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1.
Toxicol Lett ; 318: 44-49, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31639409

RESUMO

Acrolein is a neurotoxin produced through lipid peroxidation in the brain affected by ischemic stroke, which results in neuronal cell injury and inflammation. However the mechanism underlying acrolein-induced brain inflammation remains unclear. Therefore we examined how acrolein leads to astrocytic inflammation. It was found that acrolein increased the levels of NLRP3 and cleaved caspase-1, which led to the maturation of interleukin-1ß (IL-1ß). ELISA assay results, which showed that acrolein increased the secreted IL-1ß, further supported acrolein-induced astrocytic inflammation. Acrolein increased ADAM10 protein levels and the cleavage of N-cadherin. The ADAM10 inhibitor, GI 254023X blocked N-cadherin cleavage by acrolein, suggesting that ADAM10 is an upstream of N-cadherin. Furthermore, we found that acrolein activated p38 MAPK and NF-κB p65, while pretreatment with p38 MAPK inhibitor, SB203580 and GI 254023X inhibited NF-κB p65 activation and NLRP3 inflammasome. This suggests that p38 MAPK mediates the activation of NF-κB p65, which is associated with NLRP3 expression. Finally, we showed that acrolein induced cell toxicity and decrease of EAAT1 expression, suggesting that acrolein may induce a loss of glutamate uptake function. In conclusion, we demonstrate that acrolein induces astrocytic inflammation through NLRP3 inflammasome, which is regulated by ADAM10 and attributed to p38 MAPK-activated NF-κB p65 activity.


Assuntos
Proteína ADAM10/metabolismo , Acroleína/toxicidade , Apoptose/efeitos dos fármacos , Astrócitos/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encefalite/induzido quimicamente , Inflamassomos/efeitos dos fármacos , Proteína ADAM10/genética , Animais , Astrócitos/enzimologia , Astrócitos/patologia , Encéfalo/enzimologia , Encéfalo/patologia , Caderinas/metabolismo , Caspase 1/metabolismo , Linhagem Celular , Encefalite/enzimologia , Encefalite/patologia , Transportador 1 de Aminoácido Excitatório/metabolismo , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
2.
Biomed Khim ; 65(5): 380-384, 2019 Aug.
Artigo em Russo | MEDLINE | ID: mdl-31666409

RESUMO

The effects of acute (single) and chronic ethanol administration on the level of pro-inflammatory cytokines (IL-1ß and TNF-α), as well as on the level of mRNA NF-κB, TLR4 and its endogenous agonist, HMGB1 protein, were investigated in rats. It was shown that the level of TLR4, HMGB1 and cytokines was significantly higher than in control group. The ethanol withdrawal after prolonged administration resulted in dysregulation of cytokine levels, TLR4 and HMGB1. Changes in the level of TLR4 and HMGB1 mRNA demonstrated a similar pattern. The obtained data confirm that prolonged alcoholization leads to the activation of TLR4-dependent signaling in the prefrontal cortex of rats, and this can lead to a prolonged neuro-inflammatory process in the brain.


Assuntos
Alcoolismo , Encéfalo/efeitos dos fármacos , Citocinas/imunologia , Síndrome de Abstinência a Substâncias/patologia , Receptor 4 Toll-Like/imunologia , Animais , Encéfalo/imunologia , Etanol , Proteína HMGB1/metabolismo , Ratos , Transdução de Sinais , Síndrome de Abstinência a Substâncias/imunologia
3.
Biomed Khim ; 65(5): 385-387, 2019 Aug.
Artigo em Russo | MEDLINE | ID: mdl-31666410

RESUMO

The neurotransmitter systems of the brain are exposed to dysregulation during alcohol withdrawal. This contributes to the development of the pathological craving for alcohol in which corticotropin-releasing hormone receptors are may be involved. During the period of alcohol withdrawal, the level of CRFR2 mRNA in the ventral tegmental area of the brain on the seventh day of abstinence was significantly increased in comparison with the control group. This supports existing concepts on possible participation in the modulation of dopaminergic and GABA-neural neurons in the ventral tegmental area the brain.


Assuntos
Alcoolismo , Encéfalo/metabolismo , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Síndrome de Abstinência a Substâncias , Animais , Encéfalo/efeitos dos fármacos , Etanol , RNA Mensageiro , Ratos
4.
Biomed Khim ; 65(5): 388-397, 2019 Aug.
Artigo em Russo | MEDLINE | ID: mdl-31666411

RESUMO

Fibrates are well-known agonists of the PPAR family (peroxisome proliferator-activated receptors). This class of drugs is used for the treatment of dyslipidemia and atherosclerosis. Fenofibrate is one of the members of this class of synthetic PPARα receptor ligands. The oral administration of 0.3% fenofibrate caused a decrease in strength due to loss of body weight in laboratory animals when improving behavioural features. Analysis of the mitochondrial DNA of liver cells showed a genotoxic effect of fenofibrate, due to accumulation of reactive oxygen species, which could be attributed to activation of peroxisomal ß-oxidation processes, as well as to the lack of increase in the expression of genes encoding antioxidant defense proteins. Treatment with fenofibrate did not cause brain mtDNA damage. It has been shown that fenofibrate induced mitochondrial ß-oxidation in the brain, as indicated by the increased expression of the Acadm and Cpt1a and Ppargc1a and Ppara. The study found no effect of fenofibrate on the increase of mitochondrial biogenesis in brain and liver cells. Thus, we can conclude that fenofibrate significantly affects lipid metabolism in the liver and brain, but in the liver it is associated with an increase of oxidative stress, resulting in mtDNA oxidative damage. However, fenofibrate-induced increase in the expression of Ppargc1a is not associated with an increase of mitochondrial biogenesis. This is consistent with the recent suggestion that PGC-1α might not be a master regulator of mitochondrial biogenesis.


Assuntos
Encéfalo/efeitos dos fármacos , Dano ao DNA , Ácidos Graxos/metabolismo , Fenofibrato/farmacologia , Fígado/efeitos dos fármacos , Animais , Encéfalo/metabolismo , Regulação da Expressão Gênica , Fígado/metabolismo , Camundongos
5.
Biomed Khim ; 65(5): 407-417, 2019 Aug.
Artigo em Russo | MEDLINE | ID: mdl-31666414

RESUMO

Isatin (indol-2,3-dione), an endogenous biofactor found in the brain, peripheral tissues and biological body fluids of humans and animals, exhibits a wide range of biological and pharmacological activities. They are realized via interaction with numerous isatin-binding proteins. Some of these proteins identified during proteomic profiling of the brain are involved in the development of neurodegenerative pathology. In the context of the neuroprotective effect, the effect of isatin is comparable to the effects of deprenyl (selegiline), a pharmacological agent used for treatment of Parkinson's disease. In this study, we have investigated the effect of a single dose administration of isatin (100 mg/kg) and deprenyl (10 mg/kg) to mice on the profile of the brain isatin-binding proteins. Comparative proteomic analysis of brain isatin-binding proteins of mice treated with isatin or deprenyl resulted in identification of a representative group of proteins (n=200) sensitive to the administration of these substances. The change in the profile of isatin-binding proteins may be obviously attributed to accumulation of isatin and deprenyl in the brain and their interaction with target proteins; this prevents protein binding to the affinity sorbent. Thus identified brain isatin-binding proteins of the control animals obviously represent specific targets that interact directly with isatin (and also with deprenyl) in vivo. Isatin or deprenyl administered to animals interact with these proteins and thus inhibit their binding to the affinity sorbent (immobilized isatin analogue).


Assuntos
Encéfalo/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Isatina/farmacologia , Fármacos Neuroprotetores/farmacologia , Selegilina/farmacologia , Animais , Encéfalo/metabolismo , Camundongos , Proteômica
6.
Psychiatr Danub ; 31(3): 290-307, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31596822

RESUMO

Temperament traits of Novelty Seeking, Harm Avoidance, Reward Dependence, and Persistence, are well defined in terms of their neural circuitry, neurochemical modulators, and patterns of associative learning. When heritably excessive, each of these traits may become a mechanistically fundamental biogenetic trait vulnerability for personality disorder. The other main risk factor for personality disorder is environmental, notably abuse, neglect, and psychological trauma. The emerging concept of mechanism-based pharmacotherapy aims to activate the brain's homeostasis as the only available delivery system to re-calibrate complex neurophysiological participants in each of the temperament traits. In a positive feedback, a homeostasis-driven improvement of excessive temperament is expected to facilitate maturation of neocortical networks of cognition, most reliably in expert psychotherapy (Part I of this paper) and, ultimately, thereby improve top-down cortical control of subcortical affect reactivity. As an emerging concept informed by neuroscience and clinical research, mechanism-based pharmacotherapy has the potential to be superior to traditional symptom-based treatments. Such mechanism-based approach illustrates what the pharmacological treatment of Research Domain Criteria (RDoC) might look like.


Assuntos
Modelos Psicológicos , Transtornos da Personalidade/tratamento farmacológico , Temperamento , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cognição , Humanos , Personalidade , Transtornos da Personalidade/psicologia
7.
Br J Anaesth ; 123(6): 808-817, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31587833

RESUMO

BACKGROUND: Preclinical studies suggest that exposure to general anaesthesia (GA) could cause neurodegeneration consistent with Alzheimer's disease (AD) pathology. Brain magnetic resonance imaging (MRI) is useful to study structural brain changes. We tested the hypothesis that exposure to surgery with GA (surgery/GA) is associated with greater cortical thinning and increased frequency of white matter lesions. METHODS: This is a cross-sectional analysis of 70-91-yr-old participants enrolled in the Mayo Clinic Study of Aging who had baseline MRI. The thickness of selected cortical regions, the volume of white matter hyperintensities, and the frequency of cortical infarctions were compared in participants who were and were not exposed to surgery/GA within 20 yr before the first MRI obtained after enrolment. RESULTS: Of 1410 participants with MRI scans, 932 were exposed to surgery/GA before scanning. In adjusted analyses, cortical thickness in regions vulnerable to AD was significantly less in those exposed to surgery/GA in the prior 20 yr (difference -0.023 mm, [95% confidence interval (CI) -0.041 to -0.005], P=0.014). Those with surgery in the prior 20 yr were more likely to have 'abnormal thickness' compared with those without surgery (odds ratio=1.45, [95% CI 1.10-1.90], P=0.009). Exposure was not associated with white matter hyperintensities or the presence of brain infarcts. CONCLUSIONS: This study suggests that exposure of older adults to surgical anaesthesia is associated with thinning in cortical regions implicated in AD. The pathogenesis and mechanisms driving these neurodegenerative changes, and the potential clinical significance of these findings, require further study.


Assuntos
Anestesia Geral/efeitos adversos , Encéfalo/efeitos dos fármacos , Encéfalo/diagnóstico por imagem , Avaliação Geriátrica/métodos , Imagem por Ressonância Magnética/métodos , Idoso , Idoso de 80 Anos ou mais , Encéfalo/fisiopatologia , Estudos Transversais , Feminino , Humanos , Masculino
8.
Sheng Li Xue Bao ; 71(5): 749-759, 2019 Oct 25.
Artigo em Chinês | MEDLINE | ID: mdl-31646329

RESUMO

With the evolution of medical techniques and technology, an increasing number of infants, neonates, and fetuses are exposed to general anesthesia for clinical diagnostic and therapeutic process. The neurotoxic effects of general anesthetics on developing brain have been a subject of concern and considerable research interest. Population-based study confirmed that single short-term general anesthetic exposure does not affect nervous system function, but multiple exposures to general anesthesia could damage cognitive function. Animal studies further discovered the underlying mechanisms. Nervous system is most susceptible to general anesthetics during the brain growth spurt. The time-point is more critical than the duration of exposure to general anesthetics. General anesthetics can induce intracellular calcium overload, disturb energy metabolism, promote cell apoptosis and lead to cell loss. General anesthetics can damage synaptic structure, transmission and plasticity, and impair brain function. High throughput omics technologies have been used to screen the differentially expressed genes induced by general anesthetics, which provide further understanding of the mechanism of general anesthetics affecting cognitive function. This review provides an update on the pathophysiologic mechanisms underlying the anesthesia-neurotoxicity, which will be helpful to provide instructions for the clinical use of general anesthesia in children.


Assuntos
Anestésicos Gerais/efeitos adversos , Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Cognição , Anestesia Geral/efeitos adversos , Animais , Feminino , Humanos , Lactente , Recém-Nascido , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia
9.
Cancer Sci ; 110(11): 3486-3496, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31483918

RESUMO

Bone morphogenetic protein (BMP) signaling plays important roles in glioblastoma multiforme (GBM), a lethal form of brain tumor. BMP reduces GBM tumorigenicity through its differentiation- and apoptosis-inducing effects on glioma-initiating cells (GIC). However, some GIC do not respond to the tumor suppressive effects of BMP. Using a phosphoreceptor tyrosine kinase array, we found that EPHA6 (erythropoietin-producing hepatocellular carcinoma receptor A6) phosphorylation was regulated by BMP-2 signaling in some GIC. Analysis of The Cancer Genome Atlas showed that EPHA6 expression was lower in patients with GBM than in the normal brain, and that high EPHA6 expression was correlated with better prognosis. EPHA6 receptor increased the susceptibility of both sensitive and resistant GIC to BMP-2-induced apoptosis. The cooperative effect on apoptosis induction depended on the kinase activity of BMP type I receptor but was independent of EPHA6 kinase function. Overexpression of the EPHA6 receptor in GIC resulted in the formation of a protein complex of EPHA6 receptor and the BMP type I receptor ALK-2, which was associated with BMP-induced apoptosis in GIC. Intracranial injection of GIC into nude mice showed that gain-of-function of EPHA6 together with BMP-2 pretreatment slowed GBM tumor progression in the mouse brain and promoted mouse survival. In summary, EPHA6 together with BMP-2 signaling led to apoptotic cell death in GIC, and thus is a putative tumor suppressor in GBM.


Assuntos
Receptores de Ativinas Tipo I/metabolismo , Apoptose , Proteína Morfogenética Óssea 2/metabolismo , Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Receptor EphA6/metabolismo , Animais , Proteína Morfogenética Óssea 2/farmacologia , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Progressão da Doença , Glioblastoma/mortalidade , Glioblastoma/patologia , Glioma/metabolismo , Glioma/patologia , Humanos , Camundongos , Camundongos Nus , Transplante de Neoplasias , Fosforilação , Prognóstico , Proteínas Supressoras de Tumor/metabolismo
10.
Life Sci ; 235: 116844, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31499069

RESUMO

AIMS: 10-O-(N,N-dimethylaminoethyl)-ginkgolide B methanesulfonate (XQ-1H), a new derivative of ginkgolide B, has drawn great attention for its potent bioactivities against ischemia-induced injury. The purpose of this study was to further investigate the effect of XQ-1H against acute ischemic stroke by inducing middle cerebral artery occlusion/reperfusion (MCAO/R) injuries in mice. MAIN METHODS: Treatment of XQ-1H (78 or 39 mg/kg, i.g., bid) 2 h after MCAO improved motor skills and ameliorated the severity of brain infarction and apoptosis seen in the mice by diminishing pathological changes and the activation of a pro-apoptotic protein Cleaved-Caspase-3, which in turn induced anti-apoptotic Bcl-xL. Through introducing Wnt/ß-catenin signaling inhibitor XAV-939, XQ-1H was proven to intensively promoted neurogenesis in the peri-infarct cortex, subventricular area (SVZ) and the dentate gyrus (DG) subgranular area (SGZ) in a Wnt signal dependent way by compromising the activation of GSK3ß, which in turn upregulated Wnt1, ß-catenin, Neuro D1 and Cyclin D1, most possibly through the activation of PI3K/Akt signaling via the upregulation of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). KEY FINDINGS: We conclude that XQ-1H preserved the motor functions, limited apoptosis, and concomitantly promoted neurogenesis-related protein expression by Wnt signaling-dependently compromising GSK3ß/Caspase-3 activity and enhancing the expression of Wnt1/ß-catenin/Neuro D1/Cyclin D1 and Bcl-xL. SIGNIFICANCE: This research may benefit the development of stroke therapeutics targeting neurogenesis through Wnt upregulation by XQ-1H.


Assuntos
Apoptose/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Ginkgolídeos/farmacologia , Ginkgolídeos/uso terapêutico , Lactonas/farmacologia , Lactonas/uso terapêutico , Neurogênese/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Isquemia Encefálica/complicações , Isquemia Encefálica/patologia , Caspase 3/metabolismo , Ciclina D1/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Compostos Heterocíclicos com 3 Anéis/farmacologia , Infarto da Artéria Cerebral Média , Masculino , Camundongos , Fator de Crescimento Neural/metabolismo , Recuperação de Função Fisiológica/efeitos dos fármacos , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/patologia , Regulação para Cima/efeitos dos fármacos , Proteína bcl-X/metabolismo
11.
Br J Anaesth ; 123(5): 592-600, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31492526

RESUMO

BACKGROUND: Previous work on the electroencephalographic (EEG) effects of anaesthetic doses of ketamine has identified a characteristic signature of increased high frequency (beta-gamma) and theta waves alternating with episodic slow waves. It is unclear which EEG parameter is optimal for pharmacokinetic-pharmacodynamic modelling of the hypnotic actions of ketamine, or which EEG parameter is most closely linked to loss of behavioural responsiveness. METHODS: We re-analysed previously published 128-channel scalp EEG data from 15 subjects who had received a 1.5 mg kg-1 bolus i.v. dose of ketamine. We applied standard sigmoid pharmacokinetic-pharmacodynamic models to the drug-induced changes in slow wave activity, theta, and beta-gamma EEG power; and examined the morphology of the slow waves in the time domain for Fz, F3, T3, P3, and Pz average-referenced channels. RESULTS: Hypnotic doses of ketamine i.v. induced medio-frontal EEG slow waves, and loss of behavioural response when the estimated brain concentration was 1.64 (0.17) µg ml-1. Recovery of responsiveness occurred at 1.06 (0.21) µg.ml-1 after slow wave activity had markedly diminished. Pharmacokinetic-pharmacodynamic modelling fitted best to the slow wave activity and theta power (almost half the beta-gamma channels could not be modelled). Slow wave effect-site equilibration half-time (23 [4] s), and offset, was faster than for theta (47 [22] s). CONCLUSIONS: Changes in EEG slow wave activity after a hypnotic dose of ketamine could be fitted by a standard sigmoid dose-response model. Their onset, but not their offset, was consistently associated with loss of behavioural response in our small study group.


Assuntos
Analgésicos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Eletroencefalografia/métodos , Ketamina/farmacologia , Adulto , Feminino , Voluntários Saudáveis , Humanos , Masculino , Valores de Referência , Adulto Jovem
13.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(7): 601-605, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31537244

RESUMO

Objective To determine whether regulatory T cells (Tregs) are involved in sevoflurane preconditioning-induced brain protection against cerebral ischemia/reperfusion injury. Methods C57BL/6 mice were preconditioned with sevoflurane and then subjected to the middle cerebral artery occlusion modeling. The brain infarct volume and neurological score were assessed at 48 hours after cerebral reperfusion. Meanwhile, the proportion of Tregs in the spleen was analyzed by flow cytometry. Then, CD25 neutralizing antibody was administrated by intraperitoneal injection, following with the analysis of cerebral ischemia/reperfusion injury and the proportion of Tregs in the spleen after sevoflurane preconditioning. Results Compared with a control group, sevoflurane preconditioning markedly mitigated the cerebral ischemia/reperfusion injury in the mice including the infarct volume and neurological score. In the meantime, sevoflurane preconditioning significantly increased the proportion of Tregs in the spleen at 48 hours after cerebral reperfusion. Compared with the isotype antibody group, the CD25 neutralizing antibody reversed the increase of Tregs induced by sevoflurane preconditioning at 48 hours after reperfusion, which was also associated with the reversal of sevoflurane preconditioning-induced protectetion against cerebral ischemia/reperfusion injury. Conclusion Tregs are involved in sevoflurane preconditioning-induced cerebral protection against ischemia/reperfusion injury.


Assuntos
Isquemia Encefálica/prevenção & controle , Precondicionamento Isquêmico , Traumatismo por Reperfusão/prevenção & controle , Sevoflurano/farmacologia , Linfócitos T Reguladores/citologia , Animais , Encéfalo/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL
14.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 48(3): 289-295, 2019 May 25.
Artigo em Chinês | MEDLINE | ID: mdl-31496161

RESUMO

OBJECTIVE: To investigate the effect and mechanism of glucosides of chaenomeles speciosa (GCS) on ischemia/reperfusion-induced brain injury in mouse model. METHODS: Fifty 8-week C57BL/C mice were randomly divided into five groups with 10 in each group:sham group, model group, GCS 30 mg/kg group, GCS 60 mg/kg group and GCS 90 mg/kg group, and the GCS was administrated by gavage (once a day) for 14 d. HE staining was performed to investigate the cell morphology; the Zea-Longa scores were measured for neurological activity; TUNEL staining was performed to investigate the cell apoptosis; ELISA was used to detected the oxidative stress and inflammation; Western Blot was performed to investigate the key pathway and neurological functional molecules. RESULTS: Compared with the sham group, the brain tissues in model group were seriously damaged, presenting severe cell apoptosis, oxidative stress and inflammation, associated with increased NF-κB P65 and TNF-α levels as well as decreased myelin associate glycoprotein (MAG) and oligodendrocyte-myelin glycoprotein (OMgp)levels (all P<0.01). Compared with the model group, the brain tissues in GCS groups were ameliorated, and cell apoptosis, oxidative stress and inflammation were inhibited, associated with decreased NF-κB P65 and TNF-α levels as well as increased MAG and OMgp levels (all P<0.01), which were more markedly in GCS 60 mg/kg group. CONCLUSIONS: GCS can inhibit the NF-κB P65 and TNF-α, reduce the oxidative stress and inflammation, decrease the cell apoptosis in mouse ischemia/reperfusion-induced brain injury model, and 60 mg/kg GCS may be the optimal dose.


Assuntos
Lesões Encefálicas , Glucosídeos , Rosaceae , Fator de Necrose Tumoral alfa , Animais , Encéfalo/efeitos dos fármacos , Lesões Encefálicas/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Distribuição Aleatória , Rosaceae/química , Fator de Necrose Tumoral alfa/genética
15.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 48(3): 303-309, 2019 May 25.
Artigo em Chinês | MEDLINE | ID: mdl-31496163

RESUMO

OBJECTIVE: To determine the correlation of phosphorylated ribosomal S6 protein (P-S6) content in blood and brain tissue in mice and rats with seizure. METHODS: Seizure models were induced by intraperitoric injection of kainic acid (KA) in C57BL/mice and SD rats. Flow cytometry was used to detect the content of P-S6 in blood; Western blot was used to detect the expression of P-S6 in brain tissues. The correlation between P-S6 expression in blood and in brain tissue was examine by Pearson analysis, and the correlation between P-S6 expression in blood and the severity of seizure was also observed. RESULTS: Western blotting analysis showed that the expression of P-S6 was significantly increased in peripheral blood and brain tissue in mice 1 h after KA-induced seizure,and the expression levels increased to (1.49±0.45) times (P<0.05) and (2.55±0.66) times (P <0.01) of the control group, respectively. Flow cytometry showed that the positive percentage and average fluorescence intensity of P-S6 in the blood of mice increased significantly 1 h after KA-induced seizures (P<0.01), which was consistent with the expression of P-S6 in brain tissue (r=0.8474, P<0.01). Flow cytometry showed that the average fluorescence intensity of P-S6 in blood increased from 14.89±9.75 to 52.35±21.72 (P<0.01) in rats with seizure, which was consistent with the change of P-S6 in brain tissue (r=0.9385, P<0.01). Rats with higher levels of seizure were of higher levels of P-S6 in peripheral blood. CONCLUSIONS: Consistent correlation of P-S6 expression is demonstrated in peripheral blood and in brain tissue after KA-induced seizure, suggesting that the expression of P-S6 in blood can accurately reflect the changes of mTOR signaling pathway in brain tissue.


Assuntos
Encéfalo , Regulação da Expressão Gênica , Ácido Caínico , Convulsões , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Ratos , Ratos Sprague-Dawley , Convulsões/sangue , Convulsões/induzido quimicamente , Convulsões/fisiopatologia
16.
Inflammopharmacology ; 27(5): 941-948, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31482259

RESUMO

Metformin (MET), a biguanide oral hypoglycaemic agent, recently has been shown to be effective in various conditions other than type-2 diabetes including cancer, stroke, weight reduction, and polycystic ovarian syndrome, to name a few. MET has also possessed antioxidant and antiinflammatory properties by activation of AMPK . This study was aimed at evaluating the effects of MET on lipopolysaccharide (LPS)-induced systemic and neuroinflammation, oxidative stress, and behavioural changes. The study consisted of six groups, where three selected doses of MET (100, 200, and 300 mg/kg) were employed in male Swiss albino mice, with one group of imipramine (IMI), saline, and LPS each. Systemic inflammation was induced by injecting LPS (1.5 mg/kg) by intraperitoneal route. A battery of behavioural tests including open field, forced swim, and tail suspension tests were employed to assess the impact of systemic inflammation on exploratory behaviour and learned helplessness. LPS induced significant immobility with profound symptoms of sickness behaviour. Furthermore, LPS led to significant increase in serum and brain proinflammatory cytokines TNF-α and IL-6; and also increased lipid peroxidation with reduced glutathione levels. Pretreatment of the animals with 100 and 200 mg/kg of MET significantly reduced both systemic and central inflammatory markers along with protecting against LPS-induced oxidative stress. The higher dose, 300 mg/kg of MET was not effective against most of LPS-induced biochemical changes. Our preliminary results from this study suggest the antiinflammatory and neuroprotective effects of MET in LPS-induced model of sickness behaviour and neuroinflammation.


Assuntos
Encéfalo/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Inflamação/tratamento farmacológico , Metformina/farmacologia , Animais , Antioxidantes/metabolismo , Encéfalo/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Glutationa/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos
17.
J Agric Food Chem ; 67(37): 10342-10351, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31461273

RESUMO

Maltol, a maillard reaction product from ginseng (Panax ginseng C. A. Meyer), has been confirmed to inhibit oxidative stress in several animal models. Its beneficial effect on oxidative stress related brain aging is still unclear. In this study, the mouse model of d-galactose (d-Gal)-induced brain aging was employed to investigate the therapeutic effects and potential mechanisms of maltol. Maltol treatment significantly restored memory impairment in mice as determined by the Morris water maze tests. Long-term d-Gal treatment reduced expression of cholinergic regulators, i.e., the cholineacetyltransferase (ChAT) (0.456 ± 0.10 vs 0.211 ± 0.03 U/mg prot), the acetylcholinesterase (AChE) (36.4 ± 5.21 vs 66.5 ± 9.96 U/g). Maltol treatment prevented the reduction of ChAT and AChE in the hippocampus. Maltol decreased oxidative stress levels by reducing levels of reactive oxygen species (ROS) and malondialdehyde (MDA) production in the brain and by elevating antioxidative enzymes. Furthermore, maltol treatment minimized oxidative stress by increasing the phosphorylation levels of phosphatidylinositol-3-kinase (PI3K), protein kinase B (Akt), nuclear factor-erythroid 2-related factor 2 (Nrf2), and hemeoxygenase-1 (HO-1). The above results clearly indicate that supplementation of maltol diminishes d-Gal-induced behavioral dysfunction and neurological deficits via activation of the PI3K/Akt-mediated Nrf2/HO-1 signaling pathway in brain. Maltol might become a potential drug to slow the brain aging process and stimulate endogenous antioxidant defense capacity. This study provides the novel evidence that maltol may slow age-associated brain aging.


Assuntos
Envelhecimento/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Galactose/efeitos adversos , Heme Oxigenase-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Extratos Vegetais/administração & dosagem , Pironas/administração & dosagem , Envelhecimento/metabolismo , Animais , Heme Oxigenase-1/genética , Humanos , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos , Panax/química , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo
18.
Pestic Biochem Physiol ; 159: 154-162, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31400777

RESUMO

The migratory locust, Locusta migartoria, is a major agricultural insect pest and its resistance to insecticides is becoming more prevalent. Cytochrome P450 monooxygenases (CYPs) are important enzymes for biotransformations of various endogenous and xenobiotic substances. These enzymes play a major role in developing insecticide resistance in many insect species. In this study, we heterologously co-expressed a CYP enzyme (CYP6FD1) and cytochrome P450 reductase (CPR) from L. migartoria in Sf9 insect cells. The recombinant enzymes were assayed for metabolic activity towards six selected model substrates (luciferin-H, luciferin-Me, luciferin-Be, luciferin-PFBE, luciferin-CEE and 7-ethoxycoumarin), and four selected insecticides (deltamethrin, chlorpyrifos, carbaryl and methoprene). Recombinant CYP6FD1 showed activity towards 7-ethoxycoumarin and luciferin-Me, but no detectable activity towards the other luciferin derivatives. Furthermore, the enzyme efficiently oxidized deltamethrin to hydroxydeltamethrin through an aromatic hydroxylation in a time-dependent manner. However, the enzyme did not show any detectable activity towards the other three insecticides. Our results provide direct evidence that CYP6FD1 is capable of metabolizing deltamethrin. This work is a step towards a more complete characterization of the catalytic capabilities of CYP6FD1 and other xenobiotic metabolizing CYP enzymes in L. migratoria.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Família 6 do Citocromo P450/metabolismo , Proteínas de Insetos/metabolismo , Inseticidas/farmacologia , Locusta migratoria/efeitos dos fármacos , Locusta migratoria/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Família 6 do Citocromo P450/genética , Proteínas de Insetos/genética
19.
J Agric Food Chem ; 67(35): 9820-9830, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31411471

RESUMO

Brain aging is commonly associated with neurodegenerative disorders, but the ameliorative effect of krill oil and the underlying mechanism remain unclear. In this study, the components of krill oil were measured, and the antiaging effects of krill oil were investigated in mice with d-galactose (d-gal)-induced brain aging via proteomics and gut microbiota analysis. Krill oil treatment decreased the expression of truncated dopamine- and cAMP-regulated phosphoproteins and proteins involved in the calcium signaling pathway. In addition, the concentrations of dopamine were increased in the serum (p < 0.05) and brain (p > 0.05) due to the enhanced expressions of tyrosine-3-monooxygenase and aromatic l-amino acid decarboxylase. Moreover, krill oil alleviated gut microbiota dysbiosis, decreased the abundance of bacteria that consume the precursor tyrosine, and increased the abundance of Lactobacillus spp. and short-chain fatty acid producers. This study revealed the beneficial effect of krill oil against d-gal-induced brain aging and clarified the underlying mechanism through proteomics and gut microbiota analysis.


Assuntos
Envelhecimento/efeitos dos fármacos , Encéfalo/fisiopatologia , Euphausiacea/química , Galactose/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Óleos/administração & dosagem , Envelhecimento/fisiologia , Animais , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/isolamento & purificação , Encéfalo/efeitos dos fármacos , Suplementos Nutricionais/análise , Humanos , Intestinos/efeitos dos fármacos , Intestinos/microbiologia , Masculino , Camundongos , Óleos/isolamento & purificação
20.
Chem Biodivers ; 16(10): e1900362, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31400187

RESUMO

A series of novel esters and amides was synthesized on the basis of para-coumaric acid containing isobornyl groups in ortho-positions relative to the phenolic hydroxy group. Antioxidant properties of the obtained compounds were evaluated and compared on in vitro models: radical-scavenging ability, antioxidant activity on a substrate containing the lipids of animal brain, cytotoxicity of red blood cells, antioxidant and membrane-protective properties on the model of oxidative red blood cells hemolysis. Statistically significant relationship was established between the antioxidant activity of the studied compounds in model system containing animal lipids and the parameters reflecting their antioxidant properties on the model of H2 O2 -induced hemolysis of red blood cells. It was determined that an amide with a morpholine fragment has the highest antioxidant activity. The specified derivative significantly surpassed the reference substances (parent acid, BHT) and was not inferior to the effective antioxidant 2,6-diisobornyl-4-methylphenol in terms of its properties.


Assuntos
Antioxidantes/farmacologia , Bornanos/farmacologia , Encéfalo/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Propionatos/farmacologia , Animais , Antioxidantes/síntese química , Antioxidantes/química , Bornanos/química , Hidroxitolueno Butilado/química , Hemólise/efeitos dos fármacos , Peróxido de Hidrogênio/farmacologia , Camundongos , Estrutura Molecular , Propionatos/síntese química , Propionatos/química
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