RESUMEN
Acetylcholinesterase (AChE) plays a pivotal role in the cholinergic system, and its inhibition is sought after in a wide range of applications, from insect control to Alzheimer's disease treatment. While the primary physiological isoforms of AChE are membrane-bound proteins, most assays for discovering new, safer, and potent inhibitors are conducted using commercially available soluble isoforms, such as the electric eel AChE (eeAChE). In this study, we conducted a comparative analysis of the activity and selectivity to phenolic inhibitors of recombinant human AChE, eeAChE and a mutant variant of human AChE known as dAChE4. Despite numerous mutations, dAChE4 closely resembles its parental protein and serves as a suitable model for monomeric human AChE. We also established an in vitro system of membrane-bound AChE to create a model that closely mimics the physiological isoforms. This system ensures the proper work of the enzyme and allowed us to control the exact concentration of enzyme and lipids per assay.
Asunto(s)
Acetilcolinesterasa , Inhibidores de la Colinesterasa , Acetilcolinesterasa/metabolismo , Acetilcolinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/química , Humanos , Animales , Fenoles/farmacología , Fenoles/química , Electrophorus , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/química , Nanoestructuras/químicaRESUMEN
Despite the great effort that has gone into developing new molecules as multitarget compounds to treat Alzheimer's disease (AD), none of these have been approved to treat this disease. Therefore, it will be interesting to determine whether benzazoles such as benzimidazole, benzoxazole, and benzothiazole, employed as pharmacophores, could act as multitarget drugs. AD is a multifactorial disease in which several pharmacological targets have been identified-some are involved with amyloid beta (Aß) production, such as beta secretase (BACE1) and beta amyloid aggregation, while others are involved with the cholinergic system as acetylcholinesterase (AChE) and butirylcholinesterase (BChE) and nicotinic and muscarinic receptors, as well as the hyperphosphorylation of microtubule-associated protein (tau). In this review, we describe the in silico and in vitro evaluation of benzazoles on three important targets in AD: AChE, BACE1, and Aß. Benzothiazoles and benzimidazoles could be the best benzazoles to act as multitarget drugs for AD because they have been widely evaluated as AChE inhibitors, forming π-π interactions with W286, W86, Y72, and F338, as well as in the AChE gorge and catalytic site. In addition, the sulfur atom from benzothiazol interacts with S286 and the aromatic ring from W84, with these compounds having an IC50 value in the µM range. Also, benzimidazoles and benzothiazoles can inhibit Aß aggregation. However, even though benzazoles have not been widely evaluated on BACE1, benzimidazoles evaluated in vitro showed an IC50 value in the nM range. Therefore, important chemical modifications could be considered to improve multitarget benzazoles' activity, such as substitutions in the aromatic ring with electron withdrawal at position five, or a linker 3 or 4 carbons in length, which would allow for better interaction with targets.
Asunto(s)
Acetilcolinesterasa , Enfermedad de Alzheimer , Secretasas de la Proteína Precursora del Amiloide , Péptidos beta-Amiloides , Inhibidores de la Colinesterasa , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Humanos , Acetilcolinesterasa/metabolismo , Acetilcolinesterasa/química , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/síntesis química , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/metabolismo , Agregado de Proteínas/efectos de los fármacos , Bencimidazoles/química , Bencimidazoles/farmacología , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad , AnimalesRESUMEN
WHAT IS THIS SUMMARY ABOUT?: Generalized myasthenia gravis (often shortened to gMG) is a rare health condition that causes muscular weakness. This summary gives an overview of three published articles that report the results of research studies of a medicine called ravulizumab, a treatment approved for adults with gMG. These studies are: The CHAMPION MG study. The CHAMPION MG extension study. A study of how the body processes and responds to ravulizumab (known as pharmacokinetics and pharmacodynamics). These studies looked at how effective and safe ravulizumab is for people with gMG. WHAT WERE THE RESULTS?: Overall, participants with gMG who received ravulizumab showed a significant and rapid improvement in their muscle strength and ability to do daily activities. These improvements were sustained for up to 60 weeks of treatment. Ravulizumab was well-tolerated overall, and no-one in the study had a meningococcal infection (a type of bacterial infection preventable with vaccination). Results from the pharmacokinetic and pharmacodynamic study support the use of ravulizumab every 8 weeks to maintain improvements in gMG. WHAT DO THE RESULTS OF THE STUDY MEAN?: Ravulizumab can be considered as a treatment option for adults with gMG who are appropriately protected against meningococcal infection before starting treatment. The drug, administered every 8 weeks, improves muscle strength and daily performance. These positive effects have been observed to persist over a long period of time.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Miastenia Gravis , Humanos , Miastenia Gravis/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Adulto , Fuerza Muscular/efectos de los fármacos , Inhibidores de la Colinesterasa/uso terapéutico , Femenino , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Systemic arterial hypertension is accompanied by autonomic impairments that, if not contained, promotes cardiac functional and morphological damages. Pyridostigmine bromide (PYR) treatment results in positive effects on autonomic control and beneficial cardiac remodeling. These findings were also observed after aerobic physical training (APT). However, little is known about PYR effects on left ventricular contractility, mainly when it is combined with APT. We aimed to investigate the effects of chronic acetylcholinesterase inhibition on cardiac autonomic tone balance, coronary bed reactivity, and left ventricular contractility in spontaneously hypertensive rats (SHR) submitted to APT. Male SHR (18 weeks) were divided into two groups (N = 16): untrained and submitted to APT for 14 weeks (18th to 32nd week). Half of each group was treated with PYR (15 mg/kg/day) for two weeks (31st to 32nd week). The experimental protocol consisted of recording hemodynamic parameters, double autonomic blockade with atropine and propranolol, and assessment of coronary bed reactivity and ventricular contractility in isolated hearts using the Langendorff technique. PYR and APT reduced blood pressure, heart rate, and sympathetic influence on the heart. The Langendorff technique showed that APT increased coronary perfusion pressure and left ventricle contractility in response to coronary flow and ß-agonist administration. However, treatment with PYR annulled the effects of APT. In conclusion, although chronic treatment with PYR reduces cardiac sympathetic tonic influence, it does not favor coronary bed reactivity and cardiac contractility gains. PYR treatment in the trained SHR group nullified the coronary vascular reactivity and cardiac contractility gains.
Asunto(s)
Inhibidores de la Colinesterasa , Hipertensión , Contracción Miocárdica , Condicionamiento Físico Animal , Bromuro de Piridostigmina , Ratas Endogámicas SHR , Animales , Inhibidores de la Colinesterasa/farmacología , Masculino , Ratas , Contracción Miocárdica/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Bromuro de Piridostigmina/farmacología , Presión Sanguínea/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/fisiopatología , Función Ventricular Izquierda/efectos de los fármacos , Acetilcolinesterasa/metabolismoRESUMEN
The widely used insecticide chlorpyrifos (CP) is known to inhibit acetylcholinesterase (AChE) activity attributed to result in various neurological disorders and acetylcholine-dependent organ functions including heart, skeletal muscle, lung, gastrointestinal tract, and central nervous systems. Enzyme reactivators, such as oximes, are known to restore AChE activity and mitigate adverse effects. The identification of compounds that reactivate AChE constitute agents with important therapeutic beneficial effects in cases of pesticide poisoning. However, the screening of novel drugs using traditional models may raise ethical concerns. This study aimed to investigate the potential of Drosophila melanogaster as a model organism for screening AChE reactivators, with a focus on organophosphate poisoning. The efficacy of several oximes, including pralidoxime, trimedoxime, obidoxime, methoxime, HI-6, K027, and K048, against CP-induced AChE activity inhibition in D. melanogaster was determined in silico, in vitro, and in vivo experiments. Molecular docking studies indicated a strong interaction between studied oximes and the active-site gorge of AChE. Data showed that selected oximes (100 µM) are effective in the reactivation of AChE inhibited by CP (10 µM) in vitro. Finally, in vivo investigations demonstrated that selected oximes, pralidoxime and K048 (1.5 ppm), reversed the locomotor deficits, inhibition of AChE activity as well as lowered the mortality rates induced by CP (0.75 ppm). Our findings contribute to utilization of D. melanogaster as a robust model for determination of actions of identified new AChE inhibitory agents with more effective therapeutic properties that those currently in use in the clinical practice in treatment of AChE associated disorders.
Asunto(s)
Acetilcolinesterasa , Cloropirifos , Reactivadores de la Colinesterasa , Drosophila melanogaster , Simulación del Acoplamiento Molecular , Oximas , Animales , Drosophila melanogaster/efectos de los fármacos , Drosophila melanogaster/enzimología , Reactivadores de la Colinesterasa/farmacología , Cloropirifos/toxicidad , Acetilcolinesterasa/metabolismo , Oximas/farmacología , Modelos Animales , Insecticidas/toxicidad , Inhibidores de la Colinesterasa/toxicidadRESUMEN
Nerve agents are organophosphates (OPs) that act as potent inhibitors of acetylcholinesterase (AChE), the enzyme responsible for the hydrolysis of acetylcholine. After inhibition, a dealkylation reaction of the phosphorylated serine, known as the aging of AChE, can occur. When aged, reactivators of OP-inhibited AChE are no longer effective. Therefore, the realkylation of aged AChE may offer a pathway to reverse AChE aging. In this study, molecular modeling was conducted to propose new ligands as realkylators of aged AChE. We applied a methodology involving docking and quantum mechanics/molecular mechanics (QM/MM) calculations to evaluate the resurrection kinetic constants and ligand interactions with OP-aged AChE, comparing them to data found in the literature. The results obtained confirm that this method is suitable for predicting kinetic and thermodynamic parameters of ligands, which can be useful in the design and selection of new and more effective ligands for AChE realkylation.
Asunto(s)
Acetilcolinesterasa , Inhibidores de la Colinesterasa , Indolquinonas , Acetilcolinesterasa/química , Acetilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Cinética , Indolquinonas/química , Simulación del Acoplamiento Molecular , Ligandos , Termodinámica , Modelos Moleculares , Humanos , Simulación de Dinámica MolecularRESUMEN
The risk of the use of toxic chemicals for unlawful acts has been a matter of concern for different governments and multilateral agencies. The Organisation for the Prohibition of Chemical Weapons (OPCW), which oversees the implementation of the Chemical Weapons Convention (CWC), considering recent events employing chemical warfare agents as means of assassination, has recently included in the CWC "Annex on Chemicals" some organophosphorus compounds that are regarded as acting in a similar fashion to the classical G- and V-series of nerve agents, inhibiting the pivotal enzyme acetylcholinesterase. Therefore, knowledge of the activity of the pyridinium oximes, the sole class of clinically available acetylcholinesterase reactivators to date, is plainly justified. In this paper, continuing our research efforts in medicinal chemistry on this class of toxic chemicals, we synthesized an A-230 nerve agent surrogate and applied a modified Ellman's assay to evaluate its ability to inhibit our enzymatic model, acetylcholinesterase from Electrophorus eel, and if the clinically available antidotes are able to rescue the enzyme activity for the purpose of relating the findings to the previously disclosed in silico data for the authentic nerve agent and other studies with similar A-series surrogates. Our experimental data indicates that pralidoxime is the most efficient compound for reactivating acetylcholinesterase inhibited by A-230 surrogate, which is the opposite of the in silico data previously disclosed.
Asunto(s)
Acetilcolinesterasa , Sustancias para la Guerra Química , Inhibidores de la Colinesterasa , Reactivadores de la Colinesterasa , Agentes Nerviosos , Oximas , Compuestos de Piridinio , Oximas/farmacología , Acetilcolinesterasa/metabolismo , Reactivadores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/toxicidad , Compuestos de Piridinio/farmacología , Sustancias para la Guerra Química/toxicidad , Agentes Nerviosos/toxicidad , Compuestos de Pralidoxima/farmacología , Compuestos Organotiofosforados/toxicidad , Animales , Antídotos/farmacologíaRESUMEN
Alzheimer's disease (AD) is a multifactorial and fatal neurodegenerative disorder. Acetylcholinesterase (AChE) plays a key role in the regulation of the cholinergic system and particularly in the formation of amyloid plaques; therefore, the inhibition of AChE has become one of the most promising strategies for the treatment of AD, particularly concerning AChE inhibitors that interact with the peripheral anionic site (PAS). Ceanothic acid isolated from the Chilean Rhamnaceae plants is an inhibitor of AChE through its interaction with PAS. In this study, six ceanothic acid derivatives were prepared, and all showed inhibitory activity against AChE. The structural modifications were performed starting from ceanothic acid by application of simple synthetic routes: esterification, reduction, and oxidation. AChE activity was determined by the Ellmann method for all compounds. Kinetic studies indicated that its inhibition was competitive and reversible. According to the molecular coupling and displacement studies of the propidium iodide test, the inhibitory effect of compounds would be produced by interaction with the PAS of AChE. In silico predictions of physicochemical properties, pharmacokinetics, drug-likeness, and medicinal chemistry friendliness of the ceanothane derivatives were performed using the Swiss ADME tool.
Asunto(s)
Acetilcolinesterasa , Dominio Catalítico , Inhibidores de la Colinesterasa , Diseño de Fármacos , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Acetilcolinesterasa/química , Acetilcolinesterasa/metabolismo , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Cinética , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad , Aniones/química , AnimalesRESUMEN
Depression and anxiety are recognized as the most common mental diseases worldwide. New approaches have considered different therapeutic targets, such as oxidative stress and the inflammation process, due to their close association with the establishment and progression of mental diseases. In the present study, we evaluated the antioxidant and anti-inflammatory activities of the methanolic extracts of the plant species Heteropterys brachiata and Heteropterys cotinifolia and their main compounds, chlorogenic acid and rutin, as potential complementary therapeutic tools for the treatment of anxiety and depression, since the antidepressant and anxiolytic activities of these methanolic extracts have been shown previously. Additionally, we also evaluated their inhibitory activity on the enzyme acetylcholinesterase (AChE). Our results revealed that both species exhibited potent antioxidant activity (>90%) through the TBARS assay, while by means of the DPPH assay, only H. cotinifolia exerted potent antioxidant activity (>90%); additionally, low metal chelating activity (<40%) was detected for all samples tested in the ferrozine assay. The methanolic extracts of H. brachiata and H. cotinifolia exhibited significant anti-inflammatory activities in the TPA-induced ear edema, while only H. cotinifolia exerted significant anti-inflammatory activities in the MPO assay (>45%) and also exhibited a higher percentage of inhibition on AChE of even twice (>80%) as high as the control in concentrations of 100 and 1000 µg/mL. Thus, the potent antioxidant and inflammatory properties and the inhibition of AChE may be involved in the antidepressant activities of the species H. cotinifolia, which would be positioned as a candidate for study in drug development as an alternative in the treatment of depression.
Asunto(s)
Antiinflamatorios , Antioxidantes , Extractos Vegetales , Antioxidantes/farmacología , Antioxidantes/química , Extractos Vegetales/farmacología , Extractos Vegetales/química , Antiinflamatorios/farmacología , Antiinflamatorios/química , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/química , Animales , Acetilcolinesterasa/metabolismo , Antidepresivos/farmacología , Antidepresivos/química , Antidepresivos/uso terapéutico , Ratones , MéxicoRESUMEN
The Bauhinia ungulata, also known by its common name "pata de vaca", is one of the species used in Brazil for medicinal purposes, and is commonly used for the treatment of diabetes. In this study, the authors studied the interaction between the chemical constituents which are present in the essential oil of Bauhinia ungulata (EOBU), collected in Boa Vista-RR, Legal Amazon, and their effects on the enzyme acetylcholinesterase (AChE) in the essential oil. The analysis that we perform includes proton magnetic resonance ( 1H NMR), enzymatic inhibition, molecular docking, in silico toxicity prediction, enrichment analysis, and target prediction for biological interactions. According to the tests performed on the essential oil, it obtained 100% inhibition of the enzyme AChE. During 1H NMR experiments, it was found that α- Bisabolol, one of the main components, had a significant alteration in its chemical shift. A molecular docking analysis confirmed that this compound binds to the AChE enzyme, which confirms the 1H NMR analysis. The results of this work showed that the major component of EOBU acted as a possible inhibitor of AChE enzyme in vitro and in silico assays. These results show that EOBU could be potentially applied in Alzheimer's disease treatment.
Asunto(s)
Acetilcolinesterasa , Bauhinia , Inhibidores de la Colinesterasa , Simulación del Acoplamiento Molecular , Aceites Volátiles , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/química , Bauhinia/química , Brasil , Acetilcolinesterasa/metabolismo , Aceites Volátiles/química , Aceites Volátiles/farmacología , Simulación por Computador , Sesquiterpenos/farmacología , Sesquiterpenos/aislamiento & purificación , Sesquiterpenos/químicaRESUMEN
Acetylcholinesterase (AChE) inhibitors are still an important option for managing symptoms of mild to moderate Alzheimer's disease. In this study, we aimed to evaluate the potential in vitro AChE inhibitory activity of two Argentinian endemic Solanaceae species, Jaborosa bergii and J. runcinata. UHPLC-DAD-HRMS metabolite profiling revealed the presence of withanolides in the active CH2Cl2 subextracts. Their fractionation led to the isolation and identification of two known spiranoid withanolides from J. runcinata and three new withanolides with a skeleton similar to that of trechonolide-type withanolides from J. bergii. The known compounds showed moderate AChE inhibitory activity, while the new ones were inactive.
Asunto(s)
Inhibidores de la Colinesterasa , Solanaceae , Witanólidos , Witanólidos/farmacología , Witanólidos/química , Witanólidos/aislamiento & purificación , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/química , Solanaceae/química , Argentina , Acetilcolinesterasa/metabolismo , Acetilcolinesterasa/efectos de los fármacos , Estructura Molecular , Extractos Vegetales/farmacología , Extractos Vegetales/químicaRESUMEN
CONTEXT: Given the diverse pathophysiological mechanisms underlying Alzheimer's disease, it is improbable that a single targeted drug will prove successful as a therapeutic strategy. Therefore, exploring various hypotheses in drug design is imperative. The sequestration of Fe(II) and Zn(II) cations stands out as a crucial mechanism based on the mitigation of reactive oxygen species. Moreover, inhibiting acetylcholinesterase represents a pivotal strategy to enhance acetylcholine levels in the synaptic cleft. This research aims to investigate the analogs of Huperzine A, documented in scientific literature, considering of these two hypotheses. Consequently, the speciation chemistry of these structures with Fe(II) and Zn(II) was scrutinized using quantum chemistry calculations, molecular docking simulations, and theoretical predictions of pharmacokinetics properties. From the pharmacokinetic properties, only two analogs, HupA-A1 and HupA-A2, exhibited a theoretical permeability across the blood-brain barrier; on the other hand, from a thermodynamic standpoint, the enantiomers of HupA-A2 showed negligible chelation values. The enantiomers with the most favorable interaction parameters were S'R'HupA-A1 (ΔGBIND = -40.0 kcal mol-1, fitness score = 35.5) and R'R'HupA-A1 (ΔGBIND = -35.5 kcal mol-1, fitness score = 22.61), being compared with HupA (ΔGBIND = -41.75 kcal mol-1, fitness score = 39.95). From this study, some prime candidates for promising drug were S'R'HupA-A1 and R'R'HupA-A1, primarily owing to their favorable thermodynamic chelating capability and potential anticholinesterase mechanism. METHODS: Quantum chemistry calculations were carried out at B3LYP/6-31G(d) level, considering the IEF-PCM(UFF) implicit solvent model for water. The coordination compounds were assessed using the Gibbs free energy variation and hard and soft acid theory. Molecular docking calculations were conducted using the GOLD program, based on the crystal structure of the acetylcholinesterase protein (PDB code = 4EY5), where the ChemScore function was employed with the active site defined as the region within a 15-Å radius around the centroid coordinates (X = -9.557583, Y = -43.910473, Z = 31.466687). Pharmacokinetic properties were predicted using SwissADME, focusing on Lipinski's rule of five.
Asunto(s)
Acetilcolinesterasa , Alcaloides , Enfermedad de Alzheimer , Inhibidores de la Colinesterasa , Simulación del Acoplamiento Molecular , Sesquiterpenos , Enfermedad de Alzheimer/tratamiento farmacológico , Alcaloides/química , Sesquiterpenos/química , Humanos , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Acetilcolinesterasa/metabolismo , Acetilcolinesterasa/química , Barrera Hematoencefálica/metabolismo , Termodinámica , Zinc/química , Modelos Moleculares , Hierro/química , Hierro/metabolismoRESUMEN
Carbofuran (CF) is a carbamate class pesticide, widely used in agriculture for pest control in crops. This pesticide has high toxicity in non-target organisms, and its presence in the environment poses a threat to the ecosystem. Research has revealed that this pesticide acts as an inhibitor of acetylcholinesterase (AChE), inducing an accumulation of acetylcholine in the brain. Nonetheless, our understanding of CF impact on the central nervous system remains elusive. Therefore, this study explored how CF influences behavioral and neurochemical outcomes in adult zebrafish. The animals underwent a 96-hour exposure protocol to different concentrations of CF (5, 50, and 500 µg/L) and were subjected to the novel tank (NTT) and social preference tests (SPT). Subsequently, they were euthanized, and their brains were extracted to evaluate neurochemical markers associated with oxidative stress and AChE levels. In the NTT and SPT, CF did not alter the evaluated behavioral parameters. Furthermore, CF did not affect the levels of AChE, non-protein sulfhydryl groups, and thiobarbituric acid reactive species in the zebrafish brain. Nevertheless, further investigation is required to explore the effects of environmental exposure to this compound on non-target organisms.
Asunto(s)
Acetilcolinesterasa , Conducta Animal , Encéfalo , Carbofurano , Estrés Oxidativo , Pez Cebra , Animales , Pez Cebra/metabolismo , Carbofurano/toxicidad , Conducta Animal/efectos de los fármacos , Acetilcolinesterasa/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Estrés Oxidativo/efectos de los fármacos , Inhibidores de la Colinesterasa/toxicidad , Contaminantes Químicos del Agua/toxicidad , Masculino , Insecticidas/toxicidadRESUMEN
OBJECTIVE: To investigate how language deteriorates over the Alzheimer's Disease course. METHODS: A cross-sectional, observational study was carried out. 35 patients diagnosed with dementia due to AD using the NINCDS-ARDRA criteria and undergoing treatment for AD with a therapeutic dose of acetylcholinesterase inhibitors were assessed by the Boston Diagnostic Aphasia Examination (BDAE). The sample comprised 15 patients with mild AD (MMSE > 23, CDR = 0 or 0.5â1.0) and 20 patients with moderate AD (MMSE = 13â23, CDR = 2). The results for the 2 groups on all language tasks were compared. RESULTS: A statistically significant difference was found between the mild and moderate AD groups for total score on the BDAE (95% CI 47.10â114.08, t = 5.0, DF = 21, p = 0.000*), as well as on several tasks involving oral and writing comprehension, language oral expression and writing. CONCLUSION: The study results showed major changes in the moderate stage. Also, the decline in language performance correlated with the worsening of dementia syndrome, independently of sociodemographic variables.
Asunto(s)
Enfermedad de Alzheimer , Trastornos del Lenguaje , Pruebas del Lenguaje , Índice de Severidad de la Enfermedad , Humanos , Enfermedad de Alzheimer/fisiopatología , Masculino , Femenino , Estudios Transversales , Anciano , Anciano de 80 o más Años , Trastornos del Lenguaje/etiología , Trastornos del Lenguaje/fisiopatología , Progresión de la Enfermedad , Pruebas Neuropsicológicas , Persona de Mediana Edad , Factores Socioeconómicos , Inhibidores de la Colinesterasa/uso terapéuticoRESUMEN
Rhipicephalus (Boophilus) microplus is a leading cause of significant economic losses in the livestock industry, and tick populations have developed multiple forms of resistance to acaricides; therefore, the potential of novel natural bioactive compounds that are effective for targeting ticks must be addressed. The aim of this study was to evaluate the acaricidal and anticholinesterase activities of R. aculeata seeds and to identify naturally occurring compounds that potentially inhibit anticholinesterase through in silico docking. The acaricidal activity of the extract of R. aculeata seeds against larval and adult R. microplus ticks was assessed through immersion tests. Inhibition of anticholinesterase activity was measured spectrophotometrically. Extracts of R. aculeata seeds showed activity against larvae and engorged females of R. microplus, and a reduction in the reproductive index were also observed. Rutin, chlorogenic acid, quercetin, and epicatechin exhibited noteworthy interactions with the active site residues of RmAChE. These findings could significantly contribute to the exploration of novel natural products that can potentially inhibit RmAChE and could be used in the development of new acaricides for tick control.
Asunto(s)
Acaricidas , Inhibidores de la Colinesterasa , Extractos Vegetales , Rhipicephalus , Semillas , Animales , Rhipicephalus/efectos de los fármacos , Acaricidas/farmacología , Extractos Vegetales/farmacología , Extractos Vegetales/química , Semillas/química , Inhibidores de la Colinesterasa/farmacología , Simulación por Computador , Femenino , Simulación del Acoplamiento MolecularRESUMEN
The olive oil sector is a fundamental food in the Mediterranean diet. It has been demonstrated that the consumption of extra virgin olive oil (EVOO) with a high content of phenolic compounds is beneficial in the prevention and/or treatment of many diseases. The main objective of this work was to study the relationship between the content of phenolic compounds and the in vitro neuroprotective and anti-inflammatory activity of EVOOs from two PDOs in the province of Granada. To this purpose, the amounts of phenolic compounds were determined by liquid chromatography coupled to mass spectrometry (HPLC-MS) and the inhibitory activity of acetylcholinesterase (AChE) and cyclooxygenase-2 (COX-2) enzymes by spectrophotometric and fluorimetric assays. The main families identified were phenolic alcohols, secoiridoids, lignans, flavonoids, and phenolic acids. The EVOO samples with the highest total concentration of compounds and the highest inhibitory activity belonged to the Picual and Manzanillo varieties. Statistical analysis showed a positive correlation between identified compounds and AChE and COX-2 inhibitory activity, except for lignans. These results confirm EVOO's compounds possess neuroprotective potential.
Asunto(s)
Fármacos Neuroprotectores , Aceite de Oliva , Fenoles , Aceite de Oliva/química , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química , Fenoles/análisis , Fenoles/química , Fenoles/farmacología , España , Ciclooxigenasa 2/metabolismo , Acetilcolinesterasa/metabolismo , Cromatografía Líquida de Alta Presión , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/química , Inhibidores de la Ciclooxigenasa 2/farmacología , Inhibidores de la Ciclooxigenasa 2/química , Flavonoides/análisis , Flavonoides/farmacología , Flavonoides/químicaRESUMEN
Amblyomma sculptum is a species of tick in the family Ixodidae, with equids and capybaras among its preferred hosts. In this study, the acaricidal activity of the essential oil (EO) from Piper aduncum and its main component, Dillapiole, were evaluated against larvae of A. sculptum to establish lethal concentration values and assess the effects of these compounds on tick enzymes. Dillapiole exhibited slightly greater activity (LC50 = 3.38 mg/mL; 95% CI = 3.24 to 3.54) than P. aduncum EO (LC50 = 3.49 mg/mL; 95% CI = 3.36 to 3.62) against ticks. The activities of α-esterase (α-EST), ß-esterase (ß-EST), and glutathione-S-transferase (GST) enzymes in A. sculptum larvae treated with Dillapiole showed a significant increase compared to the control at all concentrations (LC5, LC25, LC50 and LC75), similar results were obtained with P. aduncum EO, except for α-EST, which did not differ from the control at the highest concentration (LC75). The results of the acetylcholinesterase (AChE) activity show an increase in enzyme activity at the two lower concentrations (LC5 and LC25) and a reduction in activity at the two higher, lethal concentrations (LC50 and LC75) compared to the control. These results suggest potential mechanisms of action for these natural acaricides and can provide guidance for the future development of potential plant-derived formulations.
Asunto(s)
Acaricidas , Acetilcolinesterasa , Amblyomma , Aceites Volátiles , Piper , Animales , Acaricidas/farmacología , Acetilcolinesterasa/metabolismo , Compuestos Alílicos , Amblyomma/efectos de los fármacos , Amblyomma/crecimiento & desarrollo , Benzodioxoles/farmacología , Inhibidores de la Colinesterasa/farmacología , Dioxoles , Esterasas/metabolismo , Glutatión Transferasa/metabolismo , Inactivación Metabólica , Larva/efectos de los fármacos , Aceites Volátiles/farmacología , Aceites Volátiles/química , Piper/químicaRESUMEN
This work evaluated the insecticidal, antifeedant and AChE inhibitory activity of compounds with eudesmane skeleton. The insecticidal activity was tested against larvae of Drosophila melanogaster and Cydia pomonella, the compounds 3 and 4 were the most active (LC50 of 104.2 and 106.7 µM; 82.0 and 84.4 µM, respectively). Likewise, the mentioned compounds were those that showed the highest acetylcholinesterase inhibitory activity, with IC50 of 0.26 ± 0.016 and 0.77 ± 0.016 µM, respectively. Enzyme kinetic studies, as well as molecular docking, show that the compounds would be non-competitive inhibitors of the enzyme. The antifeedant activity on Plodia interpunctella larvae showed an antifeedant index (AI) of 99% at 72 h for compounds 16, 27 and 20. The QSAR studies show that the properties associated with the polarity of the compounds would be responsible for the biological activities found.
Asunto(s)
Acetilcolinesterasa , Inhibidores de la Colinesterasa , Drosophila melanogaster , Insecticidas , Larva , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad Cuantitativa , Sesquiterpenos de Eudesmano , Animales , Insecticidas/farmacología , Insecticidas/química , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/química , Larva/efectos de los fármacos , Drosophila melanogaster/efectos de los fármacos , Acetilcolinesterasa/metabolismo , Sesquiterpenos de Eudesmano/farmacología , Sesquiterpenos de Eudesmano/química , Mariposas Nocturnas/efectos de los fármacos , Sesquiterpenos/farmacología , Sesquiterpenos/químicaRESUMEN
Molecular dereplication and drug-like discovery are important tools for exploring the chemical profile of metabolites in a complex mixture. In order to establish a workflow for discovering novel acetylcholinesterase (AChE) ligands, we performed the chemical study of Myrsine guianensis (Aubl.) Kuntze (Primulaceae). To carry out the bioprospection, nine extracts were obtained from different parts of the plant. Through the dereplication approaches, seventeen metabolites were annotated. In order to confirm the putative inferences, a HPLC preparative method was developed to isolate three known myrsinoic acids, A(1), B(2) and C(3). Along with, we are reporting the obtention of two new congeners, G(5) and H(6), which their structures were elucidated by NMR and HRMS data. Besides that, two extracts were submitted to affinity assays to accelerate the discovery of AChE ligands. Desorbates were analyzed through LC-HRMS for calculating the affinity ratio (AR). Thus, (1) presented AR = 4.59, therefore was considered a potential ligand.
Asunto(s)
Acetilcolinesterasa , Estructura Molecular , Ligandos , Acetilcolinesterasa/metabolismo , Fitoquímicos/aislamiento & purificación , Fitoquímicos/química , Inhibidores de la Colinesterasa/químicaRESUMEN
The repellent capacity against Sitophilus zeamais and the in vitro inhibition on AChE of 11 essential oils, isolated from six plants of the northern region of Colombia, were assessed using a modified tunnel-type device and the Ellman colorimetric method, respectively. The results were as follows: (i) the degree of repellency (DR) of the EOs against S. zeamais was 20-68% (2 h) and 28-74% (4 h); (ii) the IC50 values on AChE were 5-36 µg/mL; likewise, the %inh. on AChE (1 µg/cm3 per EO) did not show any effect in 91% of the EO tested; (iii) six EOs (Bursera graveolens-bark, B. graveolens-leaves, B. simaruba-bark, Peperomia pellucida-leaves, Piper holtonii (1b*)-leaves, and P. reticulatum-leaves) exhibited a DR (53-74%) ≥ C+ (chlorpyrifos-61%), while all EOs were less active (8-60-fold) on AChE compared to chlorpyrifos (IC50 of 0.59 µg/mL). Based on the ANOVA/linear regression and multivariate analysis of data, some differences/similarities could be established, as well as identifying the most active EOs (five: B. simaruba-bark, Pep. Pellucida-leaves, P. holtonii (1b*)-leaves, B. graveolens-bark, and B. graveolens-leaves). Finally, these EOs were constituted by spathulenol (24%)/ß-selinene (18%)/caryophyllene oxide (10%)-B. simaruba; carotol (44%)/dillapiole (21%)-Pep. pellucida; dillapiole (81% confirmed by 1H-/13C-NMR)-P. holtonii; mint furanone derivative (14%)/mint furanone (14%)-B. graveolens-bark; limonene (17%)/carvone (10%)-B. graveolens-leaves.