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1.
Adv Exp Med Biol ; 1141: 407-466, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571171

RESUMO

Blood-brain interfaces comprise the cerebral microvessel endothelium forming the blood-brain barrier (BBB) and the epithelium of the choroid plexuses forming the blood-cerebrospinal fluid barrier (BCSFB). Their main functions are to impede free diffusion between brain fluids and blood; to provide transport processes for essential nutrients, ions, and metabolic waste products; and to regulate the homeostasis of central nervous system (CNS), all of which are attributed to absent fenestrations, high expression of tight junction proteins at cell-cell contacts, and expression of multiple transporters, receptors, and enzymes. Existence of BBB is an important reason that systemic drug administration is not suitable for the treatment of CNS diseases. Some diseases, such epilepsy, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and diabetes, alter BBB function via affecting tight junction proteins or altering expression and function of these transporters. This chapter will illustrate function of BBB, expression of transporters, as well as their alterations under disease status.


Assuntos
Barreira Hematoencefálica , Proteínas de Membrana Transportadoras , Preparações Farmacêuticas , Transporte Biológico , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Humanos , Proteínas de Membrana Transportadoras/metabolismo , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/metabolismo
2.
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
3.
Adv Exp Med Biol ; 1173: 1-19, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456202

RESUMO

Iron is the most abundant trace element in the human body. It is well known that iron is an important component of hemoglobin involved in the transport of oxygen. As a component of various enzymes, it participates in the tricarboxylic acid cycle and oxidative phosphorylation. Iron in the nervous system is also involved in the metabolism of catecholamine neurotransmitters and is involved in the formation of myelin. Therefore, iron metabolism needs to be strictly regulated. Previous studies have shown that iron deficiency in the brain during infants and young children causes mental retardation, such as delayed development of language and body balance, and psychomotor disorders. However, if the iron is excessively deposited in the aged brain, it is closely related to the occurrence of various neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Friedreich's ataxia. Therefore, it is important to fully study and understand the mechanism of brain iron metabolism and its regulation. On this basis, exploring the relationship between brain iron regulation and the occurrence of nervous system diseases and discovering new therapeutic targets related to iron metabolism have important significance for breaking through the limitation of prevention and treatment of nervous system diseases. This review discusses the complete research history of iron and its significant role in the pathogenesis of the central nervous system (CNS) diseases.


Assuntos
Encéfalo/metabolismo , Doenças do Sistema Nervoso Central , Ferro/metabolismo , Humanos , Distúrbios do Metabolismo do Ferro , Doenças Neurodegenerativas
4.
Adv Exp Med Biol ; 1173: 33-44, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456204

RESUMO

With the development of research, more and more evidences suggested that mutations in the genes associated with brain iron metabolism induced diseases in the brain. Brain iron metabolism disorders might be one cause of neurodegenerative diseases. This review mainly summarizes the normal process of iron entry into the brain across the blood-brain barrier, and the distribution and transportation of iron among neurons and glial cells, as well as the underlying regulation mechanisms. To understand the mechanisms of iron metabolism in the brain will provide theoretical basis to prevent and cure brain diseases related to iron metabolism disorders.


Assuntos
Encéfalo/metabolismo , Distúrbios do Metabolismo do Ferro , Ferro/metabolismo , Barreira Hematoencefálica , Humanos , Neuroglia/metabolismo , Neurônios/metabolismo
5.
Adv Exp Med Biol ; 1173: 67-104, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456206

RESUMO

Alzheimer's disease (AD) is a multifactorial neurodegenerative condition associated with pathological accumulation of amyloid plaques and with the appearance of deposit of neurofibrillary tangles. Increasing evidence suggests that disorders of metal ion metabolism in the brain are one of the risk factors for the pathogenesis of AD. Iron, one of the endogenous metal ions, involves in many important physiological activities in the brain. Iron metabolism mainly depends on iron regulatory proteins including ferritin, transferrin and transferrin receptor, hepcidin, ferroportin, lactoferrin. Abnormal iron metabolism generates hydroxyl radicals through the Fenton reaction, triggers oxidative stress reactions, damages cell lipids, protein and DNA structure and function, leads to cell death, and ultimately influences the process of ß-amyloid (Aß) misfolding and plaque aggregation. Although the results are different, in general, iron has deposition in different brain regions of AD patients, which may impair normal cognitive function and behavior. Therefore, neuroimaging changes have so far been largely attributed to focal iron deposition accompanying the plaques at preclinical stages of AD, and iron-targeted therapeutic strategies have become a new direction. Iron chelators have received a great deal of attention and have obtained good results in scientific experiments and some clinical trials. Future research will also focus on iron as an opportunity to study the mechanism of the occurrence and development of AD from the iron steady state to more fully clarify the etiology and prevention strategies.


Assuntos
Doença de Alzheimer/patologia , Encéfalo/metabolismo , Ferro/metabolismo , Peptídeos beta-Amiloides , Encéfalo/fisiopatologia , Humanos , Emaranhados Neurofibrilares/patologia , Placa Amiloide/patologia
6.
Adv Exp Med Biol ; 1173: 145-152, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456209

RESUMO

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the degeneration of motor neurons in the motor cortex, brainstem, and spinal cord. The etiology and pathogenesis of this devastating disease remain largely unknown. Increasing evidence suggests that iron accumulation is involved in the onset and progression of ALS. In this review, we discuss the regulation of iron homoeostasis in the brain, the misregulation of iron homeostasis in ALS, and its possible roles in the mechanism of the disease. Finally, we summarize the recent progress and problems with respect to iron chelator therapies on ALS, aiming to propose a new therapeutic strategy to ameliorate the progression of the disease.


Assuntos
Esclerose Amiotrófica Lateral/fisiopatologia , Encéfalo/metabolismo , Ferro/metabolismo , Homeostase , Humanos , Neurônios Motores/patologia , Degeneração Neural
7.
Adv Exp Med Biol ; 1173: 153-177, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456210

RESUMO

Neurodegeneration with brain iron accumulation (NBIA) is a group of seriously devastating and life-threatening rare monogenic diseases characterized by focal iron accumulation in the brain. The main symptoms of NBIA comprise progressive movement disorder, often including painful dystonia, parkinsonism, mental disability, and early death. Currently, a single established therapy is not available to reverse the progression of these debilitating disorders. The complexity of NBIA emerged from the identification of various causative genes, and up to 15 genes have been identified to date. Although the NBIA genes are involved in different cellular biochemical pathways, they show the common characteristic of generating severe iron accumulation in the basal ganglia of the patients' brains. Thus, the molecular events that lead to brain iron overload and their important roles in the pathophysiology of the diseases are not easy to identify and are poorly understood. This review summarizes the current knowledge on NBIA disorders, with a particular focus on the data describing the role of iron in the pathogenic mechanisms.


Assuntos
Encéfalo/fisiopatologia , Ferro/metabolismo , Gânglios da Base , Encéfalo/metabolismo , Humanos , Sobrecarga de Ferro , Doenças Neurodegenerativas
8.
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
9.
Pharm Res ; 36(10): 141, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31367840

RESUMO

PURPOSE: The purpose of the present study was to investigate changes of blood-brain barrier (BBB) and brain parenchymal protein expression due to type II diabetes mellitus (T2DM) induced by a high-fat diet (HFD) by using SWATH-based quantitative proteomics. METHODS: Mice were fed a HFD for 2 or 10 weeks, and then SWATH-based quantitative proteomic analysis, western blot analysis, immunohistochemistry and functional transport studies were performed. RESULTS: In brain capillaries, expression levels of BBB transporters (Glut1, P-glycoprotein) and tight-junction proteins (claudin-5, occludin) were significantly reduced in HFD mice at 2 weeks, but recovered to the levels in the normal diet (ND) group at 10 weeks. P-glycoprotein function at the BBB was reduced at 2 weeks. In the cerebral cortex and hippocampus, neurofilament, which is important for neuronal function, was decreased in HFD mice at 2 weeks, but recovered at 10 weeks. CONCLUSION: Our results suggest that changes in the status of insulin resistance influence expression of BBB transporters, which in turn may alter the expression of cognitive function-related proteins.


Assuntos
Encéfalo/metabolismo , Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina , Insulina/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/irrigação sanguínea , Capilares/metabolismo , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Filamentos Intermediários/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Proteômica , Proteínas de Junções Íntimas/metabolismo
10.
Pharm Res ; 36(9): 131, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31263962

RESUMO

PURPOSE: Intranasal administration has been extensively applied to deliver drugs to the brain. In spite of its unfavorable biopharmaceutic properties, melatonin (MLT) has demonstrated anticancer effects against glioblastoma. This study describes the nose-to-brain delivery of MLT-loaded polycaprolactone nanoparticles (MLT-NP) for the treatment of glioblastoma. METHODS: MLT-NP were prepared by nanoprecipitation. Following intranasal administration in rats, brain targeting of the formulation was demonstrated by fluorescence tomography. Brain and plasma pharmacokinetic profiles were analyzed. Cytotoxicity against U87MG glioblastoma cells and MRC-5 non-tumor cells was evaluated. RESULTS: MLT-NP increased the drug apparent water solubility ~35 fold. The formulation demonstrated strong activity against U87MG cells, resulting in IC50 ~2500 fold lower than that of the free drug. No cytotoxic effect was observed against non-tumor cells. Fluorescence tomography images evidenced the direct translocation of nanoparticles from nasal cavity to the brain. Intranasal administration of MLT-NP resulted in higher AUCbrain and drug targeting index compared to the free drug by either intranasal or oral route. CONCLUSIONS: Nanoencapsulation of MLT was crucial for the selective antitumoral activity against U87MG. In vivo evaluation confirmed nose-to-brain delivery of MLT mediated by nanoparticles, highlighting the formulation as a suitable approach to improve glioblastoma therapy.


Assuntos
Antineoplásicos/farmacocinética , Encéfalo/metabolismo , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Melatonina/farmacocinética , Nanopartículas/química , Poliésteres/química , Administração Intranasal , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Humanos , Concentração Inibidora 50 , Masculino , Melatonina/administração & dosagem , Ratos Wistar , Solubilidade , Distribuição Tecidual
11.
Yakugaku Zasshi ; 139(7): 1007-1013, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31257247

RESUMO

α-Synuclein (αS) is the major component of the filamentous inclusions that constitute the defining characteristic of neurodegenerative synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. αS is deposited in a hyperphosphorylated and ubiquitinated form with a ß-sheet-rich fibrillar structure in diseased brains. In 2008, some researchers reported that embryonic neurons transplanted into Parkinson's disease brains had Lewy body-like pathologies, suggesting that pathological αS propagates from diseased neurons to young neurons. Subsequently, a growing body of evidence supported the cell-to-cell spread of αS pathologies. Recent studies have revealed that intracerebral injection of insoluble αS into wild-type mice can induce prion-like propagation of phosphorylated αS pathology even 1 month after injection, while injection into αS-knockout mice failed to induce any pathology. We also showed that intracerebral injection of insoluble αS into adult common marmoset brains results in the spreading of abundant αS pathology. These in vivo experiments clearly indicate that insoluble αS has prion-like properties and that it propagates through neural networks. The underlying mechanisms of αS propagation are still poorly understood, but αS propagation model animals could be helpful in elucidating the pathogenetic mechanisms and developing drugs for synucleinopathies.


Assuntos
Doenças Neurodegenerativas/metabolismo , Agregação Patológica de Proteínas , alfa-Sinucleína/metabolismo , Animais , Encéfalo/metabolismo , Callithrix , Humanos , Doença por Corpos de Lewy , Camundongos , Doenças Neurodegenerativas/etiologia , Doença de Parkinson , Fosforilação , Príons
12.
Yakugaku Zasshi ; 139(7): 1021-1025, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31257249

RESUMO

Abnormal proteins such as tau or α-synuclein that accumulate in brains with dementia have been shown to propagate like prion proteins. However, the expression patterns of tau in the mouse brain are different from those in humans, and the pathogenesis in the animal model of abnormal tau propagation remains incompletely understood. To overcome this problem, a novel mouse showing tau expression patterns similar to those of humans was developed using genome editing techniques. We inoculated the brain of this mouse with a sarkosyl-insoluble fraction containing abnormal tau derived from tauopathy patients and examined the accumulation of tau pathologies. We also performed a detailed analysis of the relationship between the inoculation site and the sites where tau accumulates abnormally by histochemical and neuronal circuitry and elucidated the propagation mechanism of the abnormally accumulated protein. This research is expected to lead to the development of novel drugs for the treatment of dementia using the innovative approach of "inhibition of abnormal protein propagation".


Assuntos
Encéfalo/metabolismo , Proteínas tau/metabolismo , Animais , Demência/tratamento farmacológico , Demência/metabolismo , Modelos Animais de Doenças , Descoberta de Drogas , Edição de Genes , Humanos , Camundongos , Proteínas Priônicas , Agregação Patológica de Proteínas , Tauopatias
13.
Yakugaku Zasshi ; 139(7): 999-1005, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31257259

RESUMO

Pathological α-synuclein (αSyn) has been shown to retain the ability to propagate as prions in humans and animals. However, the molecular basis underlying the prion-like properties of αSyn remains poorly understood. We examined whether brain tissues from cases of dementia with Lewy bodies (DLB), which contain serine 129 (Ser129)-phosphorylated insoluble aggregates of αSyn, exhibit prion-like seeding activity in vitro using the real-time quaking-induced conversion (RT-QuIC) seeding assay. Brain tissues from cases of diffuse neocortical DLB yielded a 50% seeding dose of 107.3-109.8/g brain. The RT-QuIC assay could discriminate between DLB and other neurological and neurodegenerative disorders, suggesting its potential applicability for differential diagnosis. Insoluble aggregates of αSyn>250 kDa detected only in DLB brain tissues by Western blotting analysis were specifically phosphorylated at Ser129. Therefore, we postulated that Ser129-phosphorylated insoluble aggregates of αSyn have prion-like seeding activity. However, insoluble aggregates of recombinant human αSyn (rSyn) with increased ß-sheet structures showed little seeding activity in either the phosphorylated or nonphosphorylated state. In contrast, prefibrillar oligomers of rSyn showed seeding activity both with and without phosphorylation. The findings of the present study suggested that soluble oligomeric αSyn, but not the fully fibrillary form, is a seeding species in vitro.


Assuntos
Encéfalo/metabolismo , Agregação Patológica de Proteínas , alfa-Sinucleína/metabolismo , Humanos , Técnicas In Vitro , Doença por Corpos de Lewy/genética , Doença por Corpos de Lewy/metabolismo , Príons/metabolismo , Dobramento de Proteína
14.
Toxicol Lett ; 314: 43-52, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31310794

RESUMO

Thioredoxin is an evolutionarily conserved antioxidant protein that plays a crucial role for fundamental cellular processes and embryonic development. Growing evidence support that Thioredoxin influences cellular response to chemicals insults, particularly those accompanying oxidative stress. The mechanisms underlying the functions of Thioredoxin1 in the embryonic development under the environmental toxicant exposure remain, however, largely unexplored. We report here that thioredoxin1 becomes differentially expressed in zebrafish embryos after exposure to 9 out of 11 environmental chemicals. In situ gene expression analysis show that thioredoxin1 is expressed in neurons, olfactory epithelia, liver and swim bladder under normal conditions. After MeHg exposure, however, thioredoxin1 is ectopically induced in the hair cells of the lateral line and in epithelia cells of the pharynx. Knockdown of Thioredoxin1 induces hydrocephalus and increases cell apoptosis in the brain ventricular epithelia cells. In comparison with 5% malformation in embryos injected with control morpholino, MeHg induces more than 77% defects in Thioredoxin1 knockdown embryos. Our data suggest that there is an association between hydrocephalus and Thioredoxin1 malfunction in embryonic development, and provide valuable information to elucidate the protective role of Thioredoxin1 against chemicals disruption.


Assuntos
Encéfalo/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Hidrocefalia/induzido quimicamente , Tiorredoxinas/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/metabolismo , Animais , Animais Geneticamente Modificados , Apoptose/efeitos dos fármacos , Encéfalo/embriologia , Encéfalo/metabolismo , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Embrião não Mamífero/patologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Regulação da Expressão Gênica no Desenvolvimento , Hidrocefalia/embriologia , Hidrocefalia/genética , Hidrocefalia/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Tiorredoxinas/genética , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética
15.
Pharm Res ; 36(9): 134, 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31297653

RESUMO

PURPOSE: Despite extensive preclinical investigations, in-vivo properties and formulation characteristics that improve CNS drug delivery following systemic dosing of nanoemulsions remain incompletely understood. METHODS: The CNS targeting potential of systemically administered nanoemulsions was evaluated by formulating rapamycin containing fish oil nanoemulsions, and testing the combined effect of formulation characteristics such as the circulation half-life and particle size distribution, on CNS delivery of rapamycin containing fish oil nanoemulsions in mice. RESULTS: Results generated with rapamycin nanoemulsions suggested that circulation half-life and particle size distribution did not impact the brain targeting efficiency of rapamycin containing fish oil nanoemulsions. Further, in the absence of any improvement in the systemic exposures of rapamycin, nanoemulsions did not outperform their aqueous counterpart with respect to the extent of CNS drug delivery. CONCLUSIONS: Our findings confirm that BBB penetration, which primarily depends on intrinsic drug-related properties, may not be significantly improved following encapsulation of drugs in nanoemulsions. Graphical Abstract The CNS targeting potential of systemically administered nanoemulsions was investigated by formulating various rapamycin containing fish oil nanoemulsions associated with different formulation characteristics such as the circulation half-life and particle size distribution. The targeting efficiency (TE) defined as the ratio of the brain exposures to the accompanying systemic exposures of rapamycin was estimated for each formulation following IV dosing in mice.


Assuntos
Encéfalo/metabolismo , Óleos de Peixe/química , Nanopartículas/química , Sirolimo/administração & dosagem , Animais , Barreira Hematoencefálica/metabolismo , Permeabilidade da Membrana Celular , Emulsões , Camundongos , Tamanho da Partícula , Polietilenoglicóis/química , Sirolimo/farmacocinética , Distribuição Tecidual
16.
Genome Biol ; 20(1): 135, 2019 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-31288836

RESUMO

BACKGROUND: The importance of cell type-specific epigenetic variation of non-coding regions in neuropsychiatric disorders is increasingly appreciated, yet data from disease brains are conspicuously lacking. We generate cell type-specific whole-genome methylomes (N = 95) and transcriptomes (N = 89) from neurons and oligodendrocytes obtained from brain tissue of patients with schizophrenia and matched controls. RESULTS: The methylomes of the two cell types are highly distinct, with the majority of differential DNA methylation occurring in non-coding regions. DNA methylation differences between cases and controls are subtle compared to cell type differences, yet robust against permuted data and validated in targeted deep-sequencing analyses. Differential DNA methylation between control and schizophrenia tends to occur in cell type differentially methylated sites, highlighting the significance of cell type-specific epigenetic dysregulation in a complex neuropsychiatric disorder. CONCLUSIONS: Our results provide novel and comprehensive methylome and transcriptome data from distinct cell populations within patient-derived brain tissues. This data clearly demonstrate that cell type epigenetic-differentiated sites are preferentially targeted by disease-associated epigenetic dysregulation. We further show reduced cell type epigenetic distinction in schizophrenia.


Assuntos
Encéfalo/metabolismo , Metilação de DNA , Epigênese Genética , Esquizofrenia/genética , Encéfalo/citologia , Estudos de Casos e Controles , Humanos , Esquizofrenia/metabolismo
17.
Zhonghua Nei Ke Za Zhi ; 58(7): 501-507, 2019 Jul 01.
Artigo em Chinês | MEDLINE | ID: mdl-31269566

RESUMO

Objective: To evaluate the clinical manifestations, metal metabolism, imaging characteristics and treatment response in patients with delayed Wilson disease (WD). Methods: Patients with untreated WD (40 with delayed onset and 40 with non-delayed onset) were enrolled. Twenty healthy people were included as normal controls. All patients were evaluated with modified Young scale neural symptom scores, grade of Child liver function and mental symptoms rating scale, magnetic resonance imaging (MRI) scan, magnetic sensitive imaging (susceptibility weighted imaging, SWI), metal metabolism. Corrected phase (CP) was measured at SWI. After 2 week treatment, neurologic symptoms, liver function, and metal metabolism were reviewed. Results: The total score of neurological symptoms in WD patients with delayed onset was lower than that of non-delayed onset (13.00±6.87 vs. 21.13±5.53, P=0.033). The scores of SCL-90 and HAMA depression scales in patients with delayed onset were lower than those of non-delayed onset. On T(2) weighted imaging, areas including substantia nigra and thalamus, the caudate nucleus, globus pallidus, putamen presented high signal rate in patients with delated onset than those with non-delayed (P=0.022, 0.037, 0.022, 0.037, 0.029 respectively). The SWI CP values of cangbai sphere and shell nucleus in patients with delayed onset were lower than those with non-delayed onset. Patients with delayed onset had higher urinary copper than those with non-delayed onset before and after treatment (P=0.040, 0.036). After treatment, the score of abnormal tremor and gait in patients with delayed onset was decreased (P=0.037, 0.044), while as the occurrence of neurological symptoms was increased by 10%, and the liver function level in patients with delayed WD was decreased in 3 cases. Conclusions: The brain of WD patients with delayed onset is mainly composed of metal deposits, however the cell damage is not apparent. Clinical symptoms are characterized by significant liver injury, but relatively mild neurological and psychiatric symptoms. Patients with delayed WD have higher urinary copper excretion than those with non-delayed WD. Chelating agents improves the neurological symptoms in patients with delayed onset.


Assuntos
Encéfalo/diagnóstico por imagem , Cobre/metabolismo , Degeneração Hepatolenticular/patologia , Encéfalo/metabolismo , Estudos de Casos e Controles , Criança , Cobre/urina , Degeneração Hepatolenticular/metabolismo , Humanos , Imagem por Ressonância Magnética , Tálamo
18.
J Biol Regul Homeost Agents ; 33(4): 1023-1040, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31309816

RESUMO

Viral dsRNA acts as the paramount pathogen-associated molecular pattern on infection and orchestrates inflammation or immune cascades of the host's tissues. The comparative effects or mechanisms of inflammation or immunity in different organs on viral infections are critical in immunology or virology. To outline the organ-based molecular mechanisms of inflammation or immunity on viral infection, we challenged mice with the viral mimic poly(I:C) and quantified inflammatory cytokines Il-1b and TNF-α in the brain and lung tissues. As cytokines showed differential expression, transcriptome screenings of mouse lung and brain tissues were analyzed. We identified 629 differentially expressed genes (DEGs) in lung and 137 DEGs in brain tissues with a few overlapping genes. Most of those DEGs were interferon-stimulated genes (ISGs) that are involved in the anti-viral defense mechanisms. The expression patterns of viral dsRNA stimulated genes, and consequently, their association with different molecular mechanisms of inflammation and immunity were specific to the organs. The effects of viral mimic were higher in the lung than in the brain in terms of the number of DEGs and ISGs. Interestingly ribosomal protein L29 (Rpl29), a cell surface heparin-binding protein, was upregulated in the brain and downregulated in the lung. The contrasting expression of Rpl29 gene might be responsible for tissue-specific inflammatory responses in lung and brain tissue on virus infection. In addition, the upregulation of Tlr13, a dsRNA and bacterial 23s rRNA receptor, in the poly(I:C)-stimulated mouse lungs suggests its important role in lung inflammatory responses. It is likely that the combined effects of these genes orchestrate the organ-specific inflammatory or immune responses. Our findings would be beneficial to explore new insights in inflammation and immunity against many critical viral diseases.


Assuntos
Encéfalo/patologia , Inflamação/metabolismo , Pulmão/patologia , Proteínas Ribossômicas/metabolismo , Receptores Toll-Like/metabolismo , Animais , Encéfalo/metabolismo , Citocinas/metabolismo , Inflamação/patologia , Pulmão/metabolismo , Camundongos
19.
Gene ; 714: 143996, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31348980

RESUMO

The uniquely human α7-nAChR gene (CHRFAM7A) is evolved from the fusion of two partially duplicated genes, FAM7 and α7-nAChR gene (CHRNA7), and is inserted on same chromosome 15, 5' end of the CHRNA7 gene. Transcription of CHRFAM7A gene produces a 1256-bp open reading frame encoding dup-α7-nAChR, where a 27-aminoacid residues from FAM7 replaced the 146-aminoacid residues of the N-terminal extracellular ligand binding domain of α7-nAChR. In vitro, dup-α7-nAChR has been shown to form hetero-pentamer with α7-nAChR and dominant-negatively regulates the channel functions of α7-nAChR. However, the contribution of CHRFAM7A gene to the biology of α7-nAChR in the brain in vivo remains largely a matter of conjecture. CHRFAM7A transgenic mouse was created and differentially expressed proteins were profiled from the whole brain using iTRAQ-2D-LC-MS/MS proteomic technology. Proteins with a fold change of ≥1.2 or ≤0.83 and p < 0.05 were considered to be significant. Bioinformatics analysis showed that over-expression of the CHRFAM7A gene significantly modulated the proteins commonly involved in the signaling pathways of α7-nAChR-mediated neuropsychiatric disorders including Parkinson's disease, Alzheimer's disease, Huntington's disease, and alcoholism, suggesting that the CHRFAM7A gene contributes to the pathogenesis of neuropsychiatric disorders mostly likely through fine-tuning the functions of α7-nAChR in the brain.


Assuntos
Camundongos Transgênicos/genética , Receptor Nicotínico de Acetilcolina alfa7/genética , Animais , Encéfalo/metabolismo , Cromatografia Líquida/métodos , Cromossomos Humanos Par 15/genética , Perfilação da Expressão Gênica/métodos , Genes Duplicados/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteômica/métodos , Transdução de Sinais/genética , Espectrometria de Massas em Tandem/métodos
20.
Biomed Environ Sci ; 32(7): 496-507, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31331434

RESUMO

OBJECTIVE: To explore the dynamic impacts of simulated microgravity (SM) on different vital brain regions of rats. METHODS: Microgravity was simulated for 7 and 21 days, respectively, using the tail-suspension rat model. Histomorphology, oxidative stress, inflammatory cytokines and the expression of some key proteins were determined in hippocampus, cerebral cortex and striatum. RESULTS: 21-day SM decreased brain derived neurotrophic factor and induced neuron atrophy in the cerebral cortex. Strong oxidative stress was triggered at day 7 and the oxidative status returned to physiological level at day 21. Inflammatory cytokines were gradually suppressed and in striatum, the suppression was regulated partially through c-Jun/c-Fos. CONCLUSION: The results revealed that the significant impacts of SM on rat brain tissue depended on durations and regions, which might help to understand the health risk and to prevent brain damage for astronauts in space travel.


Assuntos
Encéfalo/metabolismo , Citocinas/metabolismo , Simulação de Ausência de Peso , Animais , Encéfalo/patologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Masculino , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Distribuição Aleatória , Ratos
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