylamino chain or adamantyl group. The shortening of the chain length resulted in a decrease in AChE inhibition by 5-20 times. Docking studies revealed that the quinoline group within the AChE active site was positioned in the choline binding site, while the C(4)-amino group substituents, depending on their lipophilicity, could establish hydrogen bonds or π-interactions with residues of the peripheral anionic site. The most potent inhibitors of BChE were compounds with the most voluminous substituent on C(4)-amino group (adamantyl) or those with a stronger electron withdrawing substituent on C(7) (trifluormethyl group). Based on AChE inhibition, compounds with an n-octylamino chain or adamantyl substituent were shown to possess the capacity for further development as potential drugs for treatment of neurodegenerative diseases.


Assuntos
Acetilcolinesterase/química , Aminoquinolinas/química , Butirilcolinesterase/química , Inibidores da Colinesterase/química , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Aminoquinolinas/metabolismo , Sítios de Ligação , Barreira Hematoencefálica/metabolismo , Butirilcolinesterase/genética , Butirilcolinesterase/metabolismo , Domínio Catalítico , Inibidores da Colinesterase/metabolismo , Humanos , Cinética , Simulação de Acoplamento Molecular , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação
8.
Chem Biol Interact ; 308: 130-136, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31129131

RESUMO

Substance addiction is a chronic, relapsing mental disorder Characterized by compulsive drug seeking, and loss of control over drug intake and relapse after prolonged abstinence. Genetics has been shown to contribute towards an individual's vulnerability to addiction. Acetylecholine (ACh), a cholinergic neurotransmitter hydrolyzed by acetylcholinesterase (AChE), is an essential neurotransmitter and neuromodulator in central and peripheral nervous system and has regulatory influence on numerous neuronal functions including addiction. The present study was carried out to investigate the role of acetylcholinesterase (AChE) in addiction through measurement of enzyme activity and to find potential association of ACHE gene 3'UTR variants rs17228602 and rs17228616 in heroin, hashish and poly drug addicts. Both SNPs are located within microRNA (miRNA) recognition sites with potential to affect miRNA/transcript interaction. A total of 122 addicts of heroin, hashish and polydrug were recruited from local rehabilitation centers to participate in this study. AChE activity was measured in blood by Ellman's method. SNP genotyping was performed by restriction fragment length polymorphism (PCR-RFLP) and Sanger sequencing. The AChE activity was found significantly higher (p ≤ 0.005) in addicted cohort (mean ±â€¯standard error of mean 0.020 ±â€¯0.001 µmol/L/min; 95% confidence interval (CI) 0.018-0.022) in comparison to non-addicted healthy subjects (0.011 ±â€¯0.001 µmol/L/min; 95% confidence interval CI 0.010-0.013). A statistically significant association of ACHE rs17228602 SNP with addiction vulnerability in dominant (DM: Odd's ratio OR = 2.095, 95% CI = 1.157-3.807 p = 0.009) and allelic genetic models (OR = 1.854 95% CI = 1.082-3.187, p = 0.016) was observed. However, no statistically significant association of rs17228616 SNP with substance abuse disorder was found. The data presented here shows that AChE could play significant role in substance addiction. Further studies with larger sample size and other variants of AChE are recommended to identify novel therapeutic approaches for cholinergic based treatment of addiction.


Assuntos
Acetilcolinesterase/genética , Grupo com Ancestrais do Continente Asiático/genética , Transtornos Relacionados ao Uso de Substâncias/patologia , Regiões 3' não Traduzidas , Acetilcolinesterase/metabolismo , Alelos , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Heroína/efeitos adversos , Humanos , Cinética , MicroRNAs/química , MicroRNAs/metabolismo , Razão de Chances , Paquistão , Polimorfismo de Nucleotídeo Único , Transtornos Relacionados ao Uso de Substâncias/genética
9.
Int J Mol Sci ; 20(10)2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31096579

RESUMO

An in silico analysis of the interaction between the complex-ligands of nine acetylcholinesterase (AChE) structures of Lepidopteran organisms and 43 organophosphorus (OPs) pesticides with previous resistance reports was carried out. To predict the potential resistance by structural modifications in Lepidoptera insects, due to proposed point mutations in AChE, a broad analysis was performed using computational tools, such as homology modeling and molecular docking. Two relevant findings were revealed: (1) Docking results give a configuration of the most probable spatial orientation of two interacting molecules (AChE enzyme and OP pesticide) and (2) a predicted ΔGb. The mutations evaluated in the form 1 acetylcholinesterase (AChE-1) and form 2 acetylcholinesterase (AChE-2) structures of enzymes do not affect in any way (there is no regularity of change or significant deviations) the values of the binding energy (ΔGb) recorded in the AChE-OPs complexes. However, the mutations analyzed in AChE are associated with a structural modification that causes an inadequate interaction to complete the phosphorylation of the enzyme.


Assuntos
Acetilcolinesterase/química , Acetilcolinesterase/genética , Resistência a Inseticidas/efeitos dos fármacos , Resistência a Inseticidas/genética , Lepidópteros/genética , Compostos Organofosforados/farmacologia , Praguicidas/farmacologia , Mutação Puntual/efeitos dos fármacos , Animais , Biologia Computacional/métodos , Simulação por Computador , Lepidópteros/efeitos dos fármacos , Lepidópteros/enzimologia , Simulação de Acoplamento Molecular , Compostos Organotiofosforados/química , Fragmentos de Peptídeos , Fosforamidas/química , Alinhamento de Sequência , Homologia Estrutural de Proteína
10.
Chem Biol Interact ; 308: 164-169, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31100272

RESUMO

Emerging data indicate that prenatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) could interfere with myogenic differentiation in vivo. Acetylcholinesterase (EC3.1.1.7; AChE), an enzyme critical for cholinergic neurotransmission, is abundantly expressed in neurons and mature myotubes, and we recently found that muscle AChE expression was suppressed in parallel with the inhibition of myogenic differentiation upon TCDD treatment in mouse C2C12 cells. This TCDD-induced suppression of muscle AChE was proposed to involve an aryl hydrocarbon receptor (AhR)-independent mechanism, but the precise underlying mechanism remains unclear. Considering the widely recognized role of muscular activity in AChE expression and its potential crosstalk with the AhR signaling pathway, we sought to investigate the effect of TCDD on muscle AChE expression in the presence of muscular activity. Therefore, we employed a highly contractile rat primary skeletal muscle culture system in which AChE activity and the expression of genes related to it (AChE T subunit and collagen Q (ColQ)) were increased during the myogenic differentiation process. Although TCDD treatment successfully induced the expression of genes regulated by AhR activation, the treatment exerted no notable effects on myogenic differentiation. Moreover, muscle AChE enzymatic activity and mRNA level remained unchanged following TCDD treatment, and only ColQ mRNA expression was slightly increased after 4-day treatment with TCDD (10-10 M). The compensatory role of muscle-contraction-related signaling pathways in this newly identified unresponsiveness of muscle AChE to TCDD warrants further investigation.


Assuntos
Acetilcolinesterase/metabolismo , Diferenciação Celular/efeitos dos fármacos , Desenvolvimento Muscular/efeitos dos fármacos , Dibenzodioxinas Policloradas/toxicidade , Acetilcolinesterase/genética , Animais , Células Cultivadas , Colágeno/genética , Colágeno/metabolismo , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Contração Muscular/efeitos dos fármacos , Mioblastos Esqueléticos/citologia , Mioblastos Esqueléticos/efeitos dos fármacos , Mioblastos Esqueléticos/metabolismo , Dibenzodioxinas Policloradas/metabolismo , Ratos , Ratos Sprague-Dawley , Regulação para Cima/efeitos dos fármacos
11.
Arch Insect Biochem Physiol ; 101(3): e21554, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31033012

RESUMO

Acetylcholinesterase (AChE) is a vital enzyme that hydrolyzes acetylcholine. Here, full-length complementary DNAs (cDNAs) of two acetylcholinesterase genes (SeAce1 and SeAce2) were obtained from Spodoptera exigua, a widespread phytophagous pest in agriculture. The complete SeAce1 cDNA comprised 5447 nucleotides including an open reading frame (ORF) encoding 694 amino acids, while SeAce2 cDNA encompassed a 1917-bp ORF which would likely yield 638 amino acids. Both SeAce1 and SeAce2 contained specific characteristics of functional AChE. A phylogenetic tree of all lepidopteran insect Aces showed S. exigua clustered with S. litura, Helicoverpa assulta, and H. armigera, all of which are Noctuidae. In S. exigua, SeAce1 gene expression levels (reverse transcription polymerase chain reaction [RT-PCR] and quantitative RT-PCR) were markedly increased compared with SeAce2 in all developmental phases and tissue types. Both genes were down regulated by inserting the corresponding dsRNAs in 5th instar larvae, which resulted in 56.7% (SeAce1) and 24.6% (SeAce2) death. Downregulation of both SeAce1 and SeAce2 significantly reduced fecundity and vitellogenin gene expression in S. exigua. These results revealed the biological functions of the two Ace genes (SeAce1 and SeAce2), providing novel insights into the development of strategies for controlling insect pests.


Assuntos
Acetilcolinesterase/genética , Proteínas de Insetos/genética , Spodoptera/genética , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Sequência de Aminoácidos , Animais , Regulação para Baixo , Expressão Gênica , Proteínas de Insetos/química , Proteínas de Insetos/metabolismo , Filogenia , Alinhamento de Sequência , Spodoptera/enzimologia
12.
Chem Biol Interact ; 306: 147-151, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31034797

RESUMO

Flavonoids, considered as phytoestrogen mainly deriving from fruit and vegetable, are known to have beneficial effects in brain functions. The role of flavonoids in induction of a cholinergic enzyme, acetylcholinesterase (AChE), was being explored here. In cultured PC12 cells, twenty-four commonly found flavonoids were tested for its induction on AChE activity. Fourteen flavonoids showed induction, and five of them had robust effect, i.e. daidzin, alpinetin, irisflorentin, cardamonin and lysionotin. The induction of AChE was fully blocked by pre-treatment of G15 (a selective G protein-coupled receptor 30 [GPR 30] antagonist), suggesting a direct involvement of a membrane-bound estrogen receptor, named as GPR 30, in the cultures. In addition, daidzin was further identified to induce expression of tetrameric globular form of proline-rich membrane anchor (PRiMA)-linked AChE. In parallel, application of daidzin in cultured PC12 cells significantly induced expression of neurofilaments, markers for neuronal differentiation. Taken together, flavonoids could induce the expression of AChE via GPR 30 in cultured PC12 cells, which could be a good candidate for possible treatment of the brain diseases.


Assuntos
Acetilcolinesterase/genética , Flavonoides/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Receptores Acoplados a Proteínas-G/metabolismo , Acetilcolinesterase/metabolismo , Animais , Benzodioxóis/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Flavonoides/antagonistas & inibidores , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Regulação Enzimológica da Expressão Gênica , Células PC12 , Quinolinas/farmacologia , Ratos , Relação Estrutura-Atividade
13.
Food Funct ; 10(5): 2439-2449, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-30968880

RESUMO

The peptide derived from Anchovy hydrolysates, Pro-Ala-Tyr-Cys-Ser (PAYCS), was reported to display a neuroprotective effect in vitro in our previous study. The in vivo memory improving effects of PAYCS were investigated in this study. Prior to the scopolamine-induced amnesia mice trial, the stability of PAYCS during digestion was detected and the digestive products were identified. The results showed that PAYCS was susceptible to proteolytic degradation after incubation with pepsin and pancreatin and Pro-Ala-Tyr (PAY) was released and survived during the simulated GI digestion. The results of scopolamine-induced amnesia model trials showed that PAYCS and PAY treatment exhibited cognitive improvement effects in the behavioral tests and different pathways were determined. The results indicated that only PAYCS facilitated cholinergic activity by up-regulating the amount of acetylcholine (Ach) and acetylcholine receptor (AChR). Additionally, both PAYCS and PAY enhanced the superoxide dismutase (SOD) activity. Furthermore, PAYCS was found to be beneficial for the expression of the nuclear factor (erythroid-derived2)-like 2 protein (Nrf2), brain-derived neurotrophic factor (BDNF) and cAMP response element binding protein (CREB). This indicated that PAYCS could regulate the oxidative stress by activating the Nrf2/antioxidant response elements (Nrf2/ARE) pathway. In our study, we demonstrated that the memory improving effects conferred by PAYCS on amnesia mice were linked to the attenuation of the cholinergic system and the activation of Nrf2/ARE and BDNF/CREB signaling.


Assuntos
Amnésia/tratamento farmacológico , Amnésia/psicologia , Proteínas de Peixes/química , Trato Gastrointestinal/metabolismo , Peptídeos/administração & dosagem , Peptídeos/química , Acetilcolina/metabolismo , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Amnésia/etiologia , Amnésia/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cognição/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Feminino , Peixes , Humanos , Masculino , Memória/efeitos dos fármacos , Camundongos , Fármacos Neuroprotetores/administração & dosagem , Peptídeos/metabolismo , Escopolamina/efeitos adversos
14.
EBioMedicine ; 41: 649-658, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30819512

RESUMO

BACKGROUND: The most prevalent inherited form of generalized dystonia is caused by a mutation in torsinA (DYT1, ∆GAG) with incomplete penetrance. Rodent models with mutated torsinA do not develop dystonic symptoms, but previous ex vivo studies indicated abnormal excitation of cholinergic interneurons (ChI) and increased striatal acetylcholine. METHODS: We used in vivo optogenetics to exacerbate this endophenotype in order to determine its capacity to trigger dystonic symptoms in freely behaving mice. Tor1a+/Δgag DYT1 mice and wildtype littermates expressing channelrhodopsin2 under the Chat promotor were implanted bilaterally with optical LED cannulae and stimulated with blue light pulses of varied durations. FINDINGS: Six months old DYT1 KI mice but not wildtype controls responded with hyperactivity to blue light specifically at 25 ms pulse duration, 10 Hz frequency. Neuronal activity (c-Fos) in cholinergic interneurons was increased immediately after light stimulation and persisted only in DYT1 KI over 15 min. Substance P was increased specifically in striosome compartments in naïve DYT1 KI mice compared to wildtype. Under optogenetic stimulation substance P increased in wildtype to match levels in Dyt1 KI, and acetylcholinesterase was elevated in the striatum of stimulated DYT1 KI. No signs of dystonic movements were observed under stimulation of up to one hour in both genotypes and age groups, and the sensorimotor deficit previously observed in 6 months old DYT1 KI mice persisted under stimulation. INTERPRETATION: Overall this supports an endophenotype of dysregulated cholinergic activity in DYT1 dystonia, but depolarizing cholinergic interneurons was not sufficient to induce overt dystonia in DYT1 KI mice.


Assuntos
Neurônios Colinérgicos/metabolismo , Chaperonas Moleculares/genética , Optogenética , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Animais , Comportamento Animal/efeitos da radiação , Channelrhodopsins/metabolismo , Endofenótipos , Feminino , Técnicas de Introdução de Genes , Luz , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Substância P/genética , Substância P/metabolismo
15.
Parasit Vectors ; 12(1): 77, 2019 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-30732643

RESUMO

BACKGROUND: In South Asia, the epidemiology of malaria is complex, and transmission mainly occurs in remote areas near international borders. Vector control has been implemented as a key strategy in malaria prevention for decades. A rising threat to the efficacy of vector control efforts is the development of insecticide resistance, thus it is important to monitor the type and frequency of insecticide resistant alleles in the disease vectors such as An. sinensis along the China-Vietnam border. Such information is needed to synthesize effective malaria vector control strategies. METHODS: A total of 208 adults of An. sinensis, collected from seven sites in southwest Guangxi along the China-Vietnam border, were inspected for the resistance-conferring G119S mutation in acetylcholinesterase (AChE) by PCR-RFLP (polymerase chain reaction restriction fragment length polymorphism) and kdr mutations in the voltage-gated sodium channel (VGSC) by sequencing. In addition, the evolutionary origin of An. sinensis vgsc gene haplotypes was analyzed using Network 5.0. RESULTS: The frequencies of mutant 119S of AChE were between 0.61-0.85 in the seven An. sinensis populations. No susceptible homozygote (119GG) was detected in three of the seven sites (DXEC, LZSK and FCGDX). Very low frequencies of kdr (0.00-0.01) were detected in the seven populations, with most individuals being susceptible homozygote (1014LL). The 1014F mutation was detected only in the southeast part (FCGDX) at a low frequency of 0.03. The 1014S mutation was distributed in six of the seven populations with frequencies ranging from 0.04 to 0.08, but absent in JXXW. Diverse haplotypes of 1014L and 1014S were found in An. sinensis along the China-Vietnam border, while only one 1014F haplotype was detected in this study. Consistent with a previous report, resistant 1014S haplotypes did not have a single origin. CONCLUSIONS: The G119S mutation of AChE was present at high frequencies (0.61-0.85) in the An. sinensis populations along the China-Vietnam border, suggesting that the vector control authorities should be cautious when considering carbamates and organophosphates as chemicals for vector control. The low frequencies (0.00-0.11) of kdr in these populations suggest that pyrethroids remain suitable for use against An. sinensis in these regions.


Assuntos
Anopheles/genética , Resistência a Inseticidas/genética , Mosquitos Vetores/genética , Mutação , Canais de Sódio Disparados por Voltagem/genética , Acetilcolinesterase/genética , Alelos , Animais , China , Haplótipos , Inseticidas , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Piretrinas , Análise de Sequência de DNA , Vietnã
16.
J Biol Chem ; 294(16): 6253-6272, 2019 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-30787102

RESUMO

Many neurodegenerative diseases are characterized by amyloid deposition. In Alzheimer's disease (AD), ß-amyloid (Aß) peptides accumulate extracellularly in senile plaques. The AD amyloid cascade hypothesis proposes that Aß production or reduced clearance leads to toxicity. In contrast, the cholinergic hypothesis argues for a specific pathology of brain cholinergic pathways. However, neither hypothesis in isolation explains the pattern of AD pathogenesis. Evidence suggests that a connection exists between these two scenarios: the synaptic form of human acetylcholinesterase (hAChE-S) associates with plaques in AD brains; among hAChE variants, only hAChE-S enhances Aß fibrillization in vitro and Aß deposition and toxicity in vivo Only hAChE-S contains an amphiphilic C-terminal domain (T40, AChE575-614), with AChE586-599 homologous to Aß and forming amyloid fibrils, which implicates T40 in AD pathology. We previously showed that the amyloid scavenger, insulin-degrading enzyme (IDE), generates T40-derived amyloidogenic species that, as a peptide mixture, seed Aß fibrillization. Here, we characterized 11 peptides from a T40-IDE digest for ß-sheet conformation, surfactant activity, fibrillization, and seeding capability. We identified residues important for amyloidogenicity and raised polyclonal antibodies against the most amyloidogenic peptide. These new antisera, alongside other specific antibodies, labeled sections from control, hAChE-S, hAPPswe, and hAChE-S/hAPPswe transgenic mice. We observed that hAChE-S ß-sheet species co-localized with Aß in mature plaque cores, surrounded by hAChE-S α-helical species. This observation provides the first in vivo evidence of the conformation of hAChE-S species within plaques. Our results may explain the role of hAChE-S in Aß deposition and aggregation, as amyloidogenic hAChE-S ß-sheet species might seed Aß aggregation.


Assuntos
Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Peptídeos/metabolismo , Acetilcolinesterase/química , Acetilcolinesterase/genética , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/genética , Animais , Encéfalo/patologia , Proteínas Ligadas por GPI/química , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Peptídeos/química , Peptídeos/genética , Domínios Proteicos , Estrutura Secundária de Proteína
17.
G3 (Bethesda) ; 9(4): 1075-1084, 2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30760540

RESUMO

Parental care is critical for offspring survival in many species. However, parental behaviors have been lost in roughly 1% of avian species known as the obligate brood parasites. To shed light on molecular and neurobiological mechanisms mediating brood parasitic behavior, we compared brain gene expression patterns between two brood parasitic species and one closely related non-parasitic Icterid (blackbird) species. Our analyses focused on gene expression changes specifically in the preoptic area (POA), a brain region known to play a critical role in parental behavior across vertebrates. Using comparative transcriptomic approaches, we identified gene expression patterns associated with brood parasitism. We evaluated three non-mutually exclusive alternatives for the evolution of brood parasitism: (1) retention of juvenile-like (neotenic) gene expression, (2) reduced expression of maternal care-related genes in the POA, and/or (3) increased expression of genes inhibiting maternal care. We find evidence for neotenic expression patterns in both species of parasitic cowbirds as compared to maternal, non-parasites. In addition, we observed differential expression in a number of genes with previously established roles in mediating maternal care. Together, these results provide the first insight into transcriptomic and genetic mechanisms underlying the loss of maternal behavior in avian brood parasites.


Assuntos
Comportamento Animal , Comportamento Materno , Passeriformes/fisiologia , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Animais , Proteína 1 de Resposta de Crescimento Precoce/genética , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Feminino , Perfilação da Expressão Gênica , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Passeriformes/genética , Área Pré-Óptica/metabolismo , Receptores da Bombesina/genética , Receptores da Bombesina/metabolismo , Receptores de Fator de Crescimento Neural/genética , Receptores de Fator de Crescimento Neural/metabolismo , Receptores da Prolactina/metabolismo , Somatostatina/genética , Somatostatina/metabolismo
18.
Artigo em Inglês | MEDLINE | ID: mdl-30626059

RESUMO

Exposure to bisphenol A (BPA) has been shown to impact human sperm quality. The epigenetic mechanisms underlying the effect remain unknown. The acetylcholinesterase (ACHE) gene is a sperm-expressed gene encoding the acetylcholine hydrolyzing enzyme acetylcholinesterase and participates in the apoptosis of cells, including sperm. This study aimed to examine whether BPA exposure is associated with the hydroxymethylation level of the sperm ACHE gene. A total of 157 male factory workers were studied, among whom 74 had BPA exposure in the workplace (BPA exposure group) and 83 had no BPA exposure in the workplace (control group). Urine samples were collected for BPA measurement and semen samples were collected to assay for ACHE hydroxymethylation. Sperm ACHE hydroxymethylation level was higher in the BPA exposure group (p = 0.041) compared to the control group. When subjects were categorized according to tertiles of detected BPA level, higher ACHE hydroxymethylation levels were observed for the lowest, middle, and top tertiles compared to those with BPA below the limit of detection (LOD). In a linear regression analysis adjusted for confounders, a positive linear association between urine BPA concentration and 5-hydroxymethylcytosine (5hmC) rate of the sperm ACHE gene was observed, although the association did not reach statistical significance in all categories after being stratified by the BPA tertile. In conclusion, 5hmC of the sperm ACHE gene was positively associated with BPA exposure, which may provide supportive evidence for BPA's effects on male fertility or other health endpoints.


Assuntos
Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Poluentes Ocupacionais do Ar/toxicidade , Compostos Benzidrílicos/toxicidade , Epigênese Genética/efeitos dos fármacos , Hidroxilação/efeitos dos fármacos , Fenóis/toxicidade , Espermatozoides/efeitos dos fármacos , 5-Metilcitosina/análogos & derivados , 5-Metilcitosina/metabolismo , Adulto , Poluentes Ocupacionais do Ar/urina , Compostos Benzidrílicos/urina , Metilação de DNA , Humanos , Masculino , Pessoa de Meia-Idade , Fenóis/urina , Espermatozoides/enzimologia , Espermatozoides/metabolismo
19.
Pest Manag Sci ; 75(1): 286-291, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29885052

RESUMO

BACKGROUND: Arboviruses are controlled through insecticide control of their mosquito vector. However, inconsiderate use of insecticides often results in the selection of resistance in treated populations, so that monitoring is required to optimize their usage. Here, Culex pipiens (West Nile and Rift Valley Fever virus vector) specimens were collected from four Moroccan cities. Levels of susceptibility to the organophosphate (OP) insecticide malathion were assessed using World Health Organization (WHO)-recommended bioassays. Individual mosquitoes were tested for the presence of the G119S mutation in the ace-1 gene, the main OP-target resistance mutation. RESULTS: Bioassays showed that mosquitoes from Mohammedia were significantly more resistant to malathion than those from Marrakech. Analyzing the ace-1 genotypes in dead and surviving individuals suggested that other resistance mechanisms may be present in Mohammedia. The ace-1 resistance allele frequencies were relatively moderate (< 0.4). Their analyses in three Moroccan cities (Tangier, Casablanca and Marrakech) however showed disparities between two coexisting Cx. pipiens forms and revealed that the G119S mutation tends to be more frequent in urban than in rural collection sites. CONCLUSION: These findings provide a reference assessment of OP resistance in Morocco and should help the health authorities to develop informed and sustainable vector control programs. © 2018 Society of Chemical Industry.


Assuntos
Acetilcolinesterase/genética , Culex/genética , Proteínas de Insetos/genética , Resistência a Inseticidas/genética , Inseticidas/farmacologia , Malation/farmacologia , Acetilcolinesterase/metabolismo , Animais , Cidades , Culex/efeitos dos fármacos , Culex/metabolismo , Frequência do Gene , Proteínas de Insetos/metabolismo , Marrocos , Mutação
20.
Artigo em Inglês | MEDLINE | ID: mdl-30550875

RESUMO

The aim of this study was to evaluate whether rupture on blood-brain barrier (BBB) can be a pathway for trichlorfon-induced neurotoxic effects, and to investigate its implications on oxidative status, cell viability and brain neurotransmitters in silver catfish (Rhamdia quelen). The BBB permeability was increased in fish exposed for 24 h to 22 mg/L of trichlorfon compared to the control group, as well as in those exposed to 11 and 22 mg/L of trichlorfon for 48 h. Compared to the control group, brain reactive oxygen species and lipid peroxide levels were higher when exposed to 22 mg/L of trichlorfon and 11 and 22 mg/L of trichlorfon after 24 h and 48 h, respectively, while the antioxidant capacity against peroxyl radical levels was lower. Exposure to 22 mg/L of trichlorfon for 24 h reduced brain cell viability compared to the control group, together with 11 and 22 mg/L of trichlorfon for 48 h. Also, brain AChE, Na+ and K+-ATPase activities were reduced in those fish exposed to trichlorfon compared to the control group. Thus, the rupture of BBB can be considered an important pathway involved in trichlorfon-induced neurotoxic effects, which contributes to brain oxidative damage and important changes on brain neurotransmitters.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Peixes-Gato , Sobrevivência Celular/efeitos dos fármacos , Doenças dos Peixes/induzido quimicamente , Doenças do Sistema Nervoso/veterinária , Triclorfon/toxicidade , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Animais , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Diclorvós/administração & dosagem , Diclorvós/toxicidade , Relação Dose-Resposta a Droga , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Inseticidas/toxicidade , Doenças do Sistema Nervoso/induzido quimicamente , Estresse Oxidativo , ATPase Trocadora de Sódio-Potássio/genética , ATPase Trocadora de Sódio-Potássio/metabolismo , Triclorfon/administração & dosagem
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