RESUMO
BACKGROUND: Hemiptera is one of the most speciose orders of insects, and the most speciose considering Hemimetabola. Through their evolutive history, hemipterans with different feeding habits have adapted to deal with different chemical challenges. Three major gene families are involved in xenobiotic detoxification in insects: the cytochromes P450 (CYPs), carboxyl/cholinesterases (CCEs), and glutathione transferases (GSTs). Here we perform a comparative analysis on the complement of these gene superfamilies across five hemipteran species; four heteropterans (the pentatomid plant feeders Nezara viridula and Halyomorpha halys; the hematophagous Cimex lectularius, Cimicidae, and Rhodnius prolixus, Reduviidae), and one Auchenorrhyncha plant feeder (Nilaparvata lugens). RESULTS: Our results point to an expansion of several enzyme families associated with xenobiotic detoxification in heteropterans with respect to other species and the existence of a dynamic evolution pattern including CYP3 clan, hormone and pheromone processing class in the CCE superfamily, and sigma class in GST superfamily. Other detoxification-related families are reduced in the hemipteran species analyzed here: reduction or even absence of epsilon class and reduced delta class in GST superfamily; absence of mitochondrial CYP12 family; absence of CYP9 family in CYP3 clan; and reduction or even absence of some dietary/detoxification groups of CCEs. Interestingly, the most polyphagous species analyzed here (H. halys) is also the one that presents the largest repertoire of detoxification enzymes. Gene cluster analysis suggests that this could be due to gene duplication events. CONCLUSIONS: The evolutionary analysis performed here reveals characteristics that are both common and particular for heteropterans. The composition and organization of detoxification-related gene families could shed light on evolutionary forces that shaped their divergence. These families are important for both the detoxification of diet products and for conferring tolerance or resistance to synthetic insecticides. Furthermore, we present the first comprehensive analysis of detoxification gene superfamilies in N. viridula, an understudied species in spite of its economic relevance as a crop pest. The information obtained is of interest for basic insect science as well as for the control of harmful species and the management of insecticide resistance.
Assuntos
Heterópteros , Inseticidas , Rhodnius , Animais , Xenobióticos , Resistência a Inseticidas/genética , Inseticidas/farmacologia , Glutationa Transferase/genéticaRESUMO
Neuroleptic malignant syndrome is a rare and potentially fatal clinical condition frequently associated with the use of antipsychotics. In the literature, there is only one case report associated with the intake of organophosphates. We present the case of a patient who presented with a clinical picture compatible with neuroleptic malignant syndrome, after the ingestion of an organophosphate (chlorpyrifos). A 57-year-old man who consulted for attempted suicide, acute deterioration of consciousness, torpid neurological evolution, and associated autonomic instability associated with rigidity, persistent hyperthermia, and elevated CPK. Bromocriptine treatment was offered, which resolved the clinical picture. The association with the ingestion of an organophosphate was established, and he was discharged without sequelae. The diagnosis of neuroleptic malignant syndrome is clinical and should be considered in any case of exposure to substances that may lead to dysregulation of dopaminergic neurotransmission in order to initiate timely therapy and impact outcomes.
El síndrome neuroléptico maligno es una condición clínica rara y potencialmente letal que frecuentemente se asocia con el uso de antipsicóticos. En la literatura especializada se encontró únicamente un reporte de caso relacionado con la ingestión de organofosforados. Se presenta un paciente con un cuadro clínico correspondiente al síndrome neuroléptico maligno posterior a la ingestión de clorpirifós. Como resultado de un intento de suicidio con el mencionado organofosforado, el hombre de 57 años presentó deterioro agudo del estado de consciencia, evolución neurológica tórpida e inestabilidad autonómica asociada a rigidez e hipertermia persistentes, así como incremento de la creatina-fosfocinasa (creatine phosphokinase, CPK). Se le administró tratamiento con bromocriptina, con lo cual el cuadro clínico remitió, y fue dado de alta sin secuelas. El diagnóstico del síndrome neuroléptico maligno es clínico y debe contemplarse en cualquier caso de exposición a sustancias que puedan resultar en una desregulación de la neurotransmisión dopaminérgica, con el fin de iniciar el tratamiento oportuno y contrarrestar efectivamente los efectos.
Assuntos
Antipsicóticos , Clorpirifos , Síndrome Maligna Neuroléptica , Intoxicação por Organofosfatos , Antipsicóticos/efeitos adversos , Bromocriptina/uso terapêutico , Clorpirifos/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome Maligna Neuroléptica/diagnóstico , Síndrome Maligna Neuroléptica/etiologia , Síndrome Maligna Neuroléptica/terapia , Intoxicação por Organofosfatos/complicaçõesRESUMO
El síndrome neuroléptico maligno es una condición clínica rara y potencialmente letal que frecuentemente se asocia con el uso de antipsicóticos. En la literatura especializada se encontró únicamente un reporte de caso relacionado con la ingestión de organofosforados. Se presenta un paciente con un cuadro clínico correspondiente al síndrome neuroléptico maligno posterior a la ingestión de clorpirifós. Como resultado de un intento de suicidio con el mencionado organofosforado, el hombre de 57 años presentó deterioro agudo del estado de consciencia, evolución neurológica tórpida e inestabilidad autonómica asociada a rigidez e hipertermia persistentes, así como incremento de la creatina-fosfocinasa (creatine phosphokinase, CPK). Se le administró tratamiento con bromocriptina, con lo cual el cuadro clínico remitió, y fue dado de alta sin secuelas. El diagnóstico del síndrome neuroléptico maligno es clínico y debe contemplarse en cualquier caso de exposición a sustancias que puedan resultar en una desregulación de la neurotransmisión dopaminérgica, con el fin de iniciar el tratamiento oportuno y contrarrestar efectivamente los efectos.
Neuroleptic malignant syndrome is a rare and potentially fatal clinical condition frequently associated with the use of antipsychotics. In the literature, there is only one case report associated with the intake of organophosphates. We present the case of a patient who presented with a clinical picture compatible with neuroleptic malignant syndrome, after the ingestion of an organophosphate (chlorpyrifos). A 57-year-old man who consulted for attempted suicide, acute deterioration of consciousness, torpid neurological evolution, and associated autonomic instability associated with rigidity, persistent hyperthermia, and elevated CPK. Bromocriptine treatment was offered, which resolved the clinical picture. The association with the ingestion of an organophosphate was established, and he was discharged without sequelae. The diagnosis of neuroleptic malignant syndrome is clinical and should be considered in any case of exposure to substances that may lead to dysregulation of dopaminergic neurotransmission in order to initiate timely therapy and impact outcomes.
Assuntos
Inseticidas Organofosforados , Síndrome Maligna Neuroléptica , Rabdomiólise , Bromocriptina , Colinesterases , FebreRESUMO
The active ingredients in pesticides are known to be genotoxic that can cause mutations, chromosomal aberrations, or other types of DNA damage. Early detection of genotoxicity reduces the risk of developing diseases such as cancer or suffering from reproductive disorders. In turn, the genotoxic risk depends on the intrinsic capability of the individual to metabolize and eliminate the xenobiotic from the organism. This study aimed to determine if two polymorphisms of paraoxonase-1 (PON1), which is involved in the metabolism of several organophosphate (OP) pesticides, are predictors of susceptibility to DNA damage in agricultural workers and inhabitants of rural areas chronically exposed to pesticides. A cross-sectional study was made considering three groups: agricultural workers (occupational exposure, OE, n = 85), rural inhabitants (environmental exposure, EE, n = 60), and an unexposed group conformed by people living far from agricultural areas (U, n = 33). The level of individual DNA damage was measured using the comet assay, and genotyping was done to determine the PON1 Q192R and L55M polymorphisms. Acetylcholinesterase and butyrilcholinesterase activities were also measured to determine exposure to OP. Individuals belonging to EE and OE groups displayed higher levels of DNA damage compared with U group (p < .001). OP exposure was the main predictor of genotoxicity (ß = 16.19; 95% CI: 1.85, 30.52), instead of PON1 polymorphisms (ß = -12.20; 95% CI: -27.87, 3.48). These results confirm the genotoxic effects of pesticide exposure and suggest that the catalytic efficiency of PON1 to metabolize OP pesticides becomes negligible in individuals with a history of long-term environmental or occupational exposure to these substances.
Assuntos
Arildialquilfosfatase , Praguicidas , Acetilcolinesterase/metabolismo , Arildialquilfosfatase/genética , Biomarcadores , Chile , Estudos Transversais , Dano ao DNA , Humanos , Compostos Organofosforados/toxicidade , Praguicidas/toxicidadeRESUMO
The skin of anuran amphibians is a rich source of compounds with great medicinal potential. Alzheimer's disease (AD) is a complex disease associated with numerous pathological pathways, making their simultaneous modulation necessary. Nowadays the development of anti-AD drugs is focused on a Multi-Target Directed Ligands strategy. Herein we report the bioactivity of the skin extracts of the toad Rhinella arenarum obtained by an invasive and non-invasive methods, against five AD pathological targets (AChE, BChE, MAO-B, antioxidant and chelating activities). The extract derived from the non-invasive technique showed the highest biological activity, being capable of acting on all or almost all the pathological targets of AD, while also avoiding harm to the animal.
Assuntos
Doença de Alzheimer , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Antioxidantes/farmacologia , Inibidores da Colinesterase/farmacologia , Ligantes , Monoaminoxidase/metabolismo , Inibidores da MonoaminoxidaseRESUMO
The characterization of the population exposed to pesticides and the use of effective biomarkers to evaluate potential health effects are determinant to identify vulnerable groups, understanding the causality of diverse pathologies and propose prevention policies. This is particularly important in countries where intensive agricultural practices had an explosive expansion in last decades. The aim of this study was assessing the usefulness of two exposure indexes questionnaire-based: Intensity Level of the pesticide Exposure (ILE) and Cumulative Exposure Index (CEI) and their scales, in terrestrial applicators of pesticide from the Province of Córdoba (Argentina). The analysis was performed contrasting ILE and CEI results with perceived symptomatology, in addition to effect and exposure biomarkers. A cross-sectional study was designed to compare pesticides body burdens and effect biomarkers between subjects occupationally (OE) and non-occupationally exposed (NOE) to pesticides. Prevalence of perceived symptomatology and genotoxicity damage was higher in the OE group. The exposure condition was the only variable explaining these differences. Significant associations were found between CEI and neurologic symptomatology (p < 0.05) and between ILE and plasmatic cholinesterase (p < 0.1). However, residues of HCB, ß-HCH, α-endosulfan, pp'DDE, endrin, ß-endosulfan, pp'DDT, endosulfan sulfate and mirex were found in blood samples from both groups. To our knowledge, this is the first report on pesticides body burdens in occupational exposure settings in Argentina. So far, our current results indicate that the occupational condition affects the health of the workers. Significant associations found between symptomatology and biomarkers with scales of CEI and ILE suggest their usefulness to verify different levels of exposure. Further research is necessary to propose these indexes as an affordable tool for occupational health surveillance in areas with difficult access to health care centres.
RESUMO
Natural products represent a rich source of bioactive compounds that have been historically used to obtain substances with great medicinal potential. The skin of anuran amphibians is a rich source of compounds with a wide range of biological activity. Alzheimer's disease (AD) is a complex disease associated with all kind of different pathways, making their simultaneous modulation necessary. Nowadays anti-AD treatments are focused on enzymatic inhibitors. Here in we report the activity of skin extracts from nine species from Argentina, belonging to three anuran families, as inhibitors of AChE, BChE and MAO-B enzymes. The extracts also showed antioxidant activities, acting as multi-target on four important pathways of AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Anfíbios/metabolismo , Pele/química , Acetilcolinesterase/metabolismo , Animais , Antioxidantes/farmacologia , Inibidores da Colinesterase/farmacologia , Humanos , Concentração Inibidora 50 , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Peptídeos/farmacologiaRESUMO
BACKGROUND: Alzheimer's disease (AD) involves an irreversible and progressive neurodegeneration, with multifactorial pathophysiology, including the cholinergic deficit, amyloid plaques, neurofibrillary tangles, oxidative stress, and neurodegeneration. Despite the severity of the disease, the therapeutic arsenal is limited, arousing the interest of researchers to search for substances that can act on these markers. OBJECTIVE: In this review, we highlight some relevant points, such as the ability of chalcones to act on different targets related to the pathophysiology of Alzheimer's disease; cholinesterases, amyloid peptide, beta-secretase and other biomarkers. METHOD: This mini-review covered the literature concerning chalcones bioactivity from 2010 until now. In addition to the theoretical review, we included the prediction of physicochemical properties using SwissADME software. RESULTS: We found that the majority of the chalcones have been tested against cholinesterases, with moderate to good potencies, but in recent years, the number of publications related to targets of the amyloid hypothesis has been growing. Regarding the physicochemical properties, chalcones have a good profile, except for the water solubility, which is not favorable. CONCLUSION: The most important characteristic of these molecules is that many of the examples mentioned here act on more than one target, characterizing them as multi-target compounds. Regarding predicted properties, solubility stands out as the most problematic one; however, these structures can incorporate functional groups that circumvent this problem of solubility without interfering in the biological activity.
Assuntos
Doença de Alzheimer , Chalconas , Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide , Peptídeos beta-Amiloides , Chalconas/farmacologia , Chalconas/uso terapêutico , Colinesterases , HumanosRESUMO
It is estimated that 50 million people in the world live with dementia, 60-70% of whom suffer from Alzheimer's disease (AD). Different factors are involved in the development of AD, including a reduction in the cholinergic neurotransmission level. The Amaryllidaceae plant family contains an exclusive, large, and still understudied alkaloid group characterized by a singular skeleton arrangement and a broad spectrum of biological activities. The chemistry and biodiversity of Ecuadorian representatives of the Phaedranassa genus (Amaryllidaceae) have not been widely studied. In this work, five Ecuadorian Phaedranassa species were examined in vitro for their activity towards the enzymes acetyl- (AChE) and butyrylcholinesterase (BuChE), and the alkaloid profile of bulb extracts was analyzed by GC-MS. The species Phaedranassa cuencana and Phaedranassa dubia showed the most AChE and BuChE inhibitory activity, respectively. To obtain insight into the potential role of the identified alkaloids in these inhibitory effects, docking experiments were carried out, and cantabricine showed in silico inhibitory activity against both cholinesterase structures. Our results show that Amaryllidaceae species from Ecuador are a potential source of new drugs for the palliative treatment of AD.
Assuntos
Amaryllidaceae/química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Acetilcolinesterase/química , Alcaloides/química , Alcaloides/farmacologia , Sítios de Ligação , Descoberta de Drogas , Equador , Cromatografia Gasosa-Espectrometria de Massas , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
Resumen: La rivastigmina, fármaco anticolinesterásico, mejora la neurotransmisión colinérgica y es utilizado en el tratamiento de las enfermedades de Alzheimer y de Parkinson. En el Centro de Información y Asesoramiento Toxicológico se han registrado casos de intoxicación por el uso de parches transdérmicos de rivastigmina, los cuales han aumentado en número en el último tiempo. Presentamos dos casos clínicos de intoxicación aguda por parches transdérmicos de rivastigmina en los que se constataron arritmias cardíacas graves, asociando un descenso de colinesterasa plasmática. Se destacan los riesgos del uso de esta medicación con el fin de estar atentos a los primeros síntomas de intoxicación, poder actuar en forma oportuna y prevenir nuevos eventos.
Summary: Rivastigmine, an anticholinesterase drug, improves cholinergic neurotransmission and is used in the treatment of Alzheimer's and Parkinson's diseases. In the Center for Information and Toxicological Advice there have been cases of intoxication due to the use of transdermal rivastigmine patches, which have increased in recent times. We present two clinical cases of acute intoxication by transdermal patches of rivastigmine in which serious cardiac arrhythmias were found, associating a decrease in plasma cholinesterase. The risks of the use of this medication are highlighted in order to be attentive to the first symptoms of intoxication, to be able to act timely and to prevent new events.
Resumo: A rivastigmina, um anticolinesterásico, melhora a neurotransmissão colinérgica e é usada no tratamento das doenças de Alzheimer e Parkinson. No Centro de Informação e Conselhos Toxicológicos, houve casos de intoxicação devido ao uso de adesivos transdérmicos de rivastigmina, que aumentaram nos últimos tempos. Se apresentam dois relatos de caso de intoxicação aguda por adesivos transdérmicos de rivastigmina. Em ambos os casos, foram encontradas arritmias cardíacas graves, associando uma diminuição na colinesterase plasmática. Os riscos do uso desse medicamento são destacados para estar atento aos primeiros sintomas de intoxicação, para poder atuar de forma oportuna e prevenir novos eventos.
RESUMO
BACKGROUND: Microalgae are aquatic chlorophyll-containing organisms comprising unicellular microscopic forms, and their biomasses are potential sources of bioactive compounds, biofuels and food-based products. However, the neuroprotective effects of microalgal biomass have not been fully explored. In this study, biomass from two Chlorella species was characterized, and their antioxidant, anticholinesterase and anti-amyloidogenic activities were investigated. RESULTS: GCMS analysis of the extracts revealed the presence of some phenols, sterols, steroids, fatty acids and terpenes. Ethanol extract of Chlorella sorokiniana (14.21 mg GAE/g) and dichloromethane extract of Chlorella minutissima (20.65 mg QE/g) had the highest total phenol and flavonoid contents, respectively. All the extracts scavenged 2,2-diphenyl-1-picrylhydrazyl, 2,2-azinobis (3-ethylbenzothiazoline-6-sulfonate) and hydroxyl radicals. The highest metal chelating activity of the extracts was observed in the ethanol extracts of C. minutissima (102.60 µg/mL) and C. sorokiniana (107.84 µg/mL). Furthermore, the cholinesterase inhibitory activities of the extracts showed that ethanol extract of C. sorokiniana (13.34 µg/mL) exhibited the highest acetylcholinesterase inhibitory activity, while dichloromethane extract of C. minutissima (11.78 µg/mL) showed the highest butyrylcholinesterase inhibitory activity. Incubation of the ß-amyloid protein increased the aggregation of amyloid fibrils after 96 h. However, ethanol extract of C. sorokiniana and C. minutissima inhibited further aggregation of Aß142 and caused disaggregation of matured protein fibrils compared to the control. This study reveals the modulatory effects of C. sorokiniana and C. minutissima extracts on some mediators of Alzheimer's disease and provides insights into their potential benefits as functional food, nutraceutics or therapeutic agent for the management of this neurodegenerative disease.
Assuntos
Chlorella/química , Inibidores da Colinesterase/farmacologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Antioxidantes/farmacologia , Fenóis/análise , Esteroides/análise , Esteróis/análise , Terpenos/análise , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Inibidores da Colinesterase/química , Espectroscopia de Infravermelho com Transformada de Fourier , Fármacos Neuroprotetores , Biomassa , Etanol , Ácidos Graxos/análise , Microalgas , Doença de Alzheimer/prevenção & controle , Amiloide/efeitos dos fármacos , Cromatografia Gasosa-Espectrometria de Massas , Antioxidantes/químicaRESUMO
A series of hybrids containing tacrine linked to carbohydrate-based moieties, such as d-xylose, d-ribose, and d-galactose derivatives, were synthesized by the nucleophilic substitution between 9-aminoalkylamino-1,2,3,4-tetrahydroacridines and the corresponding sugar-based tosylates. All compounds were found to be potent inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in the nanomolar IC50 scale. Most of the d-xylose derivatives (6a-e) were selective for AChE and the compound 6e (IC50â¯=â¯2.2â¯nM for AChE and 4.93â¯nM for BuChE) was the most active compound for both enzymes. The d-galactose derivative 8a was the most selective for AChE exhibiting an IC50 ratio of 7.6 for AChE over BuChE. Only two compounds showed a preference for BuChE, namely 7a (d-ribose derivative) and 6b (d-xylose derivative). Molecular docking studies indicated that the inhibitors are capable of interacting with the entire binding cavity and the main contribution of the linker is to enable the most favorable positioning of the two moieties with CAS, PAS, and hydrophobic pocket to provide optimal interactions with the binding cavity. This finding is reinforced by the fact that there is no linear correlation between the linker size and the observed binding affinities. The majority of the new hybrids synthesized in this work do not violate the Lipinski's rule-of-five according to FAF-Drugs4, and do not demonstrated predicted hepatotoxicity according ProTox-II.
Assuntos
Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Tacrina/análogos & derivados , Tacrina/farmacologia , Acetilcolinesterase/metabolismo , Animais , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Galactose/análogos & derivados , Galactose/síntese química , Galactose/farmacologia , Humanos , Camundongos , Simulação de Acoplamento Molecular , Ribose/análogos & derivados , Ribose/síntese química , Ribose/farmacologia , Relação Estrutura-Atividade , Tacrina/síntese química , Torpedo , Xilose/análogos & derivados , Xilose/síntese química , Xilose/farmacologiaRESUMO
Given the wide spectrum of biological uses of pyrazolo[1,5-c]quinazoline and spiro-quinazoline derivatives as anticancer, anti-inflammatory analgesic agents, and their therapeutic applications in neurodegenerative disorders, it is compulsory to find easy, efficient, and simple methods to obtain and chemically diversify these families of compounds, thereby improving their biological applications. In this paper, we report the design and eco-friendly two-step synthesis of novel, fused spiro-pyrazolo[1,5-c]quinazoline derivatives as cholinesterase inhibitors. In addition, we studied their protein-ligand interactions via molecular docking and MM/GBSA calculations for a further rational design of more potent inhibitors. In first step, 2-(1H-pyrazol-5-yl)anilines were obtained through microwave (MW) assisted solvent-free/catalyst-free conditions and the second step involved the synthesis of the spiro-pyrazolo[1,5-c]quinazolines by a cyclocondensation reaction between 2-(1H-pyrazol-5-yl)anilines and cyclic ketones, or acetophenones, using stirring at room temperature. The compounds were obtained in high purity, good yields (50-97%), and at varying reaction times. The spiro-compounds were evaluated as acetylcholinesterase and butyrylcholinesterase inhibitors (AChEIs/BuChEIs) respectively, and the most potent compound exhibited a moderate AChE inhibitory activity (5f: IC50â¯=â¯84⯵M). Molecular docking studies indicated that the binding mode of the compound 5f share common characteristics with the galantamine/donepezil-AChE complexes. Moreover, free binding energy (ΔG) calculations showed a good agreement with the experimental biological activity values. Our theoretical results indicated that halogen bond interactions could be involved with differential potency of these compounds and provide a new starting point to design novel pyrazolo[1,5-c]quinazolines as new anti-Alzheimer agents.
Assuntos
Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Simulação de Acoplamento Molecular , Pirazóis/farmacologia , Teoria Quântica , Quinazolinas/farmacologia , Compostos de Espiro/farmacologia , Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Humanos , Micro-Ondas , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Quinazolinas/síntese química , Quinazolinas/química , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-AtividadeRESUMO
BACKGROUND: In Argentina, the Amaryllidaceae family (59 species) comprises a wide variety of genera, only a few species have been investigated as a potential source of cholinesterases inhibitors to treat Alzheimer disease (AD). PURPOSE: To study the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities of the basic dichloromethane extracts (E) from Hieronymiella aurea, H. caletensis, H. clidanthoides, H. marginata, and H. speciosa species, as well as the isolated compounds from these plant extracts. STUDY DESIGN AND METHODS: AChE and BChE inhibitory activities were evaluated with the Ellman's spectrophotometric method. The alkaloids composition from the E was obtained by gas chromatography-mass spectrometry (GC-MS). The E were successively chromatographed on a silica gel column and permeated on Sephadex LH-20 column to afford the main alkaloids identified by means of spectroscopic data. Additionally, an in silico study was carried out. RESULTS: Nine known alkaloids were isolated from the E of five Hieronymiella species. Galanthamine was identified in all the species by GC-MS standing out H. caletensis with a relative abundance of 9.79% of the total ion current. Strong AChE (IC50â¯=â¯1.84 - 15.40⯵g/ml) and moderate BChE (IC50â¯=â¯23.74 - 136.40⯵g/ml) inhibitory activities were displayed by the extracts. Among the isolated alkaloids, only sanguinine and chlidanthine (galanthamine-type alkaloids) demonstrated inhibitory activity toward both enzymes. The QTAIM study suggests that sanguinine has the strongest affinity towards AChE, attributed to an additional interaction with Ser200 as well as stronger molecular interactions Glu199 and His440.These results allowed us to differentiate the molecular behavior in the active site among alkaloids possessing different in vitro inhibitory activities. CONCLUSION: Hieronymiella species growing in Argentina represent a rich and widespread source of galanthamine and others AChE and BChE inhibitors alkaloids. Additionally, the new trend towards the use of natural extracts as pharmaceuticals rather than pure drugs opens a pathway for the development of a phytomedicine derived from extracts of Hieronymiella spp.
Assuntos
Alcaloides de Amaryllidaceae/química , Alcaloides de Amaryllidaceae/farmacologia , Amaryllidaceae/química , Inibidores da Colinesterase/farmacologia , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Argentina , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Simulação por Computador , Avaliação Pré-Clínica de Medicamentos/métodos , Cromatografia Gasosa-Espectrometria de Massas , Modelos Moleculares , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Raízes de Plantas/químicaRESUMO
The inhibition of cholinesterase (ChE) activity has been used as a biomarker of exposure to organophosphate and carbamate insecticides. ChE of nesting female green turtles (Chelonia mydas) were biochemically characterized using two substrates, acetylthiocholine iodide and butyrylthiocholine iodide, and three ChE inhibitors (eserine sulfate, BW284C51 and iso-OMPA). The results indicated that BChE is the predominant plasma ChE in female C. mydas, but with atypical properties that differ from those found in human BChE. Eggs from green turtles nesting at two sites in Laguna de Terminos contained µg g-1 (wet weight) quantities of organochlorine (OC) pesticides. Drins (aldrin, dieldrin, endrin, endrin ketone, endrin aldehyde) were found at the highest concentrations with no significant differences in the concentrations in eggs collected at the two sampling sites. A negative relationship was found between levels of OC pesticides in eggs and BChE activity in the plasma of female turtles laying the eggs. Since OC pesticides are not cholinesterase inhibitors, we hypothesized that this inverse relationship may be related to an antagonistic effect between OCs and organophosphate pesticides and mobilization of OCs from the fatty tissues of the female turtles into their eggs. However, further study is required to verify the hypothesis. It is also possible that other contaminants, such as petroleum hydrocarbons are responsible for the modulation of cholinesterase activity in female turtles.
Assuntos
Colinesterases/sangue , Ovos/análise , Monitoramento Ambiental , Hidrocarbonetos Clorados/metabolismo , Praguicidas/metabolismo , Tartarugas/fisiologia , Poluentes Químicos da Água/metabolismo , Animais , Inibidores da Colinesterase/metabolismo , Colinesterases/metabolismo , Dieldrin/metabolismo , Feminino , Humanos , Inseticidas/metabolismo , México , Tartarugas/sangueRESUMO
In this study we investigated the effect of acute and chronic treatment with Met and/or methionine sulfoxide (MetO) on ectonucleotidases and cholinesterases activities from lymphocytes and purine derivatives compounds, C-protein reactive, interleukin-10, interleukin-6, and tumor necrosis factor-α levels in serum of young rats. Adenosine triphosphate hydrolysis was decreased in lymphocytes 1 h after treatment by MetO and Met + MetO. However, adenosine triphosphate and adenosine diphosphate hydrolysis in lymphocytes was increased in the groups MetO and Met + MetO and adenosine deaminase activity was increased in MetO 3 h after the treatment. Acetylcholinesterase activity was increased in lymphocytes after 3 h and 21 days of treatment by MetO and Met + MetO, while serum butyrycholinesterase activity was decreased after 1 h and 21 days of treatment in the same groups. In chronic treatment, interleukin-6 and tumor necrosis factor-α level were increased, while that interleukin-10 level was decreased by Met, MetO, and Met + MetO when compared to control group. C-protein reactive level was increased by MetO and Met + MetO. Adenosine triphosphate and adenosine monophosphate levels were reduced in all amino acids treated groups, while adenosine diphosphate and hypoxanthine were enhanced by MetO and Met + MetO. Adenosine and xanthine were reduced in the MetO group, whereas inosine levels were decreased in the MetO and Met + MetO groups. These findings help to understand the inflammatory alterations observed in hypermethioninemia.
Assuntos
Ativação Enzimática/efeitos dos fármacos , Metionina/análogos & derivados , Metionina/farmacologia , Acetilcolinesterase/metabolismo , Nucleotídeos de Adenina/metabolismo , Adenosina Desaminase/metabolismo , Envelhecimento , Animais , Proteína C-Reativa/análise , Células Cultivadas , Interleucina-10/sangue , Interleucina-6/sangue , Linfócitos/citologia , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/sangueRESUMO
INTRODUCTION: Parasympathetic dysfunction may play a role in the genesis of arrhythmias in Chagas disease. AIM: This study evaluates the acute effects of pyridostigmine (PYR), a reversible cholinesterase inhibitor, on the occurrence of arrhythmias in patients with Chagas cardiac disease. METHOD: Following a double-blind, randomized, placebo-controlled, cross-over protocol, 17 patients (age 50±2 years) with Chagas cardiac disease type B underwent 24-hour Holter recordings after oral administration of either pyridostigmine bromide (45 mg, 3 times/day) or placebo (PLA). RESULTS: Pyridostigmine reduced the 24-hours incidence (median [25%-75%]) of premature ventricular beats-PLA: 2998 (1920-4870), PYR: 2359 (940-3253), P=.044; ventricular couplets-PLA: 84 (15-159), PYR: 33 (6-94), P=.046. Although the total number of nonsustained ventricular tachycardia in the entire group was not different (P=.19) between PLA (1 [0-8]) and PYR (0 [0-4]), there were fewer episodes under PYR in 72% of the patients presenting this type of arrhythmia (P=.033). CONCLUSION: Acute administration of pyridostigmine reduced the incidence of nonsustained ventricular arrhythmias in patients with Chagas cardiac disease. Further studies that address the use of pyridostigmine by patients with Chagas cardiac disease under a more prolonged follow-up are warranted.
Assuntos
Antiarrítmicos/administração & dosagem , Cardiomiopatia Chagásica/tratamento farmacológico , Inibidores da Colinesterase/administração & dosagem , Frequência Cardíaca/efeitos dos fármacos , Brometo de Piridostigmina/administração & dosagem , Taquicardia Ventricular/prevenção & controle , Complexos Ventriculares Prematuros/prevenção & controle , Administração Oral , Antiarrítmicos/efeitos adversos , Doenças Assintomáticas , Brasil , Cardiomiopatia Chagásica/diagnóstico , Cardiomiopatia Chagásica/parasitologia , Inibidores da Colinesterase/efeitos adversos , Estudos Cross-Over , Método Duplo-Cego , Esquema de Medicação , Eletrocardiografia Ambulatorial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Brometo de Piridostigmina/efeitos adversos , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/parasitologia , Taquicardia Ventricular/fisiopatologia , Fatores de Tempo , Resultado do Tratamento , Complexos Ventriculares Prematuros/diagnóstico , Complexos Ventriculares Prematuros/parasitologia , Complexos Ventriculares Prematuros/fisiopatologiaRESUMO
Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive impairment, associated with a reduced concentration of acetylcholine (ACh) in brain cortex and hippocampus. Recently we reported that the N-acetylcysteine (NAC) decreases brain acetylcholinesterase (AChE) activity in vitro. Thus, the aim of the current study was to investigate the effect of NAC against streptozotocin (STZ) induced AD in mice. Mice were divided into four groups: I) Sham, II) NAC, III) STZ and IV) NAC + STZ. Animals were daily treated with NAC (50 mg/kg/day, p.o.) for nine consecutive days and with STZ (2.5 mg/kg i.c.v.) at the first and third days. Step down passive avoidance (SDPA, days 7-8) and Morris water maze (MWM, days 6-9) task were assessed to evaluate learning and memory. On the tenth day animals were euthanized for AChE and butyrylcholinesterase (BChE) activities and ACh, energy-rich phosphate and brain glucose uptake levels evaluations. A learning and memory impairment was observed in SDPA and MWM in those animals that receive STZ. Nevertheless, the same was not observed in those animals that also received NAC. Brain cortex and hippocampus AChE and hippocampus BChE activities increase induced by STZ were also prevented by NAC treatment. The STZ induced a brain energy metabolism imbalance, decreasing adenosine triphosphate and increasing adenosine levels. The glucose uptake decrease in hippocampus was prevented by NAC. In conclusion, NAC treatment prevented the cognitive disturbance, by restoring the cholinergic system and brain energy metabolism disorders. NAC could modulate cholinergic imbalance without causing any changes per se in the same.
Assuntos
Acetilcisteína/farmacologia , Memória/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estreptozocina/toxicidade , Acetilcolinesterase/metabolismo , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Butirilcolinesterase/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/enzimologia , Metabolismo Energético/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , CamundongosAssuntos
Butirilcolinesterase/genética , Vitiligo/genética , Adolescente , Adulto , Idade de Início , Brasil , Butirilcolinesterase/metabolismo , Feminino , Estudos de Associação Genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Vitiligo/enzimologia , Vitiligo/etiologia , Adulto JovemRESUMO
Introducción: La determinación de la actividad enzimática colinesterasa (ChE) es el principal biomarcador de efecto de la exposición a los plaguicidas organofosforados y carbamatos. Por lo tanto, la estabilidad de la actividad de las ChEs en muestras de sangre es un parámetro pre-analítico importante que necesita ser considerado en términos de la seguridad diagnóstica. Objetivo: Determinar el efecto del tiempo y de la temperatura de almacenamiento sobre la actividad de las ChEs en muestras de sangre humana. Metodología: Muestras de sangre entera y suspensiones de eritrocitos (eritrocitos + solución salina 0.9% proporción 1:1) fueron almacenados a -20°C, 4°C y 25°C. Las determinaciones enzimáticas se realizaron una hora después de la toma de la muestra y se repitieron entre el día 1 hasta el día 90. La actividad enzimática ChE total y Acetil-ChE se determinaron respectivamente mediante el método colorimétrico de Limperos & Ranta y mediante el método potenciométrico de Michel. Resultados: La máxima estabilidad de la actividad ChE total se observó a -20°C hasta por 60 días, además, dicha estabilidad perduró hasta por el tiempo máximo del estudio a 4°C para la Acetil-ChE. Una considerable disminución de la actividad Acetil-ChE se observó después de los días 7 a 25°C y 4 a -20°C. Conclusión: Considerando la seguridad diagnóstica, nosotros recomendamos almacenar las muestras de sangre entera a -20°C por un tiempo máximo de 30 días para la determinación de la actividad ChE total y la suspensión de eritrocitos en 0.9% de NaCl a 4°C por 14 días máximo para la determinación de la Acetil-ChE.
Introduction: Determination of cholinesterase (ChE) enzyme activity is the main biomarker of exposure to pesticides organophosphorus and carbamate. Therefore, the enzyme stability of ChEsin blood samples is an important pre-analytical factor to take into account in the diagnosis. Objective: To determine the effect of storage time and temperature on ChEs enzyme activity in human blood samples. Methodology: Whole-blood samples and erythrocyte suspensions (erythrocyte + 0.9% saline solution; ratio 1:1) were stored at -20°C, 4°C and 25°C. Enzyme activity measurements were performed at one hour after the blood samples have been obtained and then were repeated between days 1 and 90. Total ChE and Acetyl-ChE activities were determined using the Limperos & Ranta colorimetric method and the potentiometric method of Michel respectively. Results: The maximum stability of the total ChE enzyme activity was achieved at -20°C for 60 days and, in the case of Acetyl-ChE, at 4°C for the time the study was conducted. A decrease of Acetyl-ChE activity was shown after 7 days at 25°C and 4 days at -20°C. Conclusion: In terms of diagnosis, we recommend that in order to measure the total ChE activity the wholeblood samples should be stored at -20°C for 30 days, whereas to measure the Acetyl-ChE activity the erythrocyte suspensions in 0.9% NaCl at 4°C for 14 days.