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1.
Adv Exp Med Biol ; 1131: 131-161, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646509

RESUMO

Calcium (Ca2+) is a fundamental regulator of cell fate and intracellular Ca2+ homeostasis is crucial for proper function of the nerve cells. Given the complexity of neurons, a constellation of mechanisms finely tunes the intracellular Ca2+ signaling. We are focusing on the sarco/endoplasmic reticulum (SR/ER) calcium (Ca2+)-ATPase (SERCA) pump, an integral ER protein. SERCA's well established role is to preserve low cytosolic Ca2+ levels ([Ca2+]cyt), by pumping free Ca2+ ions into the ER lumen, utilizing ATP hydrolysis. The SERCA pumps are encoded by three distinct genes, SERCA1-3, resulting in 12 known protein isoforms, with tissue-dependent expression patterns. Despite the well-established structure and function of the SERCA pumps, their role in the central nervous system is not clear yet. Interestingly, SERCA-mediated Ca2+ dyshomeostasis has been associated with neuropathological conditions, such as bipolar disorder, schizophrenia, Parkinson's disease and Alzheimer's disease. We summarize here current evidence suggesting a role for SERCA in the neurobiology of neuropsychiatric and neurodegenerative disorders, thus highlighting the importance of this pump in brain physiology and pathophysiology.


Assuntos
Encéfalo , Retículo Endoplasmático , Doenças do Sistema Nervoso , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático , Encéfalo/enzimologia , Encéfalo/patologia , Retículo Endoplasmático/enzimologia , Regulação Enzimológica da Expressão Gênica , Homeostase , Humanos , Doenças do Sistema Nervoso/enzimologia , Doenças do Sistema Nervoso/fisiopatologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo
2.
Neuron ; 103(3): 380-394, 2019 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-31394063

RESUMO

The Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) was touted as a memory molecule, even before its involvement in long-term potentiation (LTP) was shown. The enzyme has not disappointed, with subsequent demonstrations of remarkable structural and regulatory properties. Its neuronal functions now extend to long-term depression (LTD), and last year saw the first direct evidence for memory storage by CaMKII. Although CaMKII may have taken the spotlight, it is a member of a large family of diverse and interesting CaM kinases. Our aim is to place CaMKII in context of the other CaM kinases and then review certain aspects of this kinase that are of current interest.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/fisiologia , Sequência de Aminoácidos , Animais , Encéfalo/enzimologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/química , Cognição/fisiologia , Humanos , Potenciação de Longa Duração/fisiologia , Memória/fisiologia , Modelos Moleculares , Família Multigênica , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/fisiologia , Fosforilação , Conformação Proteica , Domínios Proteicos , Mapeamento de Interação de Proteínas , Processamento de Proteína Pós-Traducional , Proteínas Serina-Treonina Quinases/classificação , Proteínas Serina-Treonina Quinases/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Transmissão Sináptica
3.
Ecotoxicol Environ Saf ; 182: 109407, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31279280

RESUMO

Aflatoxin B1 poses the greatest risk among the mycotoxins to target-organisms particularly human, however, no studies addressed the neurotoxicity of chronic exposure of aflatoxin. The oral dose level 1/600th of LD50 for 30, 60, and 90 days was used for three aflatoxin groups, respective to negative and vehicle control groups. Activity levels of brain antioxidants viz: superoxide dismutase, catalase, glutathione, and glutathione peroxidase significantly decreased in the three experimental durations in time-dependent trend, in contrast, lipid peroxidation showed a significant increase compared to controls. Significantly, chronic-dependent increase trend was noticed in the AF60 and AF90 group for acid phosphatase (16.1%, 35.2%), alkaline phosphatase (32.1%, 50.8%), aspartate aminotransferase (38.7%, 120.0%) and lactate dehydrogenase (30.6%, 42.1%) activities, respectively. However, a significant 23.7% decrease in the brain creatine kinase activity following 90 days of AFB1administration. Chronic administration of aflatoxin also causes alterations in activities of protein carbonyl with a maximum increase (twofold) after 90 days. Further, histopathological and immunohistochemical results confirmed time-related vasodilation, necrosis and astrocytes gliosis by high glial fibrillary acidic protein immunostaining in response to AFB1. These findings infer that long-term exposure to AFB1 results in several pathophysiological circumstances in a duration-dependent manner concerning neurodegeneration especially Alzheimer's disease.


Assuntos
Aflatoxina B1/toxicidade , Astrócitos/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Poluentes Ambientais/toxicidade , Estresse Oxidativo , Animais , Antioxidantes/metabolismo , Astrócitos/imunologia , Astrócitos/patologia , Encéfalo/patologia , Relação Dose-Resposta a Droga , Proteína Glial Fibrilar Ácida/biossíntese , Imuno-Histoquímica , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/imunologia , Ratos , Ratos Wistar , Fatores de Tempo , Testes de Toxicidade Crônica
4.
Zoolog Sci ; 36(3): 223-230, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31251491

RESUMO

Serotonin (i.e., 5-hydroxytryptamine [5-HT]) plays a key role in stress responses in vertebrates. In mammals and teleosts, tryptophan hydroxylase (Tph), a rate-limiting enzyme in the biosynthesis of 5-HT, includes two paralogs: Tph 1 and Tph 2. The response of the Tphs to stress has been reported in mammals, but less is known about the responses of these enzymes to stress in fish. In the present study, we examined whether heat stress affects the mRNA expression of these Tphs in the brain of medaka fish (Oryzias latipes). We also determined the concentration of 5-HT in the brain, the mRNA expression of heat shock protein 90 alpha (Hsp90α) in the liver, plasma cortisol concentration, and blood glucose concentration in medaka. Whole-body exposure to repeated heat stress significantly decreased the mRNA expression of Tph1 and Tph2 in male and female medaka, whereas single heat stress did not affect the expression of either of the mRNAs. The 5-HT concentration also decreased significantly after repeated heat stress sessions in both sexes, but did not decrease after a single heat stress session. After single and repeated heat stress sessions, Hsp90α mRNA expression increased in both sexes; however, increments in the concentrations of plasma cortisol and blood glucose occurred in male, but not in female, medaka. These results suggest that both types of Tphs are involved in reducing 5-HT in the brain and are reliable indicators of chronic stress response in both sexes. However, stress responses in plasma cortisol and blood glucose concentrations differ between male and female medaka.


Assuntos
Encéfalo/enzimologia , Resposta ao Choque Térmico , Oryzias/metabolismo , Triptofano Hidroxilase/metabolismo , Animais , Feminino , Regulação Enzimológica da Expressão Gênica , Masculino , Reação em Cadeia da Polimerase em Tempo Real , Triptofano Hidroxilase/genética
5.
Life Sci ; 231: 116559, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31200001

RESUMO

AIM: Previously, we reported that mice deficient in most of the Zfp521 coding region (Zfp521Δ/Δ mice) displayed abnormal behaviors, including hyperlocomotion and lower anxiety. In this study, we aimed to elucidate the involvement and mechanisms of monoamine variation. MAIN METHODS: First, we compared the levels of dopamine (DA), noradrenaline (NA), and serotonin in the brains of Zfp521Δ/Δ and Zfp521+/+ mice using enzyme-linked immunosorbent assay. Next, we elucidated the mechanisms using quantitative PCR and Western Blotting. Additionally, we administered inhibitory drug to the mice and performed behavioral tests. KEY FINDINGS: Our results showed that the DA level decreased and the NA level increased in Zfp521Δ/Δ mice. We found that ZFP521 suppresses the expression of dopamine ß-hydroxylase (DBH), which converts DA into NA. We also demonstrated that paired homeodomain transcription factor 2 and early growth response protein-1, which are the transcription factors for Dbh, were involved in the upregulation of Dbh by ZFP521. The administration of nepicastat, a specific inhibitor of DBH, attenuated the abnormal behaviors of Zfp521Δ/Δ mice. SIGNIFICANCE: These results suggest that the lack of ZFP521 upregulates the expression of DBH, which leads to a decrease in the DA level and an increase in the NA level in the brain, resulting in abnormal behaviors.


Assuntos
Comportamento Animal/fisiologia , Encéfalo/metabolismo , Dopamina beta-Hidroxilase/metabolismo , Fatores de Transcrição/deficiência , Animais , Encéfalo/enzimologia , Linhagem Celular Tumoral , Dopamina/metabolismo , Imidazóis/farmacologia , Locomoção/efeitos dos fármacos , Locus Cerúleo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Norepinefrina/metabolismo , Serotonina/metabolismo , Tionas/farmacologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ativação Transcricional/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Dedos de Zinco
6.
J Biochem ; 166(2): 187-196, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30938755

RESUMO

D-amino acid oxidase (DAO) is a flavoenzyme, catalysing oxidative deamination of D-amino acids to produce corresponding α-keto acids, ammonia and hydrogen peroxide. In our search for DAO activity among various tissues, we developed a sensitive assay based on hydrogen peroxide production involving enzyme-coupled colorimetric assay with peroxidase. We first optimized buffer components to extract DAO protein from mouse tissues. Here we show that DAO activity was detected in kidney, cerebellum, medulla oblongata, midbrain and spinal cord, but not in liver. In addition, we observed that DAO activity and expression were decreased in thoracic and lumbar regions of spinal cord in aged mice when compared with young mice, indicating that decreased DAO is involved in motoneuron degeneration during senescence. We also found gender difference in DAO activity in the kidney, suggesting that DAO activity is influenced by sexual dimorphism. We newly detected DAO activity in the epididymis, although undetected in testis. Furthermore, DAO activity was significantly higher in the caput region than corpus and cauda regions of epididymis, indicating that D-amino acids present in the testis are eliminated in epididymis. Taken together, age- and gender-dependent DAO activity in each organ may underlie the human pathophysiology regulated by D-amino acid metabolism.


Assuntos
Envelhecimento/metabolismo , Encéfalo/enzimologia , D-Aminoácido Oxidase/metabolismo , Doenças Neurodegenerativas/enzimologia , Caracteres Sexuais , Aminoácidos/metabolismo , Animais , Feminino , Rim/enzimologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios Motores/enzimologia , Especificidade de Órgãos , Medula Espinal/enzimologia , Testículo/enzimologia
7.
Int J Mol Sci ; 20(8)2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-31022913

RESUMO

Mucopolysaccharidosis type II (MPSII) is a lysosomal storage disorder due to the deficit of the enzyme iduronate 2-sulfatase (IDS), which leads to the accumulation of glycosaminoglycans in most organ-systems, including the brain, and resulting in neurological involvement in about two-thirds of the patients. The main treatment is represented by a weekly infusion of the functional enzyme, which cannot cross the blood-brain barrier and reach the central nervous system. In this study, a tailored nanomedicine approach based on brain-targeted polymeric nanoparticles (g7-NPs), loaded with the therapeutic enzyme, was exploited. Fibroblasts from MPSII patients were treated for 7 days with NPs loaded with the IDS enzyme; an induced IDS activity like the one detected in healthy cells was measured, together with a reduction of GAG content to non-pathological levels. An in vivo short-term study in MPSII mice was performed by weekly administration of g7-NPs-IDS. Biochemical, histological, and immunohistochemical evaluations of liver and brain were performed. The 6-weeks treatment produced a significant reduction of GAG deposits in liver and brain tissues, as well as a reduction of some neurological and inflammatory markers (i.e., LAMP2, CD68, GFAP), highlighting a general improvement of the brain pathology. The g7-NPs-IDS approach allowed a brain-targeted enzyme replacement therapy. Based on these positive results, the future aim will be to optimize NP formulation further to gain a higher efficacy of the proposed approach.


Assuntos
Encéfalo/efeitos dos fármacos , Portadores de Fármacos/metabolismo , Sistemas de Liberação de Medicamentos , Iduronato Sulfatase/administração & dosagem , Mucopolissacaridose II/tratamento farmacológico , Nanopartículas/metabolismo , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/metabolismo , Animais , Encéfalo/enzimologia , Encéfalo/metabolismo , Encéfalo/patologia , Portadores de Fármacos/química , Terapia de Reposição de Enzimas , Glicopeptídeos/química , Glicopeptídeos/metabolismo , Humanos , Iduronato Sulfatase/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mucopolissacaridose II/enzimologia , Mucopolissacaridose II/metabolismo , Mucopolissacaridose II/patologia , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química
8.
Artigo em Inglês | MEDLINE | ID: mdl-31010095

RESUMO

In this study, several lines of evidence are provided to show that Na + , K + -ATPase activity exerts vital roles in normal brain development and function and that loss of enzyme activity is implicated in neurodevelopmental, neuropsychiatric and neurodegenerative disorders, as well as increased risk of cancer, metabolic, pulmonary and cardiovascular disease. Evidence is presented to show that fluoride (F) inhibits Na + , K + -ATPase activity by altering biological pathways through modifying the expression of genes and the activity of glycolytic enzymes, metalloenzymes, hormones, proteins, neuropeptides and cytokines, as well as biological interface interactions that rely on the bioavailability of chemical elements magnesium and manganese to modulate ATP and Na + , K + -ATPase enzyme activity. Taken together, the findings of this study provide unprecedented insights into the molecular mechanisms and biological pathways by which F inhibits Na + , K + -ATPase activity and contributes to the etiology and pathophysiology of diseases associated with impairment of this essential enzyme. Moreover, the findings of this study further suggest that there are windows of susceptibility over the life course where chronic F exposure in pregnancy and early infancy may impair Na + , K + -ATPase activity with both short- and long-term implications for disease and inequalities in health. These findings would warrant considerable attention and potential intervention, not to mention additional research on the potential effects of F intake in contributing to chronic disease.


Assuntos
Fluoretos/farmacologia , Saúde Pública , ATPase Trocadora de Sódio-Potássio/metabolismo , Animais , Encéfalo/enzimologia , Encéfalo/crescimento & desenvolvimento , Exposição Ambiental , Fluoretos/metabolismo , Humanos , Minerais/metabolismo
9.
Chemosphere ; 226: 817-824, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30965253

RESUMO

Reptiles, the most diverse taxon of terrestrial vertebrates, might be particularly vulnerable to soil pollution. Reptiles especially lizards have been rarely evaluated in ecotoxicological studies, and there is a very limited report for effects of soil pesticide contaminants on lizards. In this study, male and female lizards (Eremias argus) were exposed to Glufosinate-ammonium (GLA) and l- Glufosinate-ammonium (L-GLA) for 60 days. Slower sprint speed, higher frequency of turning back and reduced brain index were observed in treatment groups. The accumulation of GLA in the brain of lizard was higher than that of L-GLA. Moreover, the activities of neurotoxicity-related enzymes and biomarkers of oxidative stress were also investigated. In summary, the neurotoxic effects of lizards have been observed after exposure to GLA and L-GLA. Based on the result of the Integrated Biomarker Response (IBR), males were more sensitive to contaminants than females. On the other hand, the neurotoxic pathways by GLA and L-GLA triggered were slightly different: GLA mainly acted on glutamine synthetase (GS), acetylcholinesterase (AchE) and Catalase (CAT) and L-GLA aimed at AchE, Na+/K+-ATPase, Superoxide dismutase (SOD) and Malondialdehyde (MDA). In summary, the accumulation of GLA and L-GLA in lizard's brain induced neurotoxicity by altering the levels of enzymes related to nervous system and antioxidant activity and further resulted in the decrease of brain index and locomotor performance.


Assuntos
Aminobutiratos/toxicidade , Poluição Ambiental/efeitos adversos , Lagartos/metabolismo , Locomoção/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Aminobutiratos/farmacocinética , Aminobutiratos/farmacologia , Animais , Encéfalo/enzimologia , Encéfalo/metabolismo , Ecotoxicologia , Feminino , Lagartos/fisiologia , Masculino , Síndromes Neurotóxicas/enzimologia , Estresse Oxidativo/efeitos dos fármacos , Praguicidas/metabolismo , Fatores Sexuais
10.
J Vet Sci ; 20(2): e9, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30944532

RESUMO

Acetylcholinesterase (AChE) activity level can be used as a diagnostic marker for anticholinesterase pesticide poisoning. In this study, we aimed to establish a baseline level of normal brain AChE activity in wild birds. AChE activity was measured in the brains of 87dead wild birds (26 species). The level of AChE activity ranged from 6.40 to 15.9 µmol/min/g of brain tissue in normal wild birds. However, the brain tissue AChE activity level in wild birds exposed to organophosphate (OP) pesticide was 48.0%-96.3% of that in the normal birds. These results may serve as reference values to facilitate routine diagnosis and monitoring of OP-poisoned wild birds.


Assuntos
Acetilcolinesterase/metabolismo , Doenças das Aves/induzido quimicamente , Aves/metabolismo , Encéfalo/enzimologia , Intoxicação por Organofosfatos/veterinária , Animais , Animais Selvagens , Doenças das Aves/diagnóstico , Doenças das Aves/enzimologia , Intoxicação por Organofosfatos/diagnóstico , Intoxicação por Organofosfatos/enzimologia , Valores de Referência , República da Coreia
11.
Artigo em Inglês | MEDLINE | ID: mdl-30981910

RESUMO

Acetylcholinesterase (AChE) plays an important role in the therapy of Alzheimer's disease and in the detection of pesticides such as organophosphates which are also widely used in chemical warfare. The aim of this study is the physicochemical and kinetic characterization of brain and muscle ChE from Danio rerio (Zebrafish). Optimal activity was found for brain ChE at alkaline pH 9.0 at 30 °C, and for muscle ChE at alkaline pH 8.5 at temperatures between 20 °C and 35 °C. The apparent kinetic constants, Kmapp and Vmaxapp, for brain ChE were determined as 0.191 ±â€¯0.024 mM and 0.566 ±â€¯0.028 U/mg protein, and for muscle ChE as 0.230 ±â€¯0.030 mM and 0.677 ±â€¯0.039 U/mg protein. Both brain and muscle ChE showed inhibition at high substrate concentrations. Brain and muscle ChE showed IC50 values for physostigmine of 0.61 µM and 0.37 µM, respectively. The ChE activity in brain was significantly inhibited by BW254c51 in all concentrations tested, but not by Iso-OMPA, while muscle ChE presented a moderate decrease (13 to 29%) in the activity values, indicating that BuChE is present.


Assuntos
Acetilcolinesterase/metabolismo , Encéfalo/enzimologia , Músculo Esquelético/enzimologia , Peixe-Zebra/metabolismo , Animais , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/farmacologia , Relação Dose-Resposta a Droga , Concentração de Íons de Hidrogênio , Temperatura Ambiente
12.
J Stroke Cerebrovasc Dis ; 28(5): 1338-1345, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30797642

RESUMO

BACKGROUND AND OBJECTIVE: Ischemic stroke is a serious disease that endangers human health. How to reduce the damage of neurons in ischemic regions is an urgent problem to be explored. Autophagy is an important pathophysiological process in cerebral ischemia and Netrin-1 is an effective neuroprotective protein. This study aims to investigate the effect of Netrin-1 on autophagy of ischemic brain tissues and hypoxic neurons. METHODS: We constructed rat persistent middle cerebral artery occlusion model in vivo and constructed the Oxygen Glucose-Deprivation model in vitro. Rats and cells were treated with or without Netrin-1. Western blot analysis was performed to detect autophagy related proteins LC3B, P62 and pathway related proteins PI3K, p-PI3K, mTOR, p-mTOR. CCK-8 assay was performed to detect the viability of hypoxic neurons. We also performed western-blot analysis and qRT-PCR test to detect levels of Netrin-1 protein and mRNA. RESULTS: Autophagy enhanced both in ischemic brain tissues and hypoxic neurons. Netrin-1 inhibited autophagy through PI3K/mTOR pathway both in vivo and in vitro. At the same time, we found that exogenous Netrin-1 can promote the secretion of Netrin-1 protein by neurons themselves, which indicated that Netrin-1 can further amplify the neuroprotective effect through the positive feedback mechanism. CONCLUSIONS: Exogenous Netrin-1 alleviates damage of ischemic brain tissues and enhances viability of hypoxic neurons by inhibiting autophagy via PI3K/mTOR pathway. This effect can be amplified by positive feedback mechanism.


Assuntos
Autofagia/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Netrina-1/administração & dosagem , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Fosfatidilinositol 3-Quinase/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Encéfalo/enzimologia , Encéfalo/patologia , Hipóxia Celular , Células Cultivadas , Modelos Animais de Doenças , Retroalimentação Fisiológica , Infarto da Artéria Cerebral Média/enzimologia , Infarto da Artéria Cerebral Média/patologia , Masculino , Netrina-1/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
13.
Chemosphere ; 223: 124-130, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30772591

RESUMO

The objective of this study was to evaluate whether antiparasitic eprinomectin may be an environmental contaminant in water compartment in low concentrations, negatively affecting neurotransmission and, consequently, the natural behavior of the jundiá (Rhamdia quelen). Fish were randomly allocated in tanks and exposed for 24 and 48 h to eprinomectin concentrations in water [0.0 (Control), 1.124 (T1), 1.809 (T2) and 3.976 (T3) µg L-1], followed by 48 h of recovery in eprinomectin-free water, in order to evaluate the behavioral parameters, levels of reactive oxygen species (ROS) in the brain, as well as cerebral enzymatic activities of acetylcholinesterase (AChE) and of the sodium-potassium ATPase pump (Na+/K+-ATPase). Especially at the two highest concentrations of eprinomectin (T2 and T3), the fish showed alterations in natural behavior, particularly hyperlocomotion and longer time on the surface. Furthermore, at these same concentrations, cerebral ROS levels increased and cerebral AChE activity decreased. At the highest concentration (T3) cerebral Na+/K+-ATPase activity was reduced. Increased ROS and impairment of AChE and Na+/K+-ATPase enzymes in the brain may have contributed directly to behavioral changes, due to neuronal damage and synapse impairment. Even after 48 h in water without eprinomectin, behavioral changes and neurotoxic effects were observed in fish, suggesting residual effects of the antiparasitic. In conclusion, eprinomectin even in low concentrations may be a hazardous environmental contaminant for aquatic organisms, as it causes brain damage and affects the natural behavior of fish.


Assuntos
Acetilcolinesterase/efeitos dos fármacos , Peixes-Gato/fisiologia , Ivermectina/análogos & derivados , ATPase Trocadora de Sódio-Potássio/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/enzimologia , Inibidores da Colinesterase , Ivermectina/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Poluentes Químicos da Água/toxicidade
14.
Mar Pollut Bull ; 140: 30-34, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30803647

RESUMO

Polycyclic aromatic hydrocarbons (PAH) have been reported as acetylcholinesterase (AChE) inibitors, although in vitro studies on PAH effects on AChE activity are scarce and have only been performed using electric eel brain extracts. Thus, this study investigated PAH effects on brain AChE activity in a tropical fish species in Southeastern Brazil, mullet (Mugil liza). Mullet specimens were obtained from Guanabara Bay (N = 20), Rio de Janeiro, Brazil. Brain AChE was extracted and exposed to an environmentally relevant concentration of Pyrene, Chrysene, Phenanthrene, and Naphthalene, and PAH metabolites, 2-Naphthol and 1-OH-Pyrene. AChE activity inhibition was observed, although no difference was observed between high- and low- molecular weight PAH. 2-Naphthol was a less potent AChE inhibitor than Naphthalene, albeit non-significantly. Further studies are required, since only one PAH concentration was used herein. Mullet brain extracts seem to be adequate to assess possible neurotoxic PAH effects on fish AChE.


Assuntos
Encéfalo/enzimologia , Inibidores da Colinesterase/toxicidade , Exposição Ambiental/efeitos adversos , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Smegmamorpha/metabolismo , Acetilcolinesterase/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Brasil , Ecotoxicologia/métodos , Proteínas de Peixes/antagonistas & inibidores , Proteínas de Peixes/metabolismo , Hidrocarbonetos Policíclicos Aromáticos/metabolismo , Clima Tropical , Poluentes Químicos da Água/metabolismo , Poluentes Químicos da Água/toxicidade
15.
Drug Chem Toxicol ; 42(2): 220-230, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30747009

RESUMO

Chlorpyrifos (CPF) has been considered as one of the most potent organophosphates and is linked to several neurological disorders. On the other hand, Quercetin is a vital plant flavanoid and has been reported to regulate a number of physiological processes in the central nervous system. The present study was conducted to investigate the protective potential of quercetin during chlorpyrifos induced neurotoxicity. Female Wistar rats weighing 150-200 g were divided into four different groups viz: Normal control, CPF treated (13.5 mg/kg.b.wt. every alternate day), Quercetin treated (50 mg/kg.b.wt./day) and combined CPF and quercetin-treated. All the treatments were carried out for a total duration of eight weeks. Chlorpyrifos treatment showed significant alterations in the cognitive behavior and motor activities of rats, which were appreciably improved upon simultaneous supplementation with quercetin. Further, CPF treatment caused a significant inhibition in the enzyme activities of acetylcholinesterase and choline acetyltransferase, but caused an increase in the levels of acetylcholine in the brain. Further, chlorpyrifos exposure significantly elevated the levels of lipid peroxidation and protein carbonyl contents as well as the activities of catalase, superoxide dismutase, which were interestingly found to be decreased following co-treatment with quercetin. In contrast, CPF treatment decreased the activities of glutathione reductase, transferase, as well as levels of reduced and total glutathione in both the cerebrum and cerebellum but co-administration of quercetin, increased these levels. Chlorpyrifos treatment altered the neuro-histoarchitecture, which showed improvement upon quercetin supplementation. Hence, this study suggests that quercetin can be used as a prophylactic intervention to prevent CPF induced neurotoxicity.


Assuntos
Encéfalo/efeitos dos fármacos , Clorpirifos/toxicidade , Fármacos Neuroprotetores/farmacologia , Neurotoxinas/toxicidade , Quercetina/farmacologia , Acetilcolina/análise , Acetilcolinesterase/metabolismo , Animais , Encéfalo/enzimologia , Encéfalo/metabolismo , Química Encefálica/efeitos dos fármacos , Catalase/metabolismo , Clorpirifos/antagonistas & inibidores , Colina O-Acetiltransferase/metabolismo , Feminino , Peroxidação de Lipídeos/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Neurotoxinas/antagonistas & inibidores , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo
16.
Ecotoxicol Environ Saf ; 173: 482-493, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-30802737

RESUMO

Cholinesterases are frequent targets for toxic effects, namely by insecticides derived from phosphoric and carbamic acids. This effects allows the use of cholinesterase inhibition as a biomarker for contamination of aquatic environments by these specific chemical agents. However, cholinesterases are differently responsive to environmental contaminants, according to their different forms and locations. In addition, cholinesterases seem also to be inhibited by metals, so their use as an environmental criterion requires the prior characterization of their specific forms in each species and tissues, and the study of their sensitivity. The objective of this study was to characterize the cholinesterase isoenzymes present in the brain and dorsal muscle of three tropical fish species, namely Phalloceros harpagos (Lucinda, 2008), Pterygoplichthys pardalis (Castelnau, 1855) and Astyanax altiparanae (Garutti and Britski, 2000). In vitro assays were conducted to quantify the effect of pesticides (dimethoate and carbaryl) and metals (lead and copper) on cholinesterases activity. Although acetylcholinesterase seems to be the most prevalent and abundant form, as commonly described in vertebrates, the here-obtained results showed that three cholinesterase isoenzymes occur in tissues of the three fish species. In addition, the pesticide carbaryl caused a stronger inhibition than dimethoate. Copper caused a significantly higher cholinesterasic inhibition than lead, which is also in line with most results concerning the anticholinesterasic effects by these metals. The here obtained results allowed to conclude that acetylcholinesterase is the predominant form in all tissues from the three analyzed species. In addition, cholinesterases of these three fish were responsive to common environmental contaminants, namely metals and pesticides, similarly to what was already described for fish of temperate areas. This allows using the here proposed fish species in environmental studies for the assessment of the presence of neurotoxicants under neotropical conditions.


Assuntos
Peixes-Gato/metabolismo , Inibidores da Colinesterase/toxicidade , Cobre/toxicidade , Ciprinodontiformes/metabolismo , Chumbo/toxicidade , Praguicidas/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Carbaril/toxicidade , Colinesterases/metabolismo , Dimetoato/toxicidade , Feminino , Proteínas de Peixes/metabolismo , Masculino , Músculos/efeitos dos fármacos , Músculos/enzimologia
17.
Ecotoxicol Environ Saf ; 173: 494-503, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-30802738

RESUMO

Estuarine environments gather pollution from large regions including urban and industrial zones. The monitoring of environmental quality in these areas constitutes a real requirement for global sustainable development. Therefore, the aim of this study was to characterize the physicochemical and kinetic parameters of brain acetylcholinesterase (AChE) in the species Centropomus undecimalis, Diapterus auratus and Diapterus rhombeus and to assess the effects (in vitro) of pesticides and metal ions on their respective activities in order to investigate them as potential biomarkers. Physicochemical properties such as thermostability, optimal pH and temperature, as well as kinetic parameters were investigated. AChE was pointed as the predominant cholinesterase (ChE) in the brains of the species under study. The highest optimum pH value was observed for C. undecimalis (8.0), and the lowest for D. rhombeus and D. auratus, with 7.2 and 7.0, respectively. The optimal temperature was 35 °C for the three species. The AChEs of the three species presented moderate thermostability, since they retained 61%, 72% and 67% of the activity up to 45 °C (C. undecimalis, D. auratus and D. rhombeus, respectively). The carbamate carbofuran showed to be the strongest inhibitor even at very low concentrations (IC50: 0.182, 0.174 and 0.203 µmol/L - C. undecimalis, D. auratus and D. rhombeus, respectively), followed by dichlorvos and carbaryl. According to the findings, the AChE of these species may be proposed as in vitro biomarker of exposure to carbofuran and dichlorvos (all three species) and carbaryl (D. auratus and D. Rhombeus), as well as for exceeding limit concentrations of Hg2+ (D. rhombeus) and As3+ (D. auratus) in biomonitoring programs located or not at estuarine environments.


Assuntos
Acetilcolinesterase/metabolismo , Encéfalo/efeitos dos fármacos , Inibidores da Colinesterase/toxicidade , Proteínas de Peixes/metabolismo , Perciformes/metabolismo , Poluentes Químicos da Água/toxicidade , Animais , Arsênico/toxicidade , Encéfalo/enzimologia , Carbamatos/toxicidade , Diclorvós/toxicidade , Cinética , Metais Pesados/toxicidade , Praguicidas/toxicidade
18.
J Pharm Biomed Anal ; 166: 197-204, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30660034

RESUMO

Ribociclib is a selective, orally bioavailable inhibitor of cyclin-dependent kinase (CDK) 4/6, which has therapeutic potential for a variety of cancer types. This study was to develop and validate a liquid chromatography with tandem mass spectrometry (LC-MS/MS) method for determining total and unbound concentrations of ribociclib in human plasma and brain tumor tissue samples. Plasma and tumor homogenate samples were extracted using protein precipitation with acetonitrile. Unbound fraction in plasma or tumor homogenate was determined by equilibrium dialysis method. Chromatographic separation was achieved based on aqueous normal-phase chromatography mechanism on a Waters XBridge™ Amide column under isocratic elution with acetonitrile-ammonium formate (10 mM, pH 3) (75:25, v/v) at a flow rate of 0.8 mL/min. Ribociclib and the internal standard ([13C6]ribociclib) were monitored at the mass transitions m/z, 435.3 > 367.2 and 441.3 > 373.2, respectively, using positive electrospray ionization mode. The lower limit of quantitation (LLOQ) was 0.5 nM of ribociclib in plasma. Linear calibration curve was established at the concentration range of 0.5-1000 nM in plasma. Intra- and inter-day precision and accuracy were within the generally accepted criteria for bioanalytical method. The developed method was successfully applied to determine the plasma pharmacokinetics and central nervous system penetration of ribociclib in patients with malignant primary brain cancer.


Assuntos
Aminopiridinas/sangue , Antineoplásicos/sangue , Neoplasias Encefálicas/metabolismo , Encéfalo/metabolismo , Purinas/sangue , Aminopiridinas/farmacocinética , Aminopiridinas/uso terapêutico , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Encéfalo/enzimologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/enzimologia , Calibragem , Cromatografia Líquida , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Estabilidade de Medicamentos , Humanos , Limite de Detecção , Ligação Proteica , Purinas/farmacocinética , Purinas/uso terapêutico , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem
19.
Med Hypotheses ; 123: 118-124, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30696581

RESUMO

Inhalational anesthetics such as isoflurane, desflurane and halothane are the mainstay medications for surgical procedures; upon inhalation, they produce anesthesia described as reversible unconsciousness with the features of amnesia, sleep, immobility and analgesia. To date, how they produce anesthesia is unknown. This study proposes that carbonic anhydrase enzymes are likely targets mediating the actions of inhalational anesthetics. Carbonic anhydrase enzymes, commonly expressed in living organisms, utilize carbon dioxide (CO2) as a substrate and can generate H+ and HCO3- from CO2 with a great efficiency. There are remarkable lines of evidence for their likely roles in mediating anesthetic actions. Firstly, carbonic anhydrase enzymes are extensively expressed in the brain and spinal cord, and their importance in the brain activity, especially for the GABA and NMDA receptor signaling pathways, has been demonstrated in numerous studies. According to these studies, they provide HCO3- for GABA-A receptor activities and also buffer HCO3- excess resulting from NMDA receptor activation. Activation of GABA-A and inhibition of NMDA receptors are associated with the induction of anesthesia by the intravenous general anesthetics propofol and ketamine, respectively. Secondly, the carbonic anhydrase inhibitors topiramate and zonisamide are effectively used in the treatment of epilepsy for decades; their chronic use results in the requirement of increased levels of amobarbital in order to produce anesthesia in the epileptic patients during WADA test. In addition, given that CO2 is a substrate for these enzymes, their tertiary structure is likely has a hydrophobic pocket suitable for the anesthetic molecules to bind. Inhalational anesthetic molecules, which are lipophilic and inert in nature, have an ability to cross the membranes and inhibit carbonic anhydrases, which might not be accessible by topiramate and zonisamide. Unlike carbonic anhydrase inhibitors, they could bind to the hydrophobic pocket for CO2 molecules and produce a profound effect called anesthesia. Finally, there is a great deal of similarities between the physiological actions of inhalational anesthetics and carbonic anhydrase inhibitors; moreover well-known side effects of inhalational anesthetics could be associated with the inhibition of carbonic anhydrases. Therefore, this article presents a hypothesis that the anesthetic actions of inhalational anesthetics could be due to their inhibitory effects on the carbonic anhydrases. Investigating this hypothesis might lead to the development of new safer anesthetics, and more importantly it might reveal an endogenous anesthetic pathway, in which the carbonic anhydrase system is a component along with the GABA-A and NMDA receptor systems.


Assuntos
Anestésicos Inalatórios/farmacologia , Anidrases Carbônicas/metabolismo , Isoflurano/farmacologia , Anestesia , Animais , Encéfalo/enzimologia , Dióxido de Carbono , Humanos , Receptores de GABA-A/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Topiramato/farmacologia , Zonisamida/farmacologia
20.
Food Funct ; 10(2): 573-582, 2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30694278

RESUMO

Curcumin, bisdemethoxycurcumin and demethoxycurcumin are the main curcuminoids present in Curcuma longa L. and are known for their bioactivity. However, their low water solubility results in poor bioavailability and therapeutic efficacy. This work aimed to investigate the in vitro modulation capacity on the enzymes acetylcholinesterase (AChE) and glutathione S-transferase (GST), as well as the in vitro antioxidant (OxHLIA and TBARS) and anti-inflammatory activities (RAW 264.7 test) of nanoencapsulated curcuminoids. Cytotoxicity on tumor and non-tumor cell lines was also investigated. Curcuminoid nanoparticles significantly inhibited the in vitro activity of AChE (12% inhibition at 50 µM) and GST (30% inhibition at 5 µM). They presented antioxidant activity and toxic effects against breast adenocarcinoma, lung, cervical and hepatocellular carcinoma cells when dispersed in water. Encapsulated curcuminoids exhibited bioactive properties in aqueous medium (no hydrophobic solvent added), exerting antioxidant and cytotoxic effects and acting on the cholinergic and endogenous antioxidant systems.


Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/farmacologia , Curcuma/química , Nanopartículas/química , Extratos Vegetais/química , Acetilcolinesterase , Animais , Anti-Inflamatórios/química , Antineoplásicos Fitogênicos/química , Antioxidantes/química , Encéfalo/enzimologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Glutationa Transferase/antagonistas & inibidores , Humanos , Camundongos , Células RAW 264.7 , Ratos
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