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1.
Amino Acids ; 54(2): 181-192, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34738177

RESUMO

The use of acetylcholinesterase (AChE) inhibitors, antioxidants or multitarget compounds are among the main strategies against Alzheimer's disease (AD). Between AChE inhibitors, those targeting the peripheral anionic site (PAS) are of special interest. Here, we describe the rational design and synthesis of peptide analogs of a natural PAS-targeting sequence that we recently discovered, aiming at increasing its activity against AChE. We also tested their radical scavenging and metal chelating properties. Our design strategy was based on the position-specific, computer-aided insertion of aromatic residues. The analog named as W3 showed a 30-fold higher inhibitory activity than the original sequence and an improved antioxidant activity. W3 is the most potent modified natural peptide against Electrophorus electricus AChE ever reported with an IC50 of 10.42 µM (± 1.02). In addition, it showed a radical scavenging activity of 47.00% ± 3.11 at 50 µM and 93.47% ± 1.53 at 400 µM. Since peptides are receiving increasing interest as drugs, we propose the W3 analog as an attractive sequence for the development of new peptide-based multitarget drugs for AD. Besides, this work sheds light on the importance of the aromatic residues in the modulation of AChE activity and their effect on the radical scavenging activity of a peptide.


Assuntos
Doença de Alzheimer , Inibidores da Colinesterase , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Anuros/metabolismo , Inibidores da Colinesterase/química , Simulação de Acoplamento Molecular , Peptídeos/farmacologia , Relação Estrutura-Atividade
2.
BMC Neurol ; 22(1): 292, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35932018

RESUMO

BACKGROUND: Congenital myasthenic syndromes (CMSs) are rare genetic diseases due to abnormalities of the neuromuscular junction leading to permanent or transient muscle fatigability and weakness. To date, 32 genes were found to be involved in CMSs with autosomal dominant and/or recessive inheritance patterns. CMS with acetylcholinesterase deficiency, in particular, was determined to be due to biallelic mutations of COLQ gene with early-onset clinical signs. Here, we report clinical features and novel molecular findings of COLQ-related CMS in a Moroccan patient with a review of the literature for this rare form. CASE PRESENTATION: In this study, we report the case of a 28-month-old Moroccan female patient with hypotonia, associated to axial muscle weakness, global motor delay, bilateral ptosis, unilateral partial visual field deficiency with normal ocular motility, and fatigable muscle weakness. Clinical exome sequencing revealed a novel homozygous deletion of exon 13 in COLQ gene, NM_005677.4(COLQ):c.(814+1_815-1)_(954+1_955-1) del p.(Gly272Aspfs*11). This finding was subsequently confirmed by quantitative real-time PCR (qPCR) in the proband and her parents. In silico analysis of protein-protein interaction network by STRING tool revealed that 12 proteins are highly associated to COLQ with an elevated confidence score. Treatment with Salbutamol resulted in clear benefits and recovery. CONCLUSIONS: This clinical observation illustrates the important place of next-generation sequencing in the precise molecular diagnosis of heterogeneous forms of CMS, the appropriate management and targeted treatment, and genetic counseling of families, with a better characterization of the mutational profile of this rare disease in the Moroccan population.


Assuntos
Síndromes Miastênicas Congênitas , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Pré-Escolar , Colágeno/genética , Colágeno/metabolismo , Variações do Número de Cópias de DNA , Feminino , Homozigoto , Humanos , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Debilidade Muscular , Mutação/genética , Síndromes Miastênicas Congênitas/genética , Deleção de Sequência
3.
Sci Rep ; 12(1): 13649, 2022 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-35953511

RESUMO

As part of our continuous studies on natural cholinesterase inhibitors from plant kingdom, the 95% ethanol extract from tubers of Bletilla striata showed promising butyrylcholinesterase (BChE) inhibition (IC50 = 8.6 µg/mL). The extracts with different polarities (petroleum ether, ethyl acetate, n-butanol, and water) were prepared and evaluated for their inhibition of cholinesterases. The most active ethyl acetate extract was subjected to a bioassay-guided isolation and afforded twenty-two bibenzyls and phenanthrenes (1-22). All isolates were further evaluated for their BChE inhibition activity, and five phenanthrenes presented promising capacity (IC50 < 10 µM). Further kinetic studies indicated their modes of inhibition. Compounds 6, 8, and 14 were found to be mixed-type inhibitors, while compounds 10 and 12 could be classified as non-competitive inhibitors. The potential interaction mechanism of them with BChE was demonstrated by molecular docking and molecular dynamics simulation, showing that they could interact with catalytic active site and peripheral anionic site of BChE. These natural phenanthrenes provide new scaffold for the further design and optimization, with the aim to discover new selective BChE inhibitors for the treatment of AD.


Assuntos
Orchidaceae , Fenantrenos , Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Cinética , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Orchidaceae/metabolismo , Fenantrenos/farmacologia , Relação Estrutura-Atividade
4.
Pharm Biol ; 60(1): 1502-1510, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35968601

RESUMO

CONTEXT: Alzheimer's disease (AD) is a neurodegenerative disorder that affects millions of people worldwide. Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are promising therapeutic targets for AD. OBJECTIVE: To evaluate the inhibitory effects of aaptamine on two cholinesterases and investigate the in vivo therapeutic effect on AD in a zebrafish model. MATERIALS AND METHODS: Aaptamine was isolated from the sponge Aaptos suberitoides Brøndsted (Suberitidae). Enzyme inhibition, kinetic analysis, surface plasmon resonance (SPR) and molecular docking assays were used to determine its inhibitory effect on AChE and BuChE in vitro. Zebrafish were divided into six groups: control, model, 8 µM donepezil, 5 , 10 and 20 µM aaptamine. After three days of drug treatment, the behaviour assay was performed. RESULTS: The IC50 values of aaptamine towards AChE and BuChE were 16.0 and 4.6 µM. And aaptamine directly inhibited the two cholinesterases in the mixed inhibition type, with Ki values of 6.96 ± 0.04 and 6.35 ± 0.02 µM, with Kd values of 87.6 and 10.7 µM. Besides, aaptamine interacts with the crucial anionic sites of AChE and BuChE. In vivo studies indicated that the dyskinesia recovery rates of 5 , 10 and 20 µM aaptamine group were 34.8, 58.8 and 60.0%, respectively, and that of donepezil was 63.7%. DISCUSSION AND CONCLUSIONS: Aaptamine showed great potential to exert its anti-AD effects by directly inhibiting the activities of AChE and BuChE. Therefore, this study identified a novel medicinal application of aaptamine and provided a new structural scaffold for the development of anti-AD drugs.


Assuntos
Doença de Alzheimer , Butirilcolinesterase , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Animais , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Donepezila/farmacologia , Humanos , Cinética , Simulação de Acoplamento Molecular , Naftiridinas , Peixe-Zebra/metabolismo
5.
Bioorg Med Chem Lett ; 72: 128873, 2022 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-35779827

RESUMO

A novel series of 2-(2- oxoethyl)pyrimidine-5-carboxamide derivatives were designed, synthesized and evaluated as acetylcholinesterase inhibitors (AChEIs) for the treatment of Alzheimer's disease (AD). Biological activity results demonstrated that compound 10q showed the best inhibitory activity against AChE (IC50 = 0.88 ± 0.78 µM), which was better than that of Huperzine-A, and its inhibitory effect on BuChE was weak (IC50 = 10.0 ± 1.30 µM), which indicated that compound 10q was a dominant AChE inhibitor. In addition, the result of molecular docking study displayed that 10q could simultaneously bind to CAS and PAS sites of AChE, which was consistent with the mixed inhibition mode shown by the enzymatic kinetics study of 10q. Furthermore, the molecular properties of the target compounds were predicted online using the molinspiration server and pkCSM, The results exhibited that compound 10q had drug-like properties that satisfied the Lipinski's rule of five. Based on the bioactivity and molecular properties, compound 10q for further development was valuable.


Assuntos
Doença de Alzheimer , Inibidores da Colinesterase , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Desenho de Fármacos , Humanos , Simulação de Acoplamento Molecular , Pirimidinas/farmacologia , Relação Estrutura-Atividade
6.
J Enzyme Inhib Med Chem ; 37(1): 2099-2111, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35899776

RESUMO

Novel scaffolds are expected to treat Alzheimer's disease, pyrazole-5-fluorosulfates were found as selective BuChE inhibitors. Compounds K1-K26 were assayed for ChE inhibitory activity, amongst them, compound K3 showed potent BuChE and hBuChE inhibition (IC50 = 0.79 µM and 6.59 µM). SAR analysis showed that 1-, 3-, 4-subtituent and 5-fluorosulfate of pyrazole ring affected BuChE inhibitory activity. Molecular docking showed that the fluorosulfate increased the binding affinity of hBuChE through π-sulphur interaction. Compound K3 was a reversible, mixed and non-competitive BuChE inhibitor (Ki = 0.77 µM) and showed remarkable neuroprotection, safe toxicological profile and BBB penetration. In vivo behavioural study showed that K3 treatment improved the Aß1 - 42-induced cognitive impairment, and significantly prevented the effects of Aß1 - 42 toxicity. Therefore, selective BuChE inhibitor K3 has potential to be further developed as AD therapeutics.


Assuntos
Doença de Alzheimer , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Inibidores da Colinesterase/química , Desenho de Fármacos , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirazóis/química , Pirazóis/farmacologia , Relação Estrutura-Atividade
7.
Cent Nerv Syst Agents Med Chem ; 22(1): 68-78, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35899919

RESUMO

BACKGROUND: A simultaneous administration of an acetylcholinesterase (AChE) inhibitor and a NSAID as a drug cocktail has been documented to exhibit significantly protective effects in AD patients. But it suffers from poor patent compliance, pharmacodynamics and pharmacokinetic issues. OBJECTIVE: The present study is aimed to design and synthesize a hybrid molecule capable of exhibiting both AChE inhibition and anti-inflammatory activities for de-accelerating the progression of AD. The synthesized molecules will be evaluated for in vitro and in vivo models. METHODS: The present study involves the coupling of ibuprofen or naproxen to varied disubstituted amines (AChE inhibitor pharmacophore) through benzimidazole to develop two series of compounds i.e. IB01-IB05 and NP01-NP05. The synthesized compounds were characterized using FTIR, 1H-NMR, 13C-NMR and MS. All compounds were evaluated for in vitro AChE inhibitory and COX inhibitory activities. The most active compound was taken for in vivo evaluation. RESULTS: Compounds of series IB01-IB05 are found more potent as compared to NP01-NP05. The maximally potent compound IB04 in in vitro evaluation is selected for in vivo evaluation of memory restoration activity using scopolamine-induced amnesia model in mice. It significantly reverses the scopolamine-induced changes (i.e., escape latency time, mean time spent in target quadrant, brain AChE activity and oxidative stress) in a dose-dependent manner. IB04 at 8 mg/kg is significantly effective in lowering AD manifestation in comparison to donepezil. CONCLUSION: The findings indicate that Benzimidazole hybrids utilizing ibuprofen and pyrrolidine moiety may prove a useful template for the development of new chemical moieties against AD with multiple potencies.


Assuntos
Acetilcolinesterase , Doença de Alzheimer , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Animais , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Ibuprofeno/farmacologia , Ibuprofeno/uso terapêutico , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Escopolamina , Relação Estrutura-Atividade
8.
Pol J Vet Sci ; 25(2): 303-310, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35861972

RESUMO

Rebaudioside A (RebA) is a steviol glycoside used for production of sweeteners. It was shown that the glycosides affect memory and learning processes. The aim of the study was to investigate neurons immunoreactive for acetylcholinesterase (AChE) and M1 muscarinic receptors (mAChRs-M1) of the hippocampal CA1 and CA3 fields and striatal caudateputamen (CP) and globus pallidus (GP) in rats receiving RebA. RebA was administrated to adult rats for 45 days in dilutions of 1 mg and 2 mg RebA/ml water. Indirect peroxidase-antiperoxidase immunohistochemical reaction was conducted on frontal sections containing the hippocampus and striatum with use of antibodies against AChE and mAChRs-M1. Immunoreactive for the studied proteins neurons were morphologically and morphometrically assessed in hippocampal CA1 and CA3 fields and in CP and GP. Microscopic observations did not reveal significant changes in morphology of immunoreactive neurons, which suggests no neurotoxic effect of the studied glycoside on these cells. Morphometric analyses revealed an increase in the density of AChE and mAChRs-M1 immunoreactive neurons. A decrease in reaction intensity of AChE-positive neurons was also demonstrated in the hippocampal CA1 field and in GP. In contrast, an increase in reaction intensity of mAChRs-M1-positive neurons was found in CA1, CA3 fields and in CP and GP. The results of our preliminary studies indicate that RebA administrated to rats has an impact on cholinergic neurons in the studied area. The results suggest a possible increase in the activity of the cholinergic system, responsible for memory and learning processes, after administration of RebA.


Assuntos
Diterpenos do Tipo Caurano , Receptor Muscarínico M1 , Acetilcolinesterase/metabolismo , Animais , Diterpenos do Tipo Caurano/metabolismo , Diterpenos do Tipo Caurano/farmacologia , Hipocampo , Ratos , Receptor Muscarínico M1/metabolismo
9.
PLoS One ; 17(7): e0271119, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35802656

RESUMO

Midazolam is a widely used short-acting benzodiazepine. However, midazolam is also criticized for its deliriogenic potential. Since delirium is associated with a malfunction of the neurotransmitter acetylcholine, midazolam appears to interfere with its proper metabolism, which can be triggered by epigenetic modifications. Consequently, we tested the hypothesis that midazolam indeed changes the expression and activity of cholinergic genes by acetylcholinesterase assay and qPCR. Furthermore, we investigated the occurrence of changes in the epigenetic landscape by methylation specific PCR, ChiP-Assay and histone ELISA. In an in-vitro model containing SH-SY5Y neuroblastoma cells, U343 glioblastoma cells, and human peripheral blood mononuclear cells, we found that midazolam altered the activity of acetylcholinesterase /buturylcholinesterase (AChE / BChE). Interestingly, the increased expression of the buturylcholinesterase evoked by midazolam was accompanied by a reduced methylation of the BCHE gene and the di-methylation of histone 3 lysine 4 and came along with an increased expression of the lysine specific demethylase KDM1A. Last, inflammatory cytokines were not induced by midazolam. In conclusion, we found a promising mechanistic link between midazolam treatment and delirium, due to a significant disruption in cholinesterase homeostasis. In addition, midazolam seems to provoke profound changes in the epigenetic landscape. Therefore, our results can contribute to a better understanding of the hitherto poorly understood interactions and risk factors of midazolam on delirium.


Assuntos
Delírio , Neuroblastoma , Acetilcolinesterase/metabolismo , Butirilcolinesterase , Inibidores da Colinesterase/farmacologia , Delírio/etiologia , Epigênese Genética , Histona Desmetilases/metabolismo , Histonas/metabolismo , Humanos , Leucócitos Mononucleares/metabolismo , Lisina/metabolismo , Midazolam/farmacologia , Neuroblastoma/genética
10.
PLoS One ; 17(7): e0271138, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35802659

RESUMO

BACKGROUND: Alzheimer's disease is the most common cause of dementia in the elderly population. It is characterized by the accumulation of amyloid ß and intraneuronal neurofibrillary tangles in the brain. Increasing evidence shows that the disturbance of insulin signalling in the brain may contribute to the pathophysiology of Alzheimer's disease. In type 1 diabetes, these disruptions are caused by hypoinsulinemia, but in type 2 diabetes, they are caused by insulin resistance and decreased insulin secretion. Multiple studies have shown that diabetes is connected with an increased risk of acquiring Alzheimer's disease. The aim of this study was to investigate the impact of anti-diabetic agents on Alzheimer's disease progression and the levels of Alzheimer's biomarkers in a hyperglycaemic rat model, which was induced by intraperitoneal injection of streptozocin to produce insulin-deficient diabetes. METHOD: Thirty-six male Wistar albino rats were allocated into six groups of six rats each. Group I was the negative control group. Intraperitoneal injections of streptozocin (42mg/kg) were used once for the five experimental groups. Group II served as the positive control group. The rats in Groups III, IV, V, and VI received metformin (300mg/kg), donepezil (10mg/kg), insulin glargine (3 unit/animal), and glibenclamide (10mg/kg), respectively, for 21 days. RESULTS: Inducing hyperglycaemia in rats significantly increased the levels of serum glucose, haemoglobin A1c, total cholesterol, triglycerides, high-density lipoprotein, interleukin 6, tumour necrosis factor alpha, amyloid ß 42, total plasma tau, and neurofilament light. A significant increase was also found in brain amyloid ß 42, nitric oxide, acetylcholinesterase, malondialdehyde, ß secretase, and phosphorylated microtubule-associated protein tau. The greatest statistically significant reductions in serum glucose, haemoglobin A1c, triglycerides, amyloid ß 42, total plasma tau, brain amyloid ß 42, acetylcholinesterase, and malondialdehyde were observed in rats treated with metformin. In contrast, rats treated with donepezil demonstrated the greatest statistically significant reduction in serum tumour necrosis factor alpha, brain nitric oxide, and ß secretase. The levels of neurofilament light and phosphorylated microtubule-associated protein tau in the brains of rats treated with insulin glargine were significantly lower than the other treatment groups. The total cholesterol and low-density lipoprotein levels in rats treated with glibenclamide exhibited the most statistically significant reductions of all the treatment groups. CONCLUSIONS: Metformin and donepezil, when administered at appropriate doses, were shown to successfully lower most plasma and brain biomarkers, including glucose, triglycerides, tumour necrosis factor alpha, amyloid ß 42, nitric oxide, acetylcholinesterase, malondialdehyde, and ß secretase in rats suffering from Diabetes Mellitus. As a result of this research, we suggest that metformin, either alone or in conjunction with donepezil, might be an excellent drug of choice for neuro-regeneration and risk reduction in Alzheimer's like disease.


Assuntos
Doença de Alzheimer , Diabetes Mellitus Tipo 2 , Hipoglicemiantes , Metformina , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Biomarcadores , Colesterol , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Donepezila , Glucose/metabolismo , Glibureto/uso terapêutico , Hemoglobina A Glicada , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Insulina Glargina/uso terapêutico , Masculino , Malondialdeído , Metformina/farmacologia , Metformina/uso terapêutico , Proteínas Associadas aos Microtúbulos , Óxido Nítrico/uso terapêutico , Ratos , Ratos Wistar , Estreptozocina , Triglicerídeos , Fator de Necrose Tumoral alfa/uso terapêutico
11.
Molecules ; 27(14)2022 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-35889221

RESUMO

This study reports the isolation of three new C20 diterpenoid alkaloids, Chitralinine A-C (1-3) from the aerial parts of Delphinium chitralense. Their structures were established on the basis of latest spectral techniques and single crystal X-rays crystallographic studies of chitralinine A described basic skeleton of these compounds. All the isolated Compounds (1-3) showed strong, competitive type inhibition against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in comparison to standard allanzanthane and galanthamine however, chitralinine-C remained the most potent with IC50 value of 11.64 ± 0.08 µM against AChE, and 24.31 ± 0.33 µM against BChE, respectively. The molecular docking reflected a binding free energy of -16.400 K Cal-mol-1 for chitralinine-C, having strong interactions with active site residues, TYR334, ASP72, SER122, and SER200. The overall findings suggest that these new diterpenoid alkaloids could serve as lead drugs against dementia-related diseases including Alzheimer's disease.


Assuntos
Alcaloides , Delphinium , Diterpenos , Acetilcolinesterase/metabolismo , Alcaloides/química , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Delphinium/química , Diterpenos/química , Simulação de Acoplamento Molecular
12.
Molecules ; 27(14)2022 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-35889329

RESUMO

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by cognitive deficits, which are accompanied by memory loss and cognitive disruption. Rhodiola sachalinensis (RSE) is a medicinal plant that has been used in northeastern Asia for various pharmacological activities. We attempted to carry out the bioconversion of RSE (Bio-RSE) using the mycelium of Bovista plumbe to obtain tyrosol-enriched Bio-RSE. The objective of this study was to investigate the effects of Bio-RSE on the activation of the cholinergic system and the inhibition of oxidative stress in mice with scopolamine (Sco)-induced memory impairment. Sco (1 mg/kg body weight, i.p.) impaired the mice's performance on the Y-maze test, passive avoidance test, and water maze test. However, the number of abnormal behaviors was reduced in the groups supplemented with Bio-RSE. Bio-RSE treatment improved working memory and avoidance times against electronic shock, increased step-through latency, and reduced the time to reach the escape zone in the water maze test. Bio-RSE dramatically improved the cholinergic system by decreasing acetylcholinesterase activity and regulated oxidative stress by increasing antioxidant enzymes (superoxide dismutase (SOD) and catalase (CAT)). The reduction in nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling in the brain tissue due to scopolamine was restored by the administration of Bio-RSE. Bio-RSE also significantly decreased amyloid-beta 1-42 (Aß1-42) and amyloid precursor protein (APP) expression. Moreover, the increased malondialdehyde (MDA) level and low total antioxidant capacity in Sco-treated mouse brains were reversed by Bio-RSE, and an increase in Nrf2 and HO-1 was also observed. In conclusion, Bio-RSE protected against Sco-induced cognitive impairment by activating Nrf2/HO-1 signaling and may be developed as a potential beneficial material for AD.


Assuntos
Doença de Alzheimer , Rhodiola , Acetilcolinesterase/metabolismo , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Antioxidantes/metabolismo , Colinérgicos/farmacologia , Cognição , Aprendizagem em Labirinto , Transtornos da Memória/tratamento farmacológico , Camundongos , Micélio/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Álcool Feniletílico/análogos & derivados , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Rhodiola/metabolismo , Escopolamina/farmacologia
13.
Cell Biochem Funct ; 40(5): 535-545, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35790015

RESUMO

Advancing age is associated with several diseases and disorders due to multiorgan atrophy. The increasing proportion of elderly humans demands the identification of means to counteract aging and age-associated disorders. There is an increased depletion of stem cells in the aged organs, resulting in their inability to repair the damage and hence organ degeneration. Stem cell therapy has been implicated in counteracting aging and shown promise. However, the use of stem cells encounters several side effects and complications such as handling and storage of the cells for transplantation purpose. Stem cells secretome has proven to be of significant importance in a variety of disorders. In this study, we have shown that secretome derived from dental pulp stem cells (DPSCs) can reverse the age-associated degeneration induced by chronic exposure to d-galactose in a rat model. The secretome was able to increase muscle grip strength and animal activity. Secretome also improved the kidney function and hepatic biochemistry similar to healthy controls as evaluated by renal function test and Fourier-transform infrared spectroscopy. We also showed that secretome reduced the levels of monoamine oxidase and acetylcholinesterase in the brain and liver, indicating aging reversal. Finally, proteomic profiling of DPSCs secretome revealed the presence of 13 proteins which have antiaging functions. Thus, our study provides first proof of concept that DPSCs secretome can render protection against d-galactose induced accelerated aging.


Assuntos
Galactose , Proteômica , Acetilcolinesterase/metabolismo , Idoso , Envelhecimento , Animais , Diferenciação Celular , Células Cultivadas , Polpa Dentária/metabolismo , Galactose/metabolismo , Humanos , Ratos , Secretoma , Células-Tronco/metabolismo
14.
Food Res Int ; 158: 111497, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35840206

RESUMO

The present study aimed to investigate the inhibition mechanism of polyphenols from Phyllanthus emblica Linn. fruit (PEF, family Euphorbiaceous) on acetylcholinesterase (AChE). Interaction assay, enzyme kinetics, spectroscopic methods, and molecular simulations were performed. Results showed that myricetin, quercetin, fisetin, and gallic acid were the most active components in PEF, because of their low docking scores and strong inhibition ability on AChE with IC50 values of 0.1974 ± 0.0047, 0.2589 ± 0.0131, 1.0905 ± 0.0598 and 1.503 ± 0.0728 mM, respectively. Among them, the results of kinetic study showed that myricetin, quercetin, and fisetin reversibly inhibited AChE in a competitive manner, while gallic acid inhibited it through a noncompetition type. The interaction assay implied that a combination of the four polyphenols at the selected concentrations manifested a synergistic inhibition effect on AChE in a mixed inhibition type. Fluorescence and UV-vis spectrophotometry revealed that the active PEF polyphenols could strongly quench the intrinsic fluorescence of AChE via a static quenching mechanism. Circular dichroism spectroscopy analysis indicated that the active PEF polyphenols gave rise to the secondary structure changes of AChE by increasing the content of α-helix and reducing ß-sheet and random coil conformation. The molecular dynamics simulation results validated that all the four docked polyphenol-AChE complexes were relatively stable according to their root-mean-square distance, root-mean-square fluctuations, solvent accessible surface area, radius of gyration values and hydrogen bonds evaluations during the whole simulation process. Overall, our study provides a creative insight into the further utilization of PEF polyphenols as functional components in exploring natural AChE inhibitors.


Assuntos
Acetilcolinesterase , Phyllanthus emblica , Acetilcolinesterase/metabolismo , Frutas/metabolismo , Ácido Gálico , Cinética , Simulação de Acoplamento Molecular , Phyllanthus emblica/metabolismo , Polifenóis/farmacologia , Estrutura Secundária de Proteína , Quercetina , Análise Espectral
15.
Org Biomol Chem ; 20(28): 5589-5601, 2022 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-35796650

RESUMO

The management of neurological disorders such as dementia associated with Alzheimer's or Parkinson's disease includes the use of cholinesterase inhibitors. These compounds can slow down the progression of these diseases and can also be used in the treatment of glaucoma and myasthenia gravis. The majority of the cholinesterase inhibitors used in the clinic are derived from natural products and our current paper describes the use of a small marine pharmacophore to develop potent and selective cholinesterase inhibitors. Fourteen small inhibitors were designed based on recent discoveries about the inhibitory potential of a range of related marine secondary metabolites. The compounds were evaluated, in kinetic enzymatic assays, for their ability to inhibit three different cholinesterase enzymes and it was shown that compounds with a high inhibitory activity towards electric eel and human recombinant acetylcholinesterase (IC50 between 20-70 µM) could be prepared. It was also shown that this compound class was particularly active against horse serum butyrylcholinesterase, with IC50 values between 0.8-16 µM, which is an order of magnitude more potent than the clinically used positive control neostigmine. The compounds were further tested for off-target toxicity against both human umbilical vein endothelial cells and bovine and human erythrocytes and were shown to display a low mammalian cellular toxicity. Overall, the study illustrates how the brominated dipeptide marine pharmacophore can be used as a versatile natural scaffold for the design of potent, and selective cholinesterase inhibitors.


Assuntos
Doença de Alzheimer , Inibidores da Colinesterase , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Animais , Butirilcolinesterase/metabolismo , Bovinos , Inibidores da Colinesterase/química , Electrophorus , Células Endoteliais/metabolismo , Cavalos , Humanos , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
16.
ACS Chem Neurosci ; 13(14): 2122-2139, 2022 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-35797244

RESUMO

Alzheimer's disease (AD), a multifactorial complex neural disorder, is categorized with progressive memory loss and cognitive impairment as main clinical features. The multitarget directed ligand (MTDL) strategy is explored for the treatment of multifactorial diseases such as cancer and AD. Herein, we report the synthesis and screening of 24 N-propargyl-substituted diphenylpyrimidine derivatives as MTDLs against acetylcholine/butyrylcholine esterases and monoamine oxidase enzymes. In this series, VP1 showed the most potent MAO-B inhibitory activity with an IC50 value of 0.04 ± 0.002 µM. VP15 with an IC50 value of 0.04 ± 0.003 µM and a selectivity index of 626 (over BuChE) displayed the most potent AChE inhibitory activity in this series. In the reactive oxygen species (ROS) inhibition studies, VP1 reduced intercellular ROS levels in SH-SY5Y cells by 36%. This series of compounds also exhibited potent neuroprotective potential against 6-hydroxydopamine-induced neuronal damage in SH-SY5Y cells with up to 90% recovery. In the in vivo studies in the rats, the hydrochloride salt of VP15 was orally administered and found to cross the blood-brain barrier and reach the target site. VP15·HCl significantly attenuated the spatial memory impairment and improved the cognitive deficits in the mice. This series of compounds were found to be irreversible inhibitors and showed no cytotoxicity against neuronal cells. In in silico studies, the compounds attained thermodynamically stable orientation with complete occupancy at the active site of the receptors. Thus, N-propargyl-substituted diphenylpyrimidines displayed drug-like characteristics and have the potential to be developed as MTDLs for the effective treatment of AD.


Assuntos
Doença de Alzheimer , Neuroblastoma , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Animais , Inibidores da Colinesterase/uso terapêutico , Desenho de Fármacos , Humanos , Ligantes , Camundongos , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Neuroblastoma/tratamento farmacológico , Ratos , Espécies Reativas de Oxigênio , Relação Estrutura-Atividade
17.
Artigo em Inglês | MEDLINE | ID: mdl-35843445

RESUMO

The inhibitory effects of bisphenol A (BPA) and bisphenol S (BPS), which are common pollutants, especially in marine and freshwater, on the electric eel acetylcholinesterase (AChE) activity were studied in vitro and in silico. Both produced full non-competitive inhibition, but the Ki value of BPA was half that of BPS. Molecular docking analyses revealed that both interact with residues W286, F297, Y337, F338 in the PAS and ABS regions in the middle and entrance of the active site gorge, and that BPS also has hydrogen bond with S203 of the catalytic triad. The surge at IC50 values of both compounds with an inflection point at pH: 8.2 suggested that Y124 and/or Y337 in the narrow gorge are primary structural factors in binding. Less effective inhibition of BPS, especially at 25-30 °C, the temperature at which enzyme activity peaks, was attributed to the conformation of the narrow gorge. Homology analyses for AChE initially revealed a significant degree of identity, particularly in the alpha/beta hydrolase domain, which also comprises the active site, with sequences from seven distinct teleost species of various environments. Finally, it was discovered for the first time that BPS, like BPA, is a significant inhibitor of AChE, and this was confirmed by in vitro and in silico analyses done at various pH and temperature levels. It was concluded that this effect might also apply to AChE of most other bony fish.


Assuntos
Acetilcolinesterase , Inibidores da Colinesterase , Acetilcolinesterase/metabolismo , Animais , Compostos Benzidrílicos , Inibidores da Colinesterase/química , Inibidores da Colinesterase/toxicidade , Electrophorus/metabolismo , Simulação de Acoplamento Molecular , Fenóis
18.
Environ Toxicol Pharmacol ; 94: 103934, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35868620

RESUMO

Aluminium (Al) is among the most abundant metals in nature, and its presence in the environment is further increasing by anthropogenic activities. In water bodies, the Al concentrations ranged between 0.001 and 50 mg/L, raising concerns about the health of aquatic organisms. For this reason, zebrafish was chosen as the model, since it is well suited for ecotoxicological studies. Adult specimens were exposed to 11 mg/L of Al for 10, 15 and 20 days to assess both the morphology and the oxidative state of muscle tissue. Considering the involvement of ROS, the activity of the main antioxidant enzymes, metallothioneins contents, but also oxidative damage and enzymes involved in energy consumption and neuromuscular transmission were assessed. Collected data showed an increase in the thickness of the endomysium and resorbed myofibrils in the organisms exposed to Al for 10 days, and an increase of myotomes' size in the organisms exposed to Al for 15 days. Moreover, the organisms exposed for less time to Al, it was evident an activation of anaerobic metabolism and the increased activity of antioxidant enzymes such as superoxide dismutase, glutathione peroxidase and glutathione S-transferases. However, these effects stabilized with increasing exposure time. In addition, only after 20 days of treatment did the oxidative damage to the proteins and the activity of acetylcholinesterase increase while the levels of metallothioneins and the lipid peroxidation were lower for all treated animals when compared to the control group. Overall, the biochemical and histological changes induced by aluminium exposure in the muscular tissue represent a relevant contribution to understanding the environmental risk due to the diffusion of this metal within the aquatic compartment.


Assuntos
Poluentes Químicos da Água , Peixe-Zebra , Acetilcolinesterase/metabolismo , Alumínio/toxicidade , Animais , Antioxidantes/farmacologia , Músculos/metabolismo , Estresse Oxidativo , Superóxido Dismutase/metabolismo , Poluentes Químicos da Água/metabolismo , Peixe-Zebra/metabolismo
19.
Bioorg Chem ; 127: 106007, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35849893

RESUMO

Alzheimer's disease (AD) is a chronic, progressive brain neurodegenerative disorder. Up to now, there is no effective drug to halt or reverse the progress of AD. Given the complex pathogenesis of AD, the multi-target-directed ligands (MTDLs) strategy is considered as the promising therapy. Herein, a series of novel donepezil-chalone-rivastigmine hybrids was rationally designed and synthesized by fusing donepezil, chalone and rivastigmine. The in vitro bioactivity results displayed that compound 10c was a reversible huAChE (IC50 = 0.87 µM) and huBuChE (IC50 = 3.3 µM) inhibitor. It also presented significant anti-inflammation effects by suppressing the level of IL-6 and TNF-α production, and significantly inhibited self-mediated Aß1-42 aggregation (60.6%) and huAChE-mediated induced Aß1-40 aggregation (46.2%). In addition, 10c showed significant neuroprotective effect on Aß1-42-induced PC12 cell injury and activated UPS pathway in HT22 cells to degrade tau and amyloid precursor protein (APP). Furthermore, compound 10c presented good stabilty in artificial gastrointestinal fluids and liver microsomes in vitro. The pharmacokinetic study showed that compound 10c was rapidly absorbed in rats and distributed in rat brain after intragastric administration. The PET-CT imaging demonstrated that [11C]10c could quickly enter the brain and washed out gradually in vivo. Further, compound 10c at a dose of 5 mg/kg improved scopolamine-induced memory impairment, deserving further investigations.


Assuntos
Doença de Alzheimer , Chalcona , Chalconas , Fármacos Neuroprotetores , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Chalcona/uso terapêutico , Chalconas/farmacologia , Calônios , Inibidores da Colinesterase , Donepezila/farmacologia , Donepezila/uso terapêutico , Desenho de Fármacos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Ratos , Rivastigmina/farmacologia , Relação Estrutura-Atividade
20.
Int J Mol Sci ; 23(15)2022 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-35897660

RESUMO

The quest to find new inhibitors of biologically relevant targets is considered an important strategy to introduce new drug candidates for the treatment of neurodegenerative diseases. A series of (aminomethyl)benzylphosphonates 8a-c and their metallocarbonyl iron 9a-c and ruthenium 10a-c complexes were designed, synthesized, and evaluated for their inhibitory potentials against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) by determination of IC50. Metallocarbonyl derivatives, in general, did not show significant inhibition activity against these enzymes, the most potent inhibitor was the (aminomethyl)benzylphosphonate 8a (IC50 = 1.215 µM against AChE). Molecular docking analysis of AChE and (aminomethyl)benzylphosphonates 8a-c showed the strongest interactions of 8a and AChE compared to isomers 8b and 8c. Cytotoxicity studies of synthesized compounds towards the V79 cell line were also performed and discussed.


Assuntos
Butirilcolinesterase , Complexos de Coordenação , Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Complexos de Coordenação/farmacologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
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