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1.
Food Chem ; 348: 129108, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-33540300

RESUMO

Monoamine oxidase A (MAO-A) is a major enzyme responsible for the deamination of neurotransmitters such as serotonin (5-HT) in the central nervous system. The decrease in 5-HT levels is accompanied by disorders at the affective and somatic levels, leading to depression and disorders of the satiety center. The aim of this study was to evaluate the degree of MAO-A inhibition by chlorogenic acids, as well as green, light-, and dark-roasted coffee extracts and bioactive compounds from beans of the species Coffea canephora and Coffea arabica. Data for analysis was obtained using isothermal titration calorimetry and molecular docking. The results showed that caffeine and ferulic acid, as well as green Robusta coffee, demonstrated the greatest inhibition of MAO-A activity, which may increase the bioavailability of serotonin. We believe that green coffee shows potential antidepressant activity by inhibiting MAO-A, and may be used for treating depression and potentially, type 2 diabetes.


Assuntos
Café/química , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Serotonina/metabolismo , Cafeína/análise , Ácido Clorogênico/análise , Diabetes Mellitus Tipo 2/metabolismo , Inibidores da Monoaminoxidase/química , Sementes/química
2.
Ageing Res Rev ; 66: 101256, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33434685

RESUMO

Population aging is one of the most significant social changes of the twenty-first century. This increase in longevity is associated with a higher prevalence of chronic diseases, further rising healthcare costs. At the molecular level, cellular senescence has been identified as a major process in age-associated diseases, as accumulation of senescent cells with aging leads to progressive organ dysfunction. Of particular importance, mitochondrial oxidative stress and consequent organelle alterations have been pointed out as key players in the aging process, by both inducing and maintaining cellular senescence. Monoamine oxidases (MAOs), a class of enzymes that catalyze the degradation of catecholamines and biogenic amines, have been increasingly recognized as major producers of mitochondrial ROS. Although well-known in the brain, evidence showing that MAOs are also expressed in a variety of peripheral organs stimulated a growing interest in the extra-cerebral roles of these enzymes. Besides, the fact that MAO-A and/or MAO-B are frequently upregulated in aged or dysfunctional organs has uncovered new perspectives on their roles in pathological aging. In this review, we will give an overview of the major results on the regulation and function of MAOs in aging and age-related diseases, paying a special attention to the mechanisms linked to the increased degradation of MAO substrates or related to MAO-dependent ROS formation.


Assuntos
Monoaminoxidase , Estresse Oxidativo , Senescência Celular , Mitocôndrias/metabolismo , Monoaminoxidase/metabolismo
4.
Life Sci ; 267: 118904, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33338501

RESUMO

AIMS: Renalase expression is regulated by Nuclear Factor (NF)-κB and hypoxia inducible factor (HIF)-1α, and antioxidative stress function in renal cells were reported. However, dynamics of renalase and localizes in intestine were remain unknown. We evaluated the effects of oxidative stress on renalase expression and localization using model of fasting induced oxidative stress and Caco-2 cell, and examined the its physiological effects. MAIN METHODS: 24 male mice were divided into three groups: Control (Con), 72 h fasting (Fast), and 24 h refeeding after fasting (Refeed). Jejunum and ileum were collected respectively. The structure of jejunum and ileum were observed by hematoxylin and eosin (HE) stain. The expression levels of carbonylated protein, renalase, NF-κB p65 and HIF-1α were measured by immunoblotting. Localization of renalase was observed by immunofluorescent. in vitro assay was performed using Caco-2 cell. Renalase was overexpressed using adenovirus. After that, Caco-2 cell was treated with 2 mM H2O2 for 30 min or 24 h. KEY FINDINGS: Renalase was increased in Fast and it was localized in crypt. HIF-1α did not increase, but NF-κB p65 increased in Fast. Renalase overexpression protects the Caco-2 cells against H2O2 induced oxidative stress. SIGNIFICANCE: Renalase was localized in crypt and increased in Fast. This increase suggested protect response to oxidative stress because undifferenced cells were localized in crypt and need to be protected. Actually, renalase protected Caco-2 cells against H2O2 induced oxidative stress. Small intestinal renalase expression was regulated by NF-κB p65 and was considered to be a defense mechanism against oxidative stress.


Assuntos
Intestino Delgado/efeitos dos fármacos , Monoaminoxidase/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Células CACO-2 , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Jejum , Humanos , Íleo/metabolismo , Intestino Delgado/metabolismo , Intestinos/fisiologia , Jejuno/metabolismo , Rim/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Monoaminoxidase/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais
5.
Clin Nucl Med ; 46(1): e31-e33, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32657879

RESUMO

Three patients with neurological disorders (cerebral infarction, progressive multifocal leukoencephalopathy, and multiple sclerosis) underwent F-THK5351 and C-L-deprenyl PET on the same day to visualize lesions undergoing astrogliosis by measuring MAO-B activity. BPND map and SUV image with F-THK5351 as well as Ki map, Ki/K1 map and SUV image with C-L-deprenyl were created. F-THK5351 BPND maps and SUV images clearly identified the lesions undergoing astrogliosis. C-L-deprenyl Ki/K1 maps were close to F-THK5351 images, but very noisy. Ki maps and SUV images were likely affected by the effect of blood flow. Hence, F-THK5351 is superior to C-L-deprenyl for visualizing lesions undergoing astrogliosis.


Assuntos
Aminopiridinas/metabolismo , Radioisótopos de Carbono , Gliose/diagnóstico por imagem , Monoaminoxidase/metabolismo , Doenças do Sistema Nervoso/complicações , Tomografia por Emissão de Pósitrons , Quinolinas/metabolismo , Selegilina/metabolismo , Feminino , Gliose/complicações , Gliose/metabolismo , Humanos , Ligantes , Masculino
6.
Clin Nucl Med ; 45(11): e491-e492, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32657863

RESUMO

A 67-year-old woman sustained a mild traumatic brain injury (TBI) in a traffic accident and had an initial Glasgow Coma Scale score of 13. She underwent F-THK5351 PET 18 days after TBI. Fused F-THK5351 PET/MRI showed that the location of F-THK5351 accumulations corresponded anatomically to intraparenchymal lesions of acute TBI on MRI. F-THK5351 reportedly binds to monoamine oxidase B highly expressed in astrocytes. Furthermore, TBI induces reactive astrogliosis or blood-brain barrier breakdown included in primary brain injury. Therefore, F-THK5351 uptake may represent primary brain injury in acute TBI lesions.


Assuntos
Aminopiridinas , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Quinolinas , Idoso , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Lesões Encefálicas Traumáticas/metabolismo , Feminino , Humanos , Imagem por Ressonância Magnética , Monoaminoxidase/metabolismo
7.
Fortschr Neurol Psychiatr ; 88(9): 620-633, 2020 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-32588409

RESUMO

Inhibitors of COMT and MAO-B are well established in the pharmacotherapy of Parkinson's disease (PD). MAO-B inhibitors are used as monotherapy as well as in combination with levodopa, whereas COMT inhibitors exert their effects only in conjungtion with levodopa. Both classes of compounds prolong the response duration of levodopa and optimise its clinical benefit. As a result, the ON-times are prolonged significantly. In the past, MAO-B inhibitors were also adminstered for neuroprotection; however, despite convincing scientific reasoning in support of neuroprotective effects, these could not be substantiated in clinical studies performed so far.


Assuntos
Antiparkinsonianos/uso terapêutico , Inibidores de Catecol O-Metiltransferase/uso terapêutico , Inibidores da Monoaminoxidase/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Catecol O-Metiltransferase/metabolismo , Humanos , Levodopa/uso terapêutico , Monoaminoxidase/metabolismo
8.
Food Funct ; 11(6): 5565-5572, 2020 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-32520031

RESUMO

To date, no specific drug has been discovered for the treatment of COVID-19 and hence, people are in a state of anxiety. Thus, there is an urgent need to search for various possible strategies including nutritional supplementation. In this study, we have tried to provide a reference for protein supplementation. Specifically, 20 marine fish proteins were subjected to in silico hydrolysis by gastrointestinal enzymes, and a large number of active peptides were generated. Then, the binding abilities of these peptides to SARS-CoV-2 main protease and monoamine oxidase A were assessed. The results showed that NADH dehydrogenase could be a good protein source in generating potent binders to the two enzymes, followed by cytochrome b. In addition, some high-affinity oligopeptides (VIQY, ICIY, PISQF, VISAW, AIPAW, and PVSQF) were identified as dual binders to the two enzymes. In summary, the supplementation of some fish proteins can be helpful for COVID-19 patients; the identified oligopeptides can be used as the lead compounds to design potential inhibitors against COVID-19 and anxiety.


Assuntos
Antivirais/metabolismo , Betacoronavirus/metabolismo , Infecções por Coronavirus/virologia , Suplementos Nutricionais , Proteínas de Peixes/metabolismo , Monoaminoxidase/metabolismo , Pneumonia Viral/virologia , Animais , Antivirais/química , Antivirais/uso terapêutico , Organismos Aquáticos , Betacoronavirus/enzimologia , Infecções por Coronavirus/tratamento farmacológico , Decapodiformes/metabolismo , Proteínas de Peixes/química , Proteínas de Peixes/uso terapêutico , Peixes/metabolismo , Modelos Moleculares , Simulação de Acoplamento Molecular , Inibidores da Monoaminoxidase , Pandemias , Perciformes/metabolismo , Pneumonia Viral/tratamento farmacológico , Ligação Proteica , Conformação Proteica , Salmão/metabolismo , Atum/metabolismo
9.
Nat Commun ; 11(1): 2689, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32483206

RESUMO

The antiandrogen enzalutamide (Enz) has improved survival in castration resistant prostate cancer (CRPC) patients. However, most patients eventually develop Enz resistance that may involve inducing the androgen receptor (AR) splicing variant 7 (ARv7). Here we report that high expression of monoamine oxidase-A (MAO-A) is associated with positive ARv7 detection in CRPC patients following Enz treatment. Targeting MAO-A with phenelzine or clorgyline, the FDA-approved drugs for antidepression, resensitize the Enz resistant (EnzR) cells to Enz treatment and further suppress EnzR cell growth in vitro and in vivo. Our findings suggest that Enz-increased ARv7 expression can transcriptionally enhance MAO-A expression resulting in Enz resistance via altering the hypoxia HIF-1α signals. Together, our results show that targeting the Enz/ARv7/MAO-A signaling with the antidepressants phenelzine or clorgyline can restore Enz sensitivity to suppress EnzR cell growth, which may indicate that these antidepression drugs can overcome the Enz resistance to further suppress the EnzR CRPC.


Assuntos
Clorgilina/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Fenelzina/farmacologia , Feniltioidantoína/análogos & derivados , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Processamento Alternativo , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Estabilidade Enzimática , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Nus , Camundongos SCID , Monoaminoxidase/química , Monoaminoxidase/genética , Monoaminoxidase/metabolismo , Células Neoplásicas Circulantes/metabolismo , Feniltioidantoína/farmacologia , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Sci Rep ; 10(1): 6115, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32273550

RESUMO

Nasopharyngeal carcinoma (NPC) is a highly metastatic cancer that is consistently associated with Epstein-Barr virus (EBV) infection. In this study, we identify for the first time a role for monoamine oxidase A (MAOA) in NPC. MAOA is a mitochondrial enzyme that catalyzes oxidative deamination of neurotransmitters and dietary amines. Depending on the cancer type, MAOA can either have a tumour-promoting or tumour-suppressive role. We show that MAOA is down-regulated in primary NPC tissues and its down-regulation enhances the migration of NPC cells. In addition, we found that EBV infection can down-regulate MAOA expression in both pre-malignant and malignant nasopharyngeal epithelial (NPE) cells. We further demonstrate that MAOA is down-regulated as a result of IL-6/IL-6R/STAT3 signalling and epigenetic mechanisms, effects that might be attributed to EBV infection in NPE cells. Taken together, our data point to a central role for EBV in mediating the tumour suppressive effects of MAOA and that loss of MAOA could be an important step in the pathogenesis of NPC.


Assuntos
Monoaminoxidase/genética , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo , Epigênese Genética , Células Epiteliais/metabolismo , Herpesvirus Humano 4/patogenicidade , Humanos , Interleucina-6/metabolismo , Monoaminoxidase/metabolismo , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais
11.
J Enzyme Inhib Med Chem ; 35(1): 805-814, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32183602

RESUMO

Multi-target drugs can better address the cascade of events involved in oxidative stress and the reduction in cholinergic transmission that occur in Alzheimer's disease than cholinesterase inhibitors alone. We synthesised a series of 3-arylbenzofuranone derivatives and evaluated their antioxidant activity, cholinesterase inhibitory activity, and monoamine oxidase inhibitory activity. 3-Arylbenzofuranone compounds exhibit good antioxidant activity as well as selective acetylcholinesterase inhibitory activity. The IC50 value of anti-acetylcholinesterase inhibition of Compound 20 (0.089 ± 0.01 µM) is similar to the positive drug donepezil (0.059 ± 0.003 µM). According to the experimental results, Compounds 7, 13 show a certain effect in the in vitro evaluation performed and have the potential as drug candidates for the treatment of Alzheimer's disease.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Ansiolíticos/farmacologia , Antioxidantes/farmacologia , Benzofuranos/farmacologia , Inibidores da Colinesterase/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Animais , Ansiolíticos/síntese química , Ansiolíticos/química , Antioxidantes/síntese química , Antioxidantes/química , Benzofuranos/síntese química , Benzofuranos/química , Compostos de Bifenilo/antagonistas & inibidores , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Picratos/antagonistas & inibidores , Ratos , Ratos Wistar , Relação Estrutura-Atividade
12.
Phys Chem Chem Phys ; 22(13): 6838-6847, 2020 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-32191250

RESUMO

The kinetic isotope effect (KIE) is arguably the most established experimental observable reflecting nuclear quantum effects in enzymatic reactions. The role of nuclear quantum effects in enzymes is rather intriguing and has long been a source of profound investigations. Herein, we present a computational study of monoamine oxidase A (MAO A) enzyme and its substrate phenylethylamine, focusing on the impact of nuclear quantum effects on the reaction free energy barrier. Two distinct schemes of quantization of nuclear motion were used, one being the established Quantum Classical Path (QCP) approach, and the other our own code for quantum treatment along the selected nuclear coordinate (hydrogen transfer coordinate) which reasonably mimics the reaction coordinate. In excellent agreement with the experimental value of 8.5 ± 0.3, H/D KIE was computed to 8.66, corresponding to the D-H barrier difference of 1.28 kcal mol-1. The magnitude of KIE implies that nuclear quantum effects probably have only a minor role in the reaction, which is in accordance with the features of potentials computed along the reaction coordinate and with the pertinent energy levels and wavefunctions. The computed H/D KIE for the same reaction in aqueous solution and in the gas phase was fairly similar to the one in the enzyme, suggesting that the role of tunneling in the catalytic function of MAO A is insignificant. The agreement between the computed and observed KIE supported by analysis of nuclear quantum effects implicitly validates the assumed hydride transfer reaction mechanism.


Assuntos
Simulação por Computador , Monoaminoxidase/metabolismo , Fenetilaminas/metabolismo , Catálise , Isótopos/química , Cinética , Teoria Quântica
13.
J Mol Biol ; 432(10): 3269-3288, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32198115

RESUMO

The flavin-dependent amine oxidase (FAO) superfamily consists of over 9000 nonredundant sequences represented in all domains of life. Of the thousands of members identified, only 214 have been functionally annotated to date, and 40 unique structures are represented in the Protein Data Bank. The few functionally characterized members share a catalytic mechanism involving the oxidation of an amine substrate through transfer of a hydride to the FAD cofactor, with differences observed in substrate specificities. Previous studies have focused on comparing a subset of superfamily members. Here, we present a comprehensive analysis of the FAO superfamily based on reaction mechanism and substrate recognition. Using a dataset of 9192 sequences, a sequence similarity network, and subsequently, a genome neighborhood network were constructed, organizing the superfamily into eight subgroups that accord with substrate type. Likewise, through phylogenetic analysis, the evolutionary relationship of subgroups was determined, delineating the divergence between enzymes based on organism, substrate, and mechanism. In addition, using sequences and atomic coordinates of 22 structures from the Protein Data Bank to perform sequence and structural alignments, active-site elements were identified, showing divergence from the canonical aromatic-cage residues to accommodate large substrates. These specificity determinants are held in a structural framework comprising a core domain catalyzing the oxidation of amines with an auxiliary domain for substrate recognition. Overall, analysis of the FAO superfamily reveals a modular fold with cofactor and substrate-binding domains allowing for diversity of recognition via insertion/deletions. This flexibility allows facile evolution of new activities, as shown by reinvention of function between subfamilies.


Assuntos
Dinitrocresóis/metabolismo , Monoaminoxidase/química , Monoaminoxidase/metabolismo , Sequência de Aminoácidos , Domínio Catalítico , Dinitrocresóis/química , Evolução Molecular , Modelos Moleculares , Monoaminoxidase/genética , Família Multigênica , Filogenia , Conformação Proteica , Alinhamento de Sequência , Especificidade por Substrato
14.
J Agric Food Chem ; 68(8): 2426-2436, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32011134

RESUMO

Progressive degeneration of dopaminergic neurons in the substantia nigra is the characteristic feature of Parkinson's disease (PD) and the severity accelerates with aging. Therefore, improving dopamine level or dopamine receptor signaling is a standard approach for PD treatment. Herein, our results demonstrate that bromophenols 2,3,6-tribromo-4,5-dihydroxybenzyl alcohol (1), 2,3,6-tribromo-4,5-dihydroxybenzyl methyl ether (2), and bis-(2,3,6-tribromo-4,5-dihydroxybenzyl) ether (3) from red alga Symphyocladia latiuscula are moderate-selective human monoamine oxidase-A inhibitors and good dopamine D3/D4 receptor agonists. Bromophenol 3 showed a promising D4R agonist effect with a low micromole 50% effective concentration (EC50) value. All of the test ligands were docked against a three-dimensional (3D) model of hD3R and hD4R, and the result demonstrated strong binding through interaction with prime interacting residues-Asp110, Cys114, and His349 on hD3R and Asp115 and Cys119 on hD4R. Overall, the results demonstrated natural bromophenols, especially 1 and 3, from Symphyocladia latiuscula as multitarget ligands for neuroprotection, especially in PD and schizophrenia.


Assuntos
Inibidores da Monoaminoxidase/química , Monoaminoxidase/química , Doenças Neurodegenerativas/enzimologia , Fenóis/química , Extratos Vegetais/química , Receptores Dopaminérgicos/sangue , Rodófitas/química , Humanos , Estrutura Molecular , Monoaminoxidase/metabolismo , Doenças Neurodegenerativas/metabolismo , Receptores Dopaminérgicos/química , Receptores Dopaminérgicos/metabolismo
15.
Int J Mol Sci ; 21(1)2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31948051

RESUMO

Posttraumatic stress disorder (PTSD) causes mental and somatic diseases. Intermittent hypoxic conditioning (IHC) has cardio-, vaso-, and neuroprotective effects and alleviates experimental PTSD. IHC's ability to alleviate harmful PTSD effects on rat heart, liver, and brain was examined. PTSD was induced by 10-day exposure to cat urine scent (PTSD rats). Some rats were then adapted to 14-day IHC (PTSD+IHC rats), while PTSD and untreated control rats were cage rested. PTSD rats had a higher anxiety index (AI, X-maze test), than control or PTSD+IHC rats. This higher AI was associated with reduced glycogen content and histological signs of metabolic and hypoxic damage and of impaired contractility. The livers of PTSD rats had reduced glycogen content. Liver and blood alanine and aspartate aminotransferase activities of PTSD rats were significantly increased. PTSD rats had increased norepinephrine concentration and decreased monoamine oxidase A activity in cerebral cortex. The PTSD-induced elevation of carbonylated proteins and lipid peroxidation products in these organs reflects oxidative stress, a known cause of organ pathology. IHC alleviated PTSD-induced metabolic and structural injury and reduced oxidative stress. Therefore, IHC is a promising preventive treatment for PTSD-related morphological and functional damage to organs, due, in part, to IHC's reduction of oxidative stress.


Assuntos
Estresse Oxidativo , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Transtornos de Estresse Pós-Traumáticos/terapia , Alanina Transaminase/metabolismo , Animais , Ansiedade/induzido quimicamente , Ansiedade/fisiopatologia , Aspartato Aminotransferases/metabolismo , Escala de Avaliação Comportamental , Encéfalo/metabolismo , Gatos , Córtex Cerebral/enzimologia , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , Glicogênio/metabolismo , Hipóxia , Fígado/enzimologia , Fígado/metabolismo , Masculino , Aprendizagem em Labirinto , Monoaminoxidase/metabolismo , Miocárdio/citologia , Miocárdio/metabolismo , Miocárdio/patologia , Norepinefrina/metabolismo , Odorantes , Ratos , Ratos Wistar , Transtornos de Estresse Pós-Traumáticos/enzimologia , Transtornos de Estresse Pós-Traumáticos/metabolismo , Urina/química
16.
Artigo em Inglês | MEDLINE | ID: mdl-31911191

RESUMO

Environmental endocrine disruptors 4-nonylphenol (NP) and 4-tert-octylphenol (OP) may cast huge harm to human health. We used a rat model to observe the influence of NP or/and OP exposure on anxiety-related behaviors and the underlying mechanisms. Eighty male Sprague-Dawley (SD) rats were randomly divided into 10 groups: control group (corn oil), NP groups [30, 90, 270 mg/kg], OP groups [40, 120, 360 mg/kg] and NO groups [(mixed with the corresponding NP, OP alone exposed low, medium and high dose according to the natural environment exists NP:OP = 4:1]. The rats were orally administered every other day for 30 days. The neurobehaviors of rats were evaluated by open-field test (OFT) and elevated plus-maze test (EPM), and the concentrations of 5-HT, monoamine oxidase (MAOA), serotonin transporter (SERT), vesicular monoamine transporter 2 (VAMT2), 5-hydroxytryptamine 1A (5-HT1A), 5-hydroxytryptamine 2A (5-HT2A),and 5-hydroxytryptamine 2C (5-HT2C) in the rat prefrontal cortex were analyzed by ELISA. OFT and EPM tests showed that NP or/and OP exposure induced anxiety-related behaviors in rats. 5-HT levels were significantly increased compared with the control group. The levels of MAOA, SERT, VAMT2, 5-HT1A, 5-HT2A, and 5-HT2C in the prefrontal cortex reduced in different degrees by high-doses NP or/and OP exposure. In summary, NP or/and OP exposure might cause anxiety-related behaviors in rats through regulating neurotransmitter 5-HT levels by altering the expression of 5-HT decomposition enzyme MAOA, transporters SERT and VMAT2, and 5-HT receptors 5-HT1A, 5-HT2A, and 5-HT2C.


Assuntos
Fenóis/toxicidade , Córtex Pré-Frontal/metabolismo , Receptores de Serotonina/metabolismo , Serotonina/metabolismo , Animais , Ansiedade , Comportamento Animal , Masculino , Aprendizagem em Labirinto , Monoaminoxidase/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo
17.
Clin Sci (Lond) ; 134(1): 75-85, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31899483

RESUMO

Renalase, a recently discovered secreted flavoprotein, exerts anti-apoptotic and anti-inflammatory effects against renal injury in acute and chronic animal models. However, whether Renalase elicits similar effects in the development of diabetic nephropathy (DN) remains unclear. The studies presented here tested the hypothesis that Renalase may play a key role in the development of DN and may have therapeutic potential for DN. Renalase expression was measured in human kidney biopsies with DN and in kidneys of db/db mice. The role of Renalase in the development of DN was examined using a genetically engineered mouse model: Renalase knockout mice with db/db background. The renoprotective effects of Renalase in DN was evaluated in db/db mice with Renalase overexpression. In addition, the effects of Renalase on high glucose-induced mesangial cells were investigated. Renalase was down-regulated in human diabetic kidneys and in kidneys of db/db mice compared with healthy controls or db/m mice. Renalase homozygous knockout increased arterial blood pressure significantly in db/db mice while heterozygous knockout did not. Renalase heterozygous knockout resulted in elevated albuminuria and increased renal mesangial expansion in db/db mice. Mesangial hypertrophy, renal inflammation, and pathological injury in diabetic Renalase heterozygous knockout mice were significantly exacerbated compared with wild-type littermates. Moreover, Renalase overexpression significantly ameliorated renal injury in db/db mice. Mechanistically, Renalase attenuated high glucose-induced profibrotic gene expression and p21 expression through inhibiting extracellular regulated protein kinases (ERK1/2). The present study suggested that Renalase protected against the progression of DN and might be a novel therapeutic target for the treatment of DN.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Rim/metabolismo , Monoaminoxidase/metabolismo , Albuminúria/metabolismo , Animais , Modelos Animais de Doenças , Humanos , Células Mesangiais/metabolismo , Células Mesangiais/patologia , Camundongos Knockout
18.
ACS Appl Mater Interfaces ; 12(4): 4323-4332, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31899611

RESUMO

Patients with cancer have reduced immune function and are susceptible to bacterial infection after surgery, chemotherapy, or radiotherapy. Spherical nanoparticles formed by the self-assembled peptide V6K3 can be used as carriers for poorly soluble antitumor drugs to effectively deliver drugs into tumor cells. V6K3 was designed to achieve nanoparticle-to-nanofiber geometric transformation under induction by plasma amine oxidase (PAO). PAO is commercially available and functionally similar to lysyl oxidase (LO), which is widely present in serum. After the addition of fetal bovine serum (FBS) or PAO, the secondary structure of the peptide changed, while the spherical nanoparticles stretched and transformed into nanofibers. The conversion of the self-assembled morphology reveals the susceptibility of this amphiphilic peptide to subtle chemical modifications and may lead to promising strategies to control self-assembled architecture via enzyme induction. Enzymatically self-assembled V6K3 had bactericidal properties after PAO addition that were surprisingly superior to those before PAO addition, enabling this peptide to be used to prevent infection. The amphiphilic peptide V6K3 displayed antitumor properties and low toxicity in mammalian cells, demonstrating good biocompatibility, as well as bactericidal properties, to prevent bacterial contamination. These advantages indicate that enzymatically self-assembled V6K3 has great biomedical application potential in cancer therapy.


Assuntos
Antibacterianos , Antineoplásicos , Portadores de Fármacos , Monoaminoxidase/metabolismo , Nanofibras , Nanopartículas , Peptídeos , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Células HeLa , Humanos , Camundongos , Células NIH 3T3 , Nanofibras/química , Nanofibras/uso terapêutico , Nanopartículas/química , Nanopartículas/uso terapêutico , Peptídeos/química , Peptídeos/farmacologia
19.
Neurochem Res ; 45(2): 465-490, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31894463

RESUMO

Protein misfolding and aggregation of amyloid beta (Aß) peptide, as well as formation of neurofibrillary tangles (NFTs) are the signature hallmarks of Alzheimer's disease (AD) pathology. To prevent this, molecular chaperones come into play as they facilitate the refolding of the misfolded proteins and cell protection under stress. Here, we have evaluated the possible effects of Ginkgo biloba (GBE) against aggregation of the Aß through activation of heat shock proteins (HSPs) in the Aluminium (Al) induced AD based model. GBE (100 mg/kg body weight) was administered per oral to the female SD rats in conjunction with intraperitoneal (i.p.) injection of Al lactate (10 mg/kg body weight) for six weeks. Pretreated animals were administered GBE for additional two weeks prior to any exposure of Al. GBE administration resulted in decrease in Aß aggregation, ubiquitin deposition, accompanying a significant decline in APP & Tau protein hyperphosphorylation which can be attributed to activation of Heat shock factor (HSF-1) and upregulation in the protein expression of HSPs. Histopathological investigation studies have also shown the decrease in aggregation of Aß peptide by GBE administration. Additionally, the decrease in ROS levels and Aß aggregation by GBE administration prohibited the decline in the neurotransmitter levels and monoamine oxidase levels in hippocampus and cortex. This further caused improvement in learning and memory of the animals. In conclusion, our results indicate that GBE prevents the symptoms of Al induced AD like pathophysiology by upregulating the HSPs levels and decreasing the aggregation load.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Proteínas de Choque Térmico/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Síndromes Neurotóxicas/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Multimerização Proteica/efeitos dos fármacos , Acetilcolinesterase/metabolismo , Alumínio/toxicidade , Animais , Giro Denteado/patologia , Epinefrina/metabolismo , Feminino , Ginkgo biloba/química , Aprendizagem em Labirinto/efeitos dos fármacos , Monoaminoxidase/metabolismo , Síndromes Neurotóxicas/patologia , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Serotonina/metabolismo , Proteínas tau/metabolismo
20.
J Med Chem ; 63(3): 1361-1387, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-31917923

RESUMO

The resurgence of interest in monoamine oxidases (MAOs) has been fueled by recent correlations of this enzymatic activity with cardiovascular, neurological, and oncological disorders. This has promoted increased research into selective MAO-A and MAO-B inhibitors. Here, we shed light on how selective inhibition of MAO-A and MAO-B can be achieved by geometric isomers of cis- and trans-1-propargyl-4-styrylpiperidines. While the cis isomers are potent human MAO-A inhibitors, the trans analogues selectively target only the MAO-B isoform. The inhibition was studied by kinetic analysis, UV-vis spectrum measurements, and X-ray crystallography. The selective inhibition of the MAO-A and MAO-B isoforms was confirmed ex vivo in mouse brain homogenates, and additional in vivo studies in mice show the therapeutic potential of 1-propargyl-4-styrylpiperidines for central nervous system disorders. This study represents a unique case of stereoselective activity of cis/trans isomers that can discriminate between structurally related enzyme isoforms.


Assuntos
Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Inibidores da Monoaminoxidase/uso terapêutico , Piperidinas/uso terapêutico , Estirenos/uso terapêutico , Animais , Antidepressivos/síntese química , Antidepressivos/metabolismo , Encéfalo , Domínio Catalítico , Humanos , Isoenzimas/antagonistas & inibidores , Cinética , Masculino , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Monoaminoxidase/química , Monoaminoxidase/classificação , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/metabolismo , Piperidinas/síntese química , Piperidinas/metabolismo , Ligação Proteica , Estereoisomerismo , Relação Estrutura-Atividade , Estirenos/síntese química , Estirenos/metabolismo
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