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1.
Science ; 368(6496)2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32527803

RESUMO

Regulation of neurotransmitter receptor content at synapses is achieved through a dynamic equilibrium between biogenesis and degradation pathways, receptor stabilization at synaptic sites, and receptor trafficking in and out synapses. In the past 20 years, the movements of receptors to and from synapses have emerged as a series of highly regulated processes that mediate postsynaptic plasticity. Our understanding of the properties and roles of receptor movements has benefited from technological advances in receptor labeling and tracking capacities, as well as from new methods to interfere with their movements. Focusing on two key glutamatergic receptors, we review here our latest understanding of the characteristics of receptor movements and their role in tuning the efficacy of synaptic transmission in health and brain disease.


Assuntos
Receptores de Glutamato/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/fisiologia , Transmissão Sináptica , Encefalopatias/metabolismo , Humanos , Plasticidade Neuronal , Ácido gama-Aminobutírico/fisiologia
2.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(1): 20-25, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-32314720

RESUMO

Objective To investigate the role of CXCR2 in the cerebral endothelial activation and migration of neutrophils into the brain in septic encephalopathy (SE) induced by lipopolysaccharide (LPS). Methods C57BL/6J mice and CXCR2-knockout mice were randomly divided into a normal control group, a wildtype mice group with LPS treatment and CXCR2-knockout mice group with LPS treatment. Mouse SE models were induced by intraperitoneal LPS injection. Naphthol AS-D chloroacetate histochemical staining of the brain section was performed to quantitate the neutrophils infiltrating into the cerebral cortex. TNF-α and CXCL1 concentrations in the brain and plasma were determined by ELISA. After the stimulation of LPS (1 µg/mL) and TNF-α (200 ng/mL), the levels of CXCR2 protein in the primary mouse brain microvascular endothelial cells isolated from the cerebral cortex were detected by Western blotting. The levels of F-actin and vascular cell adhesion molecule 1 (VCAM-1) protein in the primary mouse brain microvascular endothelial cells stimulated by CXCL1 (100 ng/mL) were detected by Western blotting. Results After intraperitoneal LPS injection, there was a significant increase in the level of TNF-α in the brain and plasma and there was also an evident increase in the level of CXCL1 in the brain of wild type mice (C57BL/6J mice). And intraperitoneal LPS injection caused increased neutrophil infiltration into the cerebral cortex in the wild type mice (C57BL/6J mice). But CXCR2-knockout mice displayed evidently reduced neutrophil infiltration into the cerebral cortex compared with the wildtype mice. In vitro LPS and TNF-α upregulated the expression of CXCR2 in the primary brain microvascular endothelial cells. CXCL1 increased remarkably the expression of endothelial F-actin and VCAM-1. Conclusion In the SE model, CXCR2 participates in the cerebral endothelial activation and neutrophil migration into the brain.


Assuntos
Encefalopatias/metabolismo , Movimento Celular , Células Endoteliais/citologia , Neutrófilos/citologia , Receptores de Interleucina-8B/metabolismo , Sepse/metabolismo , Actinas/metabolismo , Animais , Encefalopatias/patologia , Lipopolissacarídeos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Distribuição Aleatória , Sepse/patologia , Molécula 1 de Adesão de Célula Vascular/metabolismo
3.
Nat Neurosci ; 23(4): 583-593, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32152537

RESUMO

Most risk variants for brain disorders identified by genome-wide association studies reside in the noncoding genome, which makes deciphering biological mechanisms difficult. A commonly used tool, multimarker analysis of genomic annotation (MAGMA), addresses this issue by aggregating single nucleotide polymorphism associations to nearest genes. Here we developed a platform, Hi-C-coupled MAGMA (H-MAGMA), that advances MAGMA by incorporating chromatin interaction profiles from human brain tissue across two developmental epochs and two brain cell types. By analyzing gene regulatory relationships in the disease-relevant tissue, H-MAGMA identified neurobiologically relevant target genes. We applied H-MAGMA to five psychiatric disorders and four neurodegenerative disorders to interrogate biological pathways, developmental windows and cell types implicated for each disorder. Psychiatric-disorder risk genes tended to be expressed during mid-gestation and in excitatory neurons, whereas neurodegenerative-disorder risk genes showed increasing expression over time and more diverse cell-type specificities. H-MAGMA adds to existing analytic frameworks to help identify the neurobiological principles of brain disorders.


Assuntos
Encefalopatias/genética , Encéfalo/metabolismo , Cromatina/metabolismo , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Encefalopatias/metabolismo , Genômica , Humanos , Fatores de Risco
4.
Am J Hum Genet ; 106(2): 272-279, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32004445

RESUMO

Recent studies have identified both recessive and dominant forms of mitochondrial disease that result from ATAD3A variants. The recessive form includes subjects with biallelic deletions mediated by non-allelic homologous recombination. We report five unrelated neonates with a lethal metabolic disorder characterized by cardiomyopathy, corneal opacities, encephalopathy, hypotonia, and seizures in whom a monoallelic reciprocal duplication at the ATAD3 locus was identified. Analysis of the breakpoint junction fragment indicated that these 67 kb heterozygous duplications were likely mediated by non-allelic homologous recombination at regions of high sequence identity in ATAD3A exon 11 and ATAD3C exon 7. At the recombinant junction, the duplication allele produces a fusion gene derived from ATAD3A and ATAD3C, the protein product of which lacks key functional residues. Analysis of fibroblasts derived from two affected individuals shows that the fusion gene product is expressed and stable. These cells display perturbed cholesterol and mitochondrial DNA organization similar to that observed for individuals with severe ATAD3A deficiency. We hypothesize that the fusion protein acts through a dominant-negative mechanism to cause this fatal mitochondrial disorder. Our data delineate a molecular diagnosis for this disorder, extend the clinical spectrum associated with structural variation at the ATAD3 locus, and identify a third mutational mechanism for ATAD3 gene cluster variants. These results further affirm structural variant mutagenesis mechanisms in sporadic disease traits, emphasize the importance of copy number analysis in molecular genomic diagnosis, and highlight some of the challenges of detecting and interpreting clinically relevant rare gene rearrangements from next-generation sequencing data.


Assuntos
ATPases Associadas a Diversas Atividades Celulares/genética , Colesterol/metabolismo , Duplicação Gênica , Recombinação Homóloga , Proteínas de Membrana/genética , Mitocôndrias/patologia , Doenças Mitocondriais/patologia , Proteínas Mitocondriais/genética , ATPases Associadas a Diversas Atividades Celulares/química , Sequência de Aminoácidos , Encefalopatias/etiologia , Encefalopatias/metabolismo , Encefalopatias/patologia , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Opacidade da Córnea/etiologia , Opacidade da Córnea/metabolismo , Opacidade da Córnea/patologia , Variações do Número de Cópias de DNA , Feminino , Rearranjo Gênico , Humanos , Lactente , Recém-Nascido , Masculino , Proteínas de Membrana/química , Mitocôndrias/genética , Mitocôndrias/metabolismo , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , Proteínas Mitocondriais/química , Hipotonia Muscular/etiologia , Hipotonia Muscular/metabolismo , Hipotonia Muscular/patologia , Mutação , Conformação Proteica , Convulsões/etiologia , Convulsões/metabolismo , Convulsões/patologia , Homologia de Sequência
5.
Crit Rev Food Sci Nutr ; 60(3): 351-374, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30614244

RESUMO

Brain is a central and pivotal organ of human body containing the highest lipids content next to adipose tissue. It works as a monitor for the whole body and needs an adequate supply of energy to maintain its physiological activities. This high demand of energy in the brain is chiefly maintained by the lipids along with its reservoirs. Thus, the lipid metabolism is also an important for the proper development and function of the brain. Being a prominent part of the brain, lipids play a vast number of physiological activities within the brain starting from the structural development, impulse conduction, insulation, neurogenesis, synaptogenesis, myelin sheath formation and finally to act as the signaling molecules. Interestingly, lipids bilayer also maintains the structural integrity for the physiological functions of protein. Thus, in light to all of these activities, lipids and its metabolism can be attributed pivotal for brain health and its activities. Decisively, the impaired/altered metabolism of lipids and its intermediates puts forward a key step in the progression of different brain ailments including neurodegenerative, neurological and neuropsychiatry disorders. Depending on their associated underlying pathways, they serve as the potential biomarkers of these disorders and are considered as necessary diagnostic tools. The present review discusses the role and level of altered lipids metabolism in brain diseases including neurodegenerative diseases, neurological diseases, and neuropsychiatric diseases. Moreover, the possible mechanisms of altered level of lipids and their metabolites have also been discussed in detail.


Assuntos
Encefalopatias/metabolismo , Metabolismo dos Lipídeos , Lipídeos/análise , Biomarcadores/análise , Biomarcadores/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Encefalopatias/patologia , Humanos
6.
Brain ; 143(2): 491-502, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31851307

RESUMO

Primary familial brain calcification is a monogenic disease characterized by bilateral calcifications in the basal ganglia and other brain regions, and commonly presents motor, psychiatric, and cognitive symptoms. Currently, four autosomal dominant (SLC20A2, PDGFRB, PDGFB, XPR1) and one autosomal recessive (MYORG) causative genes have been identified. Compared with patients with autosomal dominant primary familial brain calcification, patients with the recessive form of the disease present with more severe clinical and imaging phenotypes, and deserve more clinical and research attention. Biallelic mutations in MYORG cannot explain all autosomal recessive primary familial brain calcification cases, indicating the existence of novel autosomal recessive genes. Using homozygosity mapping and whole genome sequencing, we detected a homozygous frameshift mutation (c.140delT, p.L48*) in the JAM2 gene in a consanguineous family with two affected siblings diagnosed with primary familial brain calcification. Further genetic screening in a cohort of 398 probands detected a homozygous start codon mutation (c.1A>G, p.M1?) and compound heterozygous mutations [c.504G>C, p.W168C and c.(67+1_68-1)_(394+1_395-1), p.Y23_V131delinsL], respectively, in two unrelated families. The clinical phenotypes of the four patients included parkinsonism (3/4), dysarthria (3/4), seizures (1/4), and probable asymptomatic (1/4), with diverse onset ages. All patients presented with severe calcifications in the cortex in addition to extensive calcifications in multiple brain areas (lenticular nuclei, caudate nuclei, thalamus, cerebellar hemispheres, ± brainstem; total calcification scores: 43-77). JAM2 encodes junctional adhesion molecule 2, which is highly expressed in neurovascular unit-related cell types (endothelial cells and astrocytes) and is predominantly localized on the plasma membrane. It may be important in cell-cell adhesion and maintaining homeostasis in the CNS. In Chinese hamster ovary cells, truncated His-tagged JAM2 proteins were detected by western blot following transfection of p.Y23_V131delinsL mutant plasmid, while no protein was detected following transfection of p.L48* or p.1M? mutant plasmids. In immunofluorescence experiments, the p.W168C mutant JAM2 protein failed to translocate to the plasma membrane. We speculated that mutant JAM2 protein resulted in impaired cell-cell adhesion functions and reduced integrity of the neurovascular unit. This is similar to the mechanisms of other causative genes for primary familial brain calcification or brain calcification syndromes (e.g. PDGFRB, PDGFB, MYORG, JAM3, and OCLN), all of which are highly expressed and functionally important in the neurovascular unit. Our study identifies a novel causative gene for primary familial brain calcification, whose vital function and high expression in the neurovascular unit further supports impairment of the neurovascular unit as the root of primary familial brain calcification pathogenesis.


Assuntos
Encefalopatias/genética , Encéfalo/metabolismo , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Células Endoteliais/metabolismo , Adulto , Encéfalo/patologia , Encefalopatias/metabolismo , Calcinose/genética , Feminino , Genes Recessivos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/metabolismo , Linhagem , Fenótipo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo
7.
Int J Mol Sci ; 20(24)2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31817343

RESUMO

There is a huge demand for pro-/anti-angiogenic nanomedicines to treat conditions such as ischemic strokes, brain tumors, and neurodegenerative diseases such as Alzheimer's and Parkinson's. Nanomedicines are therapeutic particles in the size range of 10-1000 nm, where the drug is encapsulated into nano-capsules or adsorbed onto nano-scaffolds. They have good blood-brain barrier permeability, stability and shelf life, and able to rapidly target different sites in the brain. However, the relationship between the nanomedicines' physical and chemical properties and its ability to travel across the brain remains incompletely understood. The main challenge is the lack of a reliable drug testing model for brain angiogenesis. Recently, microfluidic platforms (known as "lab-on-a-chip" or LOCs) have been developed to mimic the brain micro-vasculature related events, such as vasculogenesis, angiogenesis, inflammation, etc. The LOCs are able to closely replicate the dynamic conditions of the human brain and could be reliable platforms for drug screening applications. There are still many technical difficulties in establishing uniform and reproducible conditions, mainly due to the extreme complexity of the human brain. In this paper, we review the prospective of LOCs in the development of nanomedicines for brain angiogenesis-related conditions.


Assuntos
Indutores da Angiogênese , Inibidores da Angiogênese , Barreira Hematoencefálica/metabolismo , Encefalopatias , Dispositivos Lab-On-A-Chip , Modelos Biológicos , Nanomedicina , Indutores da Angiogênese/química , Indutores da Angiogênese/farmacocinética , Indutores da Angiogênese/uso terapêutico , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacocinética , Inibidores da Angiogênese/uso terapêutico , Barreira Hematoencefálica/patologia , Encefalopatias/tratamento farmacológico , Encefalopatias/metabolismo , Encefalopatias/patologia , Avaliação Pré-Clínica de Medicamentos , Humanos , Nanomedicina/instrumentação , Nanomedicina/métodos , Permeabilidade
8.
Am J Hum Genet ; 105(6): 1126-1147, 2019 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-31735293

RESUMO

The redox state of the neural progenitors regulates physiological processes such as neuronal differentiation and dendritic and axonal growth. The relevance of endoplasmic reticulum (ER)-associated oxidoreductases in these processes is largely unexplored. We describe a severe neurological disorder caused by bi-allelic loss-of-function variants in thioredoxin (TRX)-related transmembrane-2 (TMX2); these variants were detected by exome sequencing in 14 affected individuals from ten unrelated families presenting with congenital microcephaly, cortical polymicrogyria, and other migration disorders. TMX2 encodes one of the five TMX proteins of the protein disulfide isomerase family, hitherto not linked to human developmental brain disease. Our mechanistic studies on protein function show that TMX2 localizes to the ER mitochondria-associated membranes (MAMs), is involved in posttranslational modification and protein folding, and undergoes physical interaction with the MAM-associated and ER folding chaperone calnexin and ER calcium pump SERCA2. These interactions are functionally relevant because TMX2-deficient fibroblasts show decreased mitochondrial respiratory reserve capacity and compensatory increased glycolytic activity. Intriguingly, under basal conditions TMX2 occurs in both reduced and oxidized monomeric form, while it forms a stable dimer under treatment with hydrogen peroxide, recently recognized as a signaling molecule in neural morphogenesis and axonal pathfinding. Exogenous expression of the pathogenic TMX2 variants or of variants with an in vitro mutagenized TRX domain induces a constitutive TMX2 polymerization, mimicking an increased oxidative state. Altogether these data uncover TMX2 as a sensor in the MAM-regulated redox signaling pathway and identify it as a key adaptive regulator of neuronal proliferation, migration, and organization in the developing brain.


Assuntos
Encefalopatias/patologia , Encéfalo/anormalidades , Deficiências do Desenvolvimento/patologia , Proteínas de Membrana/metabolismo , Mitocôndrias/metabolismo , Tiorredoxinas/metabolismo , Adolescente , Adulto , Encefalopatias/genética , Encefalopatias/metabolismo , Criança , Pré-Escolar , Estudos de Coortes , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/metabolismo , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Proteínas de Membrana/genética , Mitocôndrias/patologia , Oxirredução , Prognóstico , Pele/metabolismo , Pele/patologia , Tiorredoxinas/genética , Transcriptoma
9.
Int J Mol Sci ; 20(23)2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31771121

RESUMO

Neurological-related disorders are seen as an increasingly important aspect of welfare. While conventional medicine is still the mainstay for the treatment of these diseases, it is becoming apparent that patients are also seeking more natural and preventative interventions. Panax ginseng G115® and Ginkgo biloba GK501® extracts alone or in combination were used in two in vitro experimental models of primary cultures exposed to excitotoxicity: rat organotypic hippocampal slices exposed to either 5 µM kainic acid or 10 µM N-Methyl-d-aspartate for 24 hours, and mixed cortical cells exposed to 300 µM NMDA for 10 min. Cell death in the Cornu Ammonis areas CA3 or CA1 subregions of slices was quantified by measuring propidium iodide fluorescence, whereas in cortical cells, it was assessed by measuring the amount of lactate dehydrogenase. In slices, treatment with extracts alone or in combination significantly attenuated CA3 and CA1 damage induced by exposure to kainic acid or NMDA, respectively. A similar neuroprotective effect was observed in cortical cells exposed to NMDA. Analysis of cell signaling pathways found that the two extracts induced an increase of the phosphorylation and they reversed the decrease of phosphorylation of ERK1/2 and Akt induced by kainic acid and NMDA in organotypic hippocampal slices. These results suggest that P. ginseng G115® and G. biloba GK501® extracts may mediate their effects by activating phosphorylation of ERK1/2 and Akt signaling pathways, protecting against excitotoxicity-induced damage in in vitro models.


Assuntos
Encefalopatias , Ginkgo biloba/química , Fármacos Neuroprotetores , Panax/química , Extratos Vegetais , Animais , Encefalopatias/induzido quimicamente , Encefalopatias/tratamento farmacológico , Encefalopatias/metabolismo , Encefalopatias/patologia , Modelos Animais de Doenças , Feminino , Masculino , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ratos , Ratos Wistar
10.
Molecules ; 24(22)2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31752279

RESUMO

The discovery of endogenous peptide ligands for morphine binding sites occurred in parallel with the identification of three subclasses of opioid receptor (OR), traditionally designated as µ, δ, and κ, along with the more recently defined opioid-receptor-like (ORL1) receptor. Early efforts in opioid receptor radiochemistry focused on the structure of the prototype agonist ligand, morphine, although N-[methyl-11C]morphine, -codeine and -heroin did not show significant binding in vivo. [11C]Diprenorphine ([11C]DPN), an orvinol type, non-selective OR antagonist ligand, was among the first successful PET tracers for molecular brain imaging, but has been largely supplanted in research studies by the µ-preferring agonist [11C]carfentanil ([11C]Caf). These two tracers have the property of being displaceable by endogenous opioid peptides in living brain, thus potentially serving in a competition-binding model. Indeed, many clinical PET studies with [11C]DPN or [11C]Caf affirm the release of endogenous opioids in response to painful stimuli. Numerous other PET studies implicate µ-OR signaling in aspects of human personality and vulnerability to drug dependence, but there have been very few clinical PET studies of µORs in neurological disorders. Tracers based on naltrindole, a non-peptide antagonist of the δ-preferring endogenous opioid enkephalin, have been used in PET studies of δORs, and [11C]GR103545 is validated for studies of κORs. Structures such as [11C]NOP-1A show selective binding at ORL-1 receptors in living brain. However, there is scant documentation of δ-, κ-, or ORL1 receptors in healthy human brain or in neurological and psychiatric disorders; here, clinical PET research must catch up with recent progress in radiopharmaceutical chemistry.


Assuntos
Imagem Molecular , Receptores Opioides/metabolismo , Animais , Biomarcadores , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encefalopatias/diagnóstico por imagem , Encefalopatias/etiologia , Encefalopatias/metabolismo , Humanos , Ligantes , Transtornos Mentais/diagnóstico por imagem , Transtornos Mentais/etiologia , Transtornos Mentais/metabolismo , Imagem Molecular/métodos , Neuroimagem/métodos , Peptídeos/química , Peptídeos/metabolismo , Tomografia por Emissão de Pósitrons , Traçadores Radioativos , Receptores Opioides/agonistas , Receptores Opioides/química
11.
Int J Mol Sci ; 20(22)2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31726793

RESUMO

Excitatory amino acid transporters (EAATs) encompass a class of five transporters with distinct expression in neurons and glia of the central nervous system (CNS). EAATs are mainly recognized for their role in uptake of the amino acid glutamate, the major excitatory neurotransmitter. EAATs-mediated clearance of glutamate released by neurons is vital to maintain proper glutamatergic signalling and to prevent toxic accumulation of this amino acid in the extracellular space. In addition, some EAATs also act as chloride channels or mediate the uptake of cysteine, required to produce the reactive oxygen speciesscavenger glutathione. Given their central role in glutamate homeostasis in the brain, as well as their additional activities, it comes as no surprise that EAAT dysfunctions have been implicated in numerous acute or chronic diseases of the CNS, including ischemic stroke and epilepsy, cerebellar ataxias, amyotrophic lateral sclerosis, Alzheimer's disease and Huntington's disease. Here we review the studies in cellular and animal models, as well as in humans that highlight the roles of EAATs in the pathogenesis of these devastating disorders. We also discuss the mechanisms regulating EAATs expression and intracellular trafficking and new exciting possibilities to modulate EAATs and to provide neuroprotection in course of pathologies affecting the CNS.


Assuntos
Encefalopatias/metabolismo , Encefalopatias/fisiopatologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/fisiopatologia , Proteínas de Transporte de Glutamato da Membrana Plasmática/metabolismo , Transmissão Sináptica , Animais , Transporte Biológico , Encefalopatias/patologia , Sistema Nervoso Central/patologia , Humanos , Neurônios/metabolismo , Neurônios/patologia
12.
Curr Drug Metab ; 20(11): 855-866, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31631816

RESUMO

BACKGROUND: Monocarboxylate Transporter 1 (MCT1), an important membrane transport protein, mediates the translocation of monocarboxylates together with protons across biological membranes. Due to its pathological significance, MCT1 plays an important role in the progression of some diseases, such as brain diseases and cancers. METHODS: We summarize the general description of MCT1 and provide a comprehensive understanding of the role of MCT1 in brain diseases and cancers. Furthermore, this review discusses the opportunities and challenges of MCT1- targeting drug-delivery systems in the treatment of brain diseases and cancers. RESULTS: In the brain, loss of MCT1 function is associated with pathologies of degeneration and injury of the nervous system. In tumors, MCT1 regulates the activity of signaling pathways and controls the exchange of monocarboxylates in aerobic glycolysis to affect tumor metabolism, proliferation and invasion. Meanwhile, MCT1 also acts as a good biomarker for the prediction and diagnosis of cancer progressions. CONCLUSION: MCT1 is an attractive transporter in brain diseases and cancers. Moreover, the development of MCT1- based small molecule drugs and MCT1 inhibitors in the clinic is promising. This review systematically summarizes the basic characteristics of MCT1 and its role in brain diseases and cancers, laying the foundation for further research on MCT1.


Assuntos
Encefalopatias/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Neoplasias/metabolismo , Simportadores/metabolismo , Encéfalo/metabolismo , Transportadores de Ácidos Monocarboxílicos/antagonistas & inibidores , Transportadores de Ácidos Monocarboxílicos/química , Transportadores de Ácidos Monocarboxílicos/fisiologia , Simportadores/antagonistas & inibidores , Simportadores/química , Simportadores/fisiologia
13.
Nutrients ; 11(10)2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31591353

RESUMO

Iron deficiency anemia (IDA) is one of the most prevalent nutritional deficiencies worldwide. Iron plays critical roles in nervous system development and cognition. Despite the known detrimental consequences of IDA on cognition, available studies do not provide molecular mechanisms elucidating the role of iron in brain functions during iron deficiency and recovery with dairy components. In this study, 100 male Wistar rats were placed on a pre-experimental period of 40 days and randomly divided in two groups: a control group receiving a normal-Fe diet, (45 mg/kg), and an Fe-deficient group receiving a low-Fe diet (5 mg/kg). At day 40, 10 rats per group were sacrificed to anemia control, and 80 rats were divided into eight experimental groups fed with fermented goat or cow milk-based diets, with normal Fe content or Fe overload (450 mg/kg) for 30 days. IDA decreased most of the parameters related to brain molecular functions, namely dopamine, irisin, MAO-A, oxytocin, ß-endorphin, and α-MSH, while it increased synaptophysin. These alterations result in an impairment of brain molecular functions. In general, during anemia recovery, fermented goat milk diet consumption increased dopamine, oxytocin, serotonin, synaptophysin, and α-MSH, and decreased MAO-A and MAO-B, suggesting a potential neuroprotective effect in brain functions, which could enhance brain molecular functions.


Assuntos
Anemia Ferropriva/dietoterapia , Encefalopatias/prevenção & controle , Encéfalo/metabolismo , Produtos Fermentados do Leite , Leite , Anemia Ferropriva/sangue , Anemia Ferropriva/fisiopatologia , Ração Animal , Animais , Biomarcadores/sangue , Encéfalo/fisiopatologia , Encefalopatias/metabolismo , Encefalopatias/fisiopatologia , Modelos Animais de Doenças , Cabras , Masculino , Ratos Wistar
15.
Int J Dev Neurosci ; 79: 21-31, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31629800

RESUMO

Docosahexaenoic acid,22:6n-3 (DHA) and its metabolites are vital for the structure and functional brain development of the fetus and infants, and also for maintenance of healthy brain function of adults. DHA is thought to be an essential nutrient required throughout the life cycle for the maintenance of overall brain health. The mode of actions of DHA and its derivatives at both cellular and molecular levels in the brain are emerging. DHA is the major prevalent fatty acid in the brain membrane. The brain maintains its fatty acid levels mainly via the uptake of plasma free fatty acids. Therefore, circulating plasma DHA is significantly related to cognitive abilities during ageing and is inversely associated with cognitive decline. The signaling pathways of DHA and its metabolites are involved in neurogenesis, antinociceptive effects, anti-apoptotic effect, synaptic plasticity, Ca2+ homeostasis in brain diseases, and the functioning of nigrostriatal activities. Mechanisms of action of DHA metabolites on various processes in the brain are not yet well known. Epidemiological studies support a link between low habitual intake of DHA and a higher risk of brain disorders. A diet characterized by higher intakes of foods containing high in n-3 fatty acids, and/or lower intake of n-6 fatty acids was strongly associated with a lower Alzheimer's Disease and other brain disorders. Supplementation of DHA improves some behaviors associated with attention deficit hyperactivity disorder, bipolar disorder, schizophrenia, and impulsive behavior, as well as cognition. Nevertheless, the outcomes of trials with DHA supplementation have been controversial. Many intervention studies with DHA have shown an apparent benefit in brain function. However, clinical trials are needed for definitive conclusions. Dietary deficiency of n-3 fatty acids during fetal development in utero and the postnatal state has detrimental effects on cognitive abilities. Further research in humans is required to assess a variety of clinical outcomes, including quality of life and mental status, by supplementation of DHA.


Assuntos
Envelhecimento/metabolismo , Encefalopatias/metabolismo , Encéfalo/metabolismo , Cognição/fisiologia , Ácidos Docosa-Hexaenoicos/metabolismo , Neurogênese/fisiologia , Animais , Ácidos Graxos/metabolismo , Humanos
16.
Hum Genet ; 138(11-12): 1247-1257, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31538237

RESUMO

The reversible oxidation of L-malate to oxaloacetate is catalyzed by NAD(H)-dependent malate dehydrogenase (MDH). MDH plays essential roles in the malate-aspartate shuttle and the tricarboxylic acid cycle. These metabolic processes are important in mitochondrial NADH supply for oxidative phosphorylation. Recently, bi-allelic mutations in mitochondrial MDH2 were identified in patients with global developmental delay, epilepsy and lactic acidosis. We now report two patients from an extended consanguineous family with a deleterious variant in the cytosolic isoenzyme of MDH (MDH1). The homozygous missense variant in the NAD+-binding domain of MDH1 led to severely diminished MDH protein expression. The patients presented with global developmental delay, epilepsy and progressive microcephaly. Both patients had normal concentrations of plasma amino acids, acylcarnitines, lactate, and urine organic acids. To identify the metabolic consequences of MDH1 deficiency, untargeted metabolomics was performed on dried blood spots (DBS) from the patients and in MDH1 knockout HEK293 cells that were generated by Crispr/Cas9. Increased levels of glutamate and glycerol-3-phosphate were found in DBS of both patients. In MDH1 KO HEK293 cells, increased levels of glycerol-3-phosphate were also observed, as well as increased levels of aspartate and decreased levels of fumarate. The consistent finding of increased concentrations of glycerol-3-phosphate may represent a compensatory mechanism to enhance cytosolic oxidation of NADH by the glycerol-P-shuttle. In conclusion, MDH1 deficiency is a new metabolic defect in the malate-aspartate shuttle characterized by a severe neurodevelopmental phenotype with elevated concentrations of glycerol-3-phosphate as a potential biomarker.


Assuntos
Ácido Aspártico/metabolismo , Encefalopatias/metabolismo , Encefalopatias/patologia , Malato Desidrogenase/deficiência , Malatos/metabolismo , Doenças Metabólicas/etiologia , Idade de Início , Encefalopatias/complicações , Pré-Escolar , Feminino , Humanos , Masculino , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Metaboloma , Linhagem
17.
Methods Mol Biol ; 2034: 69-80, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31392678

RESUMO

Microglia are the sole immune responding cells in the central nervous system. Their role as neuroimmune cells in the pathogenesis of various neurodegenerative and infectious diseases of the brain have been extensively studied. Upon brain disease and infection, they adopt an activated phenotype associated with the release of cytokines and neurotrophic factors and resulting in neuroprotective or neurotoxic outcomes. However, microglia are resident also in the healthy or physiological brain, but much less is known about their role(s) in the healthy brain, partly due to technical limitations regarding investigation of these highly reactive cells in the intact brain. Recent developments in molecular probes and in vivo optical imaging techniques has now helped to characterize microglia in the physiological or healthy brain. In vivo two-photon imaging of fluorescently labeled microglia have revealed that they are highly motile cells in the healthy brain, extending and retracting their processes that extend from a largely stationary cell soma. In this chapter, we briefly summarize some of the physiological functions of microglia in the uninjured brain, with a focus on interactions they have with synapses.


Assuntos
Encefalopatias , Infecções , Microglia , Sinapses , Animais , Encefalopatias/metabolismo , Encefalopatias/patologia , Humanos , Infecções/metabolismo , Infecções/patologia , Microglia/metabolismo , Microglia/patologia , Microscopia de Fluorescência por Excitação Multifotônica , Sinapses/metabolismo , Sinapses/patologia
18.
Physiol Rev ; 99(4): 1877-2013, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31460832

RESUMO

The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within and on our bodies) as one of the key regulators of gut-brain function and has led to the appreciation of the importance of a distinct microbiota-gut-brain axis. This axis is gaining ever more traction in fields investigating the biological and physiological basis of psychiatric, neurodevelopmental, age-related, and neurodegenerative disorders. The microbiota and the brain communicate with each other via various routes including the immune system, tryptophan metabolism, the vagus nerve and the enteric nervous system, involving microbial metabolites such as short-chain fatty acids, branched chain amino acids, and peptidoglycans. Many factors can influence microbiota composition in early life, including infection, mode of birth delivery, use of antibiotic medications, the nature of nutritional provision, environmental stressors, and host genetics. At the other extreme of life, microbial diversity diminishes with aging. Stress, in particular, can significantly impact the microbiota-gut-brain axis at all stages of life. Much recent work has implicated the gut microbiota in many conditions including autism, anxiety, obesity, schizophrenia, Parkinson's disease, and Alzheimer's disease. Animal models have been paramount in linking the regulation of fundamental neural processes, such as neurogenesis and myelination, to microbiome activation of microglia. Moreover, translational human studies are ongoing and will greatly enhance the field. Future studies will focus on understanding the mechanisms underlying the microbiota-gut-brain axis and attempt to elucidate microbial-based intervention and therapeutic strategies for neuropsychiatric disorders.


Assuntos
Bactérias/metabolismo , Encefalopatias/microbiologia , Encéfalo/microbiologia , Microbioma Gastrointestinal , Intestinos/microbiologia , Fatores Etários , Envelhecimento , Animais , Bactérias/imunologia , Bactérias/patogenicidade , Comportamento , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Encefalopatias/metabolismo , Encefalopatias/fisiopatologia , Encefalopatias/psicologia , Disbiose , Sistema Nervoso Entérico/metabolismo , Sistema Nervoso Entérico/microbiologia , Sistema Nervoso Entérico/fisiopatologia , Interações Hospedeiro-Patógeno , Humanos , Intestinos/imunologia , Neuroimunomodulação , Plasticidade Neuronal , Fatores de Risco
19.
Pediatrics ; 144(2)2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31324704

RESUMO

Idiopathic hyperammonemia is a rare complication with a high mortality rate that occurs in persons with hematologic malignancies or hematopoietic stem cell or solid organ transplant. Patients present with encephalopathy and hyperammonemia in the absence of liver disease or inborn errors of metabolism. Several etiologies have been proposed, including chemotherapeutic agents, medications, and a catabolic state with an elevated nitrogen load in the setting of acute illness. Recently, cases of hyperammonemia in adult lung transplant recipients have been attributed to infection from Ureaplasma parvum or U urealyticum Herein, we report a 12-year-old girl with acute myeloid leukemia and neutropenic fever who developed acute encephalopathy. Laboratory testing revealed severe hyperammonemia (blood ammonia level >1609 µmol/L) with normal liver function studies. U parvum was detected in blood, urine, and respiratory specimens by polymerase chain reaction testing. After antibiotic therapy directed against U parvum, blood ammonia levels normalized, the infection was eradicated, and the patient recovered. We propose that clinicians should test for invasive infection from Ureaplasma species in immunocompromised children with unexplained hyperammonemia.


Assuntos
Encefalopatias/diagnóstico , Hiperamonemia/diagnóstico , Hospedeiro Imunocomprometido , Infecções por Ureaplasma/diagnóstico , Ureaplasma , Encefalopatias/etiologia , Encefalopatias/metabolismo , Criança , Evolução Fatal , Feminino , Humanos , Hiperamonemia/etiologia , Hiperamonemia/metabolismo , Hospedeiro Imunocomprometido/fisiologia , Ureaplasma/isolamento & purificação , Infecções por Ureaplasma/complicações , Infecções por Ureaplasma/metabolismo
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