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1.
Biomater Sci ; 9(11): 4178-4190, 2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-33982040

RESUMO

The development and use of nanosystems is an emerging strategy for the diagnosis and treatment of a broad number of diseases, such as Alzheimer's disease (AD). Here, we developed a neurotheranostic nanosystem based on gold nanorods (GNRs) that works as a therapeutic peptide delivery system and can be detected in vivo for microcomputed tomography (micro-CT), being a diagnostic tool. GNRs functionalized with the peptides Ang2 (a shuttle to the Central Nervous System) and D1 (that binds to the Aß peptide, also inhibiting its aggregation) allowed detecting differences in vivo between wild type and AD mice (APPswe/PSEN1dE9) 15 minutes after a single dose by micro-CT. Moreover, after a recurrent treatment for one month with GNRs-D1/Ang2, we observed a diminution of amyloid load and inflammatory markers in the brain. Thus, this new designed nanosystem exhibits promising properties for neurotheranostics of AD.


Assuntos
Doença de Alzheimer , Nanotubos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Ouro , Camundongos , Camundongos Transgênicos , Microtomografia por Raio-X
2.
Nat Commun ; 12(1): 2878, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001886

RESUMO

Structural variations of the human brain are heritable and highly polygenic traits, with hundreds of associated genes identified in recent genome-wide association studies (GWAS). Transcriptome-wide association studies (TWAS) can both prioritize these GWAS findings and also identify additional gene-trait associations. Here we perform cross-tissue TWAS analysis of 211 structural neuroimaging and discover 278 associated genes exceeding Bonferroni significance threshold of 1.04 × 10-8. The TWAS-significant genes for brain structures have been linked to a wide range of complex traits in different domains. Through TWAS gene-based polygenic risk scores (PRS) prediction, we find that TWAS PRS gains substantial power in association analysis compared to conventional variant-based GWAS PRS, and up to 6.97% of phenotypic variance (p-value = 7.56 × 10-31) can be explained in independent testing data sets. In conclusion, our study illustrates that TWAS can be a powerful supplement to traditional GWAS in imaging genetics studies for gene discovery-validation, genetic co-architecture analysis, and polygenic risk prediction.


Assuntos
Encéfalo/metabolismo , Perfilação da Expressão Gênica/métodos , Pleiotropia Genética/genética , Estudo de Associação Genômica Ampla/métodos , Herança Multifatorial/genética , Encéfalo/diagnóstico por imagem , Estudos de Associação Genética/métodos , Predisposição Genética para Doença/genética , Humanos , Neuroimagem/métodos , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética
3.
Nat Commun ; 12(1): 2855, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001896

RESUMO

Ebola virus (EBOV) causes neurological symptoms yet its effects on the central nervous system (CNS) are not well-described. Here, we longitudinally assess the acute effects of EBOV on the brain, using quantitative MR-relaxometry, 18F-Fluorodeoxyglucose PET and immunohistochemistry in a monkey model. We report blood-brain barrier disruption, likely related to high cytokine levels and endothelial viral infection, with extravasation of fluid, Gadolinium-based contrast material and albumin into the extracellular space. Increased glucose metabolism is also present compared to the baseline, especially in the deep gray matter and brainstem. This regional hypermetabolism corresponds with mild neuroinflammation, sporadic neuronal infection and apoptosis, as well as increased GLUT3 expression, consistent with increased neuronal metabolic demands. Neuroimaging changes are associated with markers of disease progression including viral load and cytokine/chemokine levels. Our results provide insight into the pathophysiology of CNS involvement with EBOV and may help assess vaccine/treatment efficacy in real time.


Assuntos
Encéfalo/diagnóstico por imagem , Modelos Animais de Doenças , Fluordesoxiglucose F18 , Doença pelo Vírus Ebola/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Animais , Barreira Hematoencefálica/diagnóstico por imagem , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/virologia , Encéfalo/metabolismo , Encéfalo/virologia , Citocinas/metabolismo , Ebolavirus/fisiologia , Haplorrinos , Doença pelo Vírus Ebola/virologia , Interações Hospedeiro-Patógeno , Humanos
4.
Pestic Biochem Physiol ; 175: 104833, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33993958

RESUMO

Neurochemical and ATPase deregulations play important role in toxicant-induced neurodegeneration. Previous studies have shown that loss of ATPase ionic-pumps alters neurochemical balance via increased ammonia, oxidative and nitrosative stress. Thus, this study investigated the ameliorative potentials of quercetin on neurochemical, ATPase changes, hyperammonemia and oxidative/nitrosative status in the brains of Wistar rats exposed to endosulfan, a known toxic environmental pesticide that is casually used in many developing countries. Adult rats were divided into five treatment groups (n = 5). Groups 1-2 received normal saline and corn oil (vehicle) (10 mL/kg/day), group 3 received quercetin (20 mg/kg/day) orally for 28 days consecutively. However, animals in groups 4-5 were given endosulfan (5 mg/kg/day, p.o) for 28 days. But, from the 14th to 28th day, group 4 additionally received vehicle (10 mL/kg/day, p.o.), while group 5 was treated with quercetin (20 mg/kg/day, p.o.). Thereafter, brain levels of neurochemicals, ATPase activities, ammonia and oxidative/nitrosative stress were investigated by employing standardized biochemical assay protocols. Quercetin increased endosulfan-induced decreased levels of norepinephrine, dopamine, GABA, and decreased elevated concentrations of glutamate and serotonin. Quercetin normalized the increased levels of acetylcholinesterase and ammonia. Furthermore, quercetin significantly reversed the decrease in Na+/K+, Ca2+, Mg2+-ATPase activities induced by endosulfan. Also, quercetin increased superoxide dismutase, catalase and glutathione peroxidase activities, and reduced nitrite and peroxynitrite levels in brains of rats. These findings further provide evidence of the ameliorative potential of quercetin against endosulfan-induced neurotoxicity via attenuation of neurochemical, ATPase changes, and inhibition of acetylcholinesterase activity, ammonia release and oxidative/nitrosative stress in rat brains.


Assuntos
Estresse Nitrosativo , Quercetina , Adenosina Trifosfatases/metabolismo , Animais , Antioxidantes , Encéfalo/metabolismo , Catalase/metabolismo , Endossulfano/toxicidade , Estresse Oxidativo , Quercetina/farmacologia , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo
5.
Nat Commun ; 12(1): 2669, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976144

RESUMO

Transcriptomic atlases have improved our understanding of the correlations between gene-expression patterns and spatially varying properties of brain structure and function. Gene-category enrichment analysis (GCEA) is a common method to identify functional gene categories that drive these associations, using gene-to-category annotation systems like the Gene Ontology (GO). Here, we show that applying standard GCEA methodology to spatial transcriptomic data is affected by substantial false-positive bias, with GO categories displaying an over 500-fold average inflation of false-positive associations with random neural phenotypes in mouse and human. The estimated false-positive rate of a GO category is associated with its rate of being reported as significantly enriched in the literature, suggesting that published reports are affected by this false-positive bias. We show that within-category gene-gene coexpression and spatial autocorrelation are key drivers of the false-positive bias and introduce flexible ensemble-based null models that can account for these effects, made available as a software toolbox.


Assuntos
Encéfalo/metabolismo , Perfilação da Expressão Gênica/métodos , Ontologia Genética , Anotação de Sequência Molecular/métodos , Animais , Humanos , Masculino , Camundongos Endogâmicos C57BL , Reprodutibilidade dos Testes , Software
6.
Nat Commun ; 12(1): 2695, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976205

RESUMO

mTOR signaling, involving mTORC1 and mTORC2 complexes, critically regulates neural development and is implicated in various brain disorders. However, we do not fully understand all of the upstream signaling components that can regulate mTOR signaling, especially in neurons. Here, we show a direct, regulated inhibition of mTOR by Tanc2, an adaptor/scaffolding protein with strong neurodevelopmental and psychiatric implications. While Tanc2-null mice show embryonic lethality, Tanc2-haploinsufficient mice survive but display mTORC1/2 hyperactivity accompanying synaptic and behavioral deficits reversed by mTOR-inhibiting rapamycin. Tanc2 interacts with and inhibits mTOR, which is suppressed by mTOR-activating serum or ketamine, a fast-acting antidepressant. Tanc2 and Deptor, also known to inhibit mTORC1/2 minimally affecting neurodevelopment, distinctly inhibit mTOR in early- and late-stage neurons. Lastly, Tanc2 inhibits mTORC1/2 in human neural progenitor cells and neurons. In summary, our findings show that Tanc2 is a mTORC1/2 inhibitor affecting neurodevelopment.


Assuntos
Encéfalo/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Neurônios/metabolismo , Proteínas/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Células Cultivadas , Células HEK293 , Humanos , Imunossupressores/farmacologia , Deficiências da Aprendizagem/genética , Deficiências da Aprendizagem/fisiopatologia , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/genética , Transtornos da Memória/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/genética , Plasticidade Neuronal/fisiologia , Proteínas/genética , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia
7.
Nat Commun ; 12(1): 2698, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976215

RESUMO

Gut microbiome profoundly affects many aspects of host physiology and behaviors. Here we report that gut microbiome modulates aggressive behaviors in Drosophila. We found that germ-free males showed substantial decrease in inter-male aggression, which could be rescued by microbial re-colonization. These germ-free males are not as competitive as wild-type males for mating with females, although they displayed regular levels of locomotor and courtship behaviors. We further found that Drosophila microbiome interacted with diet during a critical developmental period for the proper expression of octopamine and manifestation of aggression in adult males. These findings provide insights into how gut microbiome modulates specific host behaviors through interaction with diet during development.


Assuntos
Agressão/fisiologia , Drosophila melanogaster/fisiologia , Microbioma Gastrointestinal/fisiologia , Octopamina/metabolismo , Comportamento Sexual Animal/fisiologia , Animais , Bactérias/classificação , Bactérias/genética , Encéfalo/citologia , Encéfalo/metabolismo , Encéfalo/fisiologia , Drosophila melanogaster/metabolismo , Drosophila melanogaster/microbiologia , Feminino , Microbioma Gastrointestinal/genética , Masculino , Atividade Motora/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , RNA Ribossômico 16S/genética , Transdução de Sinais/fisiologia , Organismos Livres de Patógenos Específicos
8.
Nat Commun ; 12(1): 2662, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976218

RESUMO

Central leptin action rescues type 1 diabetic (T1D) hyperglycemia; however, the underlying mechanism and the identity of mediating neurons remain elusive. Here, we show that leptin receptor (LepR)-expressing neurons in arcuate (LepRArc) are selectively activated in T1D. Activation of LepRArc neurons, Arc GABAergic (GABAArc) neurons, or arcuate AgRP neurons, is able to reverse the leptin's rescuing effect. Conversely, inhibition of GABAArc neurons, but not AgRP neurons, produces leptin-mimicking rescuing effects. Further, AgRP neuron function is not required for T1D hyperglycemia or leptin's rescuing effects. Finally, T1D LepRArc neurons show defective nutrient sensing and signs of cellular energy deprivation, which are both restored by leptin, whereas nutrient deprivation reverses the leptin action. Our results identify aberrant activation of LepRArc neurons owing to energy deprivation as the neural basis for T1D hyperglycemia and that leptin action is mediated by inhibiting LepRArc neurons through reversing energy deprivation.


Assuntos
Encéfalo/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Hiperglicemia/metabolismo , Leptina/metabolismo , Neurônios/metabolismo , Receptores para Leptina/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Proteína Relacionada com Agouti/metabolismo , Animais , Glicemia/metabolismo , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/sangue , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/metabolismo , Infusões Intraventriculares , Leptina/administração & dosagem , Masculino , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Receptores para Leptina/genética , Transdução de Sinais/efeitos dos fármacos
9.
Nat Commun ; 12(1): 2941, 2021 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-34011929

RESUMO

Myelin insulates neuronal axons and enables fast signal transmission, constituting a key component of brain development, aging and disease. Yet, myelin-specific imaging of macroscopic samples remains a challenge. Here, we exploit myelin's nanostructural periodicity, and use small-angle X-ray scattering tensor tomography (SAXS-TT) to simultaneously quantify myelin levels, nanostructural integrity and axon orientations in nervous tissue. Proof-of-principle is demonstrated in whole mouse brain, mouse spinal cord and human white and gray matter samples. Outcomes are validated by 2D/3D histology and compared to MRI measurements sensitive to myelin and axon orientations. Specificity to nanostructure is exemplified by concomitantly imaging different myelin types with distinct periodicities. Finally, we illustrate the method's sensitivity towards myelin-related diseases by quantifying myelin alterations in dysmyelinated mouse brain. This non-destructive, stain-free molecular imaging approach enables quantitative studies of myelination within and across samples during development, aging, disease and treatment, and is applicable to other ordered biomolecules or nanostructures.


Assuntos
Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/ultraestrutura , Bainha de Mielina/metabolismo , Bainha de Mielina/ultraestrutura , Tomografia Computadorizada por Raios X/métodos , Animais , Axônios/metabolismo , Axônios/ultraestrutura , Encéfalo/metabolismo , Encéfalo/ultraestrutura , Sistema Nervoso Central/diagnóstico por imagem , Pré-Escolar , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas da Mielina/metabolismo , Nanoestruturas/química , Nanoestruturas/ultraestrutura , Neuroimagem/métodos , Estudo de Prova de Conceito , Espalhamento a Baixo Ângulo , Medula Espinal/metabolismo , Medula Espinal/ultraestrutura
10.
Int J Mol Sci ; 22(9)2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33946947

RESUMO

The cation channel TRPV2 is known to be expressed by murine macrophages and is crucially involved in their functionality. Macrophages are frequent cells of the mouse testis, an immune-privileged and steroid-producing organ. TRPV2 expression by testicular macrophages and possible changes associated with age or inflammation have not been investigated yet. Therefore, we studied testes of young adult and old wild-type (WT) and AROM+ mice, i.e., transgenic mice overexpressing aromatase. In these animals, inflammatory changes are described in the testis, involving active macrophages, which increase with age. This is associated with impaired spermatogenesis and therefore AROM+ mice are a model for male infertility associated with sterile inflammation. In WT animals, testicular TRPV2 expression was mapped to interstitial CD206+ and peritubular MHC II+ macrophages, with higher levels in CD206+ cells. Expression levels of TRPV2 and most macrophage markers did not increase significantly in old mice, with the exception of CD206. As the number of TRPV2+ testicular macrophages was relatively small, their possible involvement in testicular functions and in aging in WT mice remains to be further studied. In AROM+ testis, TRPV2 was readily detected and levels increased significantly with age, together with macrophage markers and TNF-α. TRPV2 co-localized with F4/80 in macrophages and further studies showed that TRPV2 is mainly expressed by unusual CD206+MHC II+ macrophages, arising in the testis of these animals. Rescue experiments (aromatase inhibitor treatment and crossing with ERαKO mice) restored the testicular phenotype and also abolished the elevated expression of TRPV2, macrophage and inflammation markers. This suggests that TRPV2+ macrophages of the testis are part of an inflammatory cascade initiated by an altered sex hormone balance in AROM+ mice. The changes in testis are distinct from the described alterations in other organs of AROM+, such as prostate and spleen. When we monitored TRPV2 levels in another immune-privileged organ, namely the brain, we found that levels of TRPV2 were not elevated in AROM+ and remained stable during aging. In the adrenal, which similar to the testis produces steroids, we found slight, albeit not significant increases in TRPV2 in both AROM+ and WT mice, which were associated with age. Thus, the changes in the testis are specific for this organ.


Assuntos
Canais de Cálcio/fisiologia , Macrófagos/metabolismo , Orquite/metabolismo , Canais de Cátion TRPV/fisiologia , Testículo/metabolismo , Glândulas Suprarrenais/metabolismo , Fatores Etários , Animais , Aromatase/genética , Encéfalo/metabolismo , Canais de Cálcio/biossíntese , Canais de Cálcio/genética , Modelos Animais de Doenças , Genótipo , Infertilidade Masculina/metabolismo , Lectinas Tipo C/análise , Masculino , Lectinas de Ligação a Manose/análise , Camundongos , Camundongos Transgênicos , NADPH Oxidase 2/biossíntese , NADPH Oxidase 2/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptores de Superfície Celular/análise , Espermatogênese , Canais de Cátion TRPV/biossíntese , Canais de Cátion TRPV/genética , Fator de Necrose Tumoral alfa/biossíntese
11.
Proc Natl Acad Sci U S A ; 118(22)2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34001664

RESUMO

Comprehensive and accurate comparisons of transcriptomic distributions of cells from samples taken from two different biological states, such as healthy versus diseased individuals, are an emerging challenge in single-cell RNA sequencing (scRNA-seq) analysis. Current methods for detecting differentially abundant (DA) subpopulations between samples rely heavily on initial clustering of all cells in both samples. Often, this clustering step is inadequate since the DA subpopulations may not align with a clear cluster structure, and important differences between the two biological states can be missed. Here, we introduce DA-seq, a targeted approach for identifying DA subpopulations not restricted to clusters. DA-seq is a multiscale method that quantifies a local DA measure for each cell, which is computed from its k nearest neighboring cells across a range of k values. Based on this measure, DA-seq delineates contiguous significant DA subpopulations in the transcriptomic space. We apply DA-seq to several scRNA-seq datasets and highlight its improved ability to detect differences between distinct phenotypes in severe versus mildly ill COVID-19 patients, melanomas subjected to immune checkpoint therapy comparing responders to nonresponders, embryonic development at two time points, and young versus aging brain tissue. DA-seq enabled us to detect differences between these phenotypes. Importantly, we find that DA-seq not only recovers the DA cell types as discovered in the original studies but also reveals additional DA subpopulations that were not described before. Analysis of these subpopulations yields biological insights that would otherwise be undetected using conventional computational approaches.


Assuntos
Envelhecimento/genética , Linhagem da Célula/genética , Melanoma/genética , RNA Citoplasmático Pequeno/genética , Neoplasias Cutâneas/genética , Envelhecimento/metabolismo , Linfócitos B/imunologia , Linfócitos B/virologia , Encéfalo/citologia , Encéfalo/metabolismo , /patologia , Linhagem da Célula/imunologia , Citocinas/genética , Citocinas/imunologia , Conjuntos de Dados como Assunto , Células Dendríticas/imunologia , Células Dendríticas/virologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Melanoma/imunologia , Melanoma/patologia , Monócitos/imunologia , Monócitos/virologia , Fenótipo , RNA Citoplasmático Pequeno/imunologia , Índice de Gravidade de Doença , Análise de Célula Única/métodos , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Linfócitos T/imunologia , Linfócitos T/virologia , Transcriptoma
12.
AAPS PharmSciTech ; 22(4): 149, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33961149

RESUMO

Parkinson's disease (PD) is the second most common neurological disorder, associated with decreased dopamine levels in the brain. The goal of this study was to assess the potential of a regenerative medicine-based cell therapy approach to increase dopamine levels. In this study, we used rat adrenal pheochromocytoma (PC12) cells that can produce, store, and secrete dopamine. These cells were microencapsulated in the selectively permeable polymer membrane to protect them from immune responses. For fabrication of the microcapsules, we used a modified Buchi spray dryer B-190 that allows for fast manufacturing of microcapsules and is industrially scalable. Size optimization of the microcapsules was performed by systematically varying key parameters of the spraying device. The short- and long-term stabilities of the microcapsules were assessed. In the in vitro study, the cells were found viable for a period of 30 days. Selective permeability of the microcapsules was confirmed via dopamine release assay and micro BCA protein assay. We found that the microcapsules were permeable to the small molecules including dopamine and were impermeable to the large molecules like BSA. Thus, they can provide the protection to the encapsulated cells from the immune cells. Griess's assay confirmed the non-immunogenicity of the microcapsules. These results demonstrate the effective fabrication of microcapsules encapsulating cells using an industrially scalable device. The microcapsules were stable, and the cells were viable inside the microcapsules and were found to release dopamine. Thus, these microcapsules have the potential to serve as the alternative or complementary treatment approach for PD.


Assuntos
Compostos de Alumínio/síntese química , Cápsulas/síntese química , Encapsulamento de Células/métodos , Terapia Baseada em Transplante de Células e Tecidos/métodos , Doença de Parkinson , Compostos de Sódio/síntese química , Compostos de Alumínio/administração & dosagem , Compostos de Alumínio/metabolismo , Animais , Encéfalo/metabolismo , Cápsulas/administração & dosagem , Cápsulas/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Dopamina/metabolismo , Camundongos , Células PC12 , Doença de Parkinson/metabolismo , Doença de Parkinson/terapia , Polímeros/administração & dosagem , Polímeros/síntese química , Polímeros/metabolismo , Estudos Prospectivos , Células RAW 264.7 , Ratos , Compostos de Sódio/administração & dosagem , Compostos de Sódio/metabolismo , Resultado do Tratamento
13.
Adv Exp Med Biol ; 1269: 57-61, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33966195

RESUMO

Here, we demonstrate the therapeutic effects of transcranial photobiomodulation (tPBM, 1267 nm, 32 J/cm2, a 9-day course) in mice with the injected model of Alzheimer's disease (AD) associated with accumulation of beta-amyloid (Aß) in the brain resulting in neurocognitive deficit vs. the control group (CG) (the neurological severity score (NNS), AD 3.67 ± 0.58 vs. CG 1.00 ± 0.26%, p < 0.05) and mild cerebral hypoxia (AD 72 ± 6% vs. CG 97 ± 2%, p < 0.001). The course of tPBM improved neurocognitive status of mice with AD (NNS, AD 2.03 ± 0.14 vs. CG 1.00 ± 0.26, vs. 2.03 ± 0.14, p < 0.05) due to stimulation of clearance of Aß from the brain via the meningeal lymphatic vessels (the immunohistochemical and confocal data) and an increase in blood oxygen saturation of the brain tissues (the pulse oximetry data) till 85 ± 2%, p < 0.05. These results open breakthrough strategies for non-pharmacological therapy of AD and clearly demonstrate that tPBM might be a promising therapeutic target for preventing or delaying AD based on stimulation of oxygenation of the brain tissues and activation of clearance of toxic molecules via the cerebral lymphatics.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/metabolismo , Camundongos , Camundongos Transgênicos , Oximetria , Oxigênio
14.
Adv Exp Med Biol ; 1269: 347-352, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33966241

RESUMO

Brain death is the irreversible loss of all the functions of the brain and brainstem. Compared to traditional diagnostic methods of brain death, near-infrared spectroscopy (NIRS) is a noninvasive, objective, cost-effective, and safe way of assessment of brain death. Eighteen brain dead patients and 20 healthy subjects were studied by NIRS, with a multiple-phase protocol at varied fractions of inspired O2 (FIO2). We found that the changes in the concentration ratios of oxyhemoglobin to deoxyhemoglobin (Δ[HbO2]/Δ[Hb]) in the cerebral cortex of brain dead patients were significantly higher than those of healthy subjects, and its low-to-high FIO2 phase was most sensitive, with a recommended threshold in the range 1.40-1.50. Our study indicated that NIRS is a promising technology for assessing brain death. The success of this application potentially offers a supplementary technique for the assessment of brain death in real time in order to be able to promptly offer quality-assured donor organs.


Assuntos
Morte Encefálica , Espectroscopia de Luz Próxima ao Infravermelho , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Voluntários Saudáveis , Hemoglobinas/metabolismo , Humanos , Oxiemoglobinas/metabolismo
15.
Rev Neurol ; 72(11): 384-396, 2021 06 01.
Artigo em Espanhol | MEDLINE | ID: mdl-34042167

RESUMO

INTRODUCTION: Many patients with mild or severe COVID-19 do not make a full recovery and have a wide range of chronic symptoms for weeks or months after infection, often of a neurological, cognitive or psychiatric nature. The epidemiological evidence, diagnostic criteria and pathogenesis of post-COVID-19 syndrome are reviewed. DEVELOPMENT: Post-COVID-19 syndrome is defined by persistent clinical signs and symptoms that appear while or after suffering COVID-19, persist for more than 12 weeks and cannot be explained by an alternative diagnosis. The symptoms can fluctuate or cause relapses. It is a heterogeneous condition that includes post-viral chronic fatigue syndrome, sequelae in multiple organs and the effects of severe hospitalisation/post-intensive care syndrome. It has been reported in patients with mild or severe COVID-19 and irrespective of the severity of the symptoms in the acute phase. Between 10% and 65% of survivors who had mild/moderate COVID-19 present symptoms of post-COVID-19 syndrome for 12 weeks or more. At six months, subjects report an average of 14 persistent symptoms. The most common symptoms are fatigue, dyspnoea, anxiety, depression, and impaired attention, concentration, memory and sleep. The underlying biological mechanisms are unknown, although an abnormal or excessive autoimmune and inflammatory response may play an important role. CONCLUSIONS: Clinical manifestations are diverse, fluctuating and variable, although fatigue and neurocognitive complaints predominate. There is no defined consensus on post-COVID-19 syndrome and its diagnostic criteria have not been subjected to adequate psychometric evaluation.


Assuntos
/complicações , Autoimunidade , Encéfalo/metabolismo , /epidemiologia , Doenças Cardiovasculares/etiologia , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/fisiopatologia , Infecções por Coronavirus/complicações , Dispneia/etiologia , Síndrome de Fadiga Crônica/etiologia , Gastroenteropatias/etiologia , Hospitalização , Interações Hospedeiro-Patógeno , Humanos , Inflamação , Transtornos Mentais/etiologia , Doenças do Sistema Nervoso/etiologia , Especificidade de Órgãos , Pandemias , Disautonomias Primárias/etiologia , Fatores de Risco , Síndrome Respiratória Aguda Grave/complicações
16.
Neuroscience ; 465: 128-141, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33951504

RESUMO

The Small Optic Lobe (SOL) family of calpains are intracellular cysteine proteases that are expressed in the nervous system and play an important role in neuronal development in both Drosophila, where loss of this calpain leads to the eponymous small optic lobes, and in mouse and human, where loss of this calpain leads to eye anomalies. Some human individuals with biallelic variants in CAPN15 also have developmental delay and autism. However, neither the specific effect of the loss of the Capn15 protein on brain development nor the brain regions where this calpain is expressed in the adult is known. Here we show using small animal MRI that mice with the complete loss of Capn15 have smaller brains overall with larger decreases in the thalamus and subregions of the hippocampus. These losses are not seen in Capn15 conditional knockout (KO) mice where Capn15 is knocked out only in excitatory neurons in the adult. Based on ß-galactosidase expression in an insert strain where lacZ is expressed under the control of the Capn15 promoter, we show that Capn15 is expressed in adult mice, particularly in neurons involved in plasticity such as the hippocampus, lateral amygdala and Purkinje neurons, and partially in other non-characterized cell types. The regions of the brain in the adult where Capn15 is expressed do not correspond well to the regions of the brain most affected by the complete knockout suggesting distinct roles of Capn15 in brain development and adult brain function.


Assuntos
Calpaína , Neurônios , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Calpaína/genética , Calpaína/metabolismo , Imagem por Ressonância Magnética , Camundongos , Camundongos Knockout , Neurônios/metabolismo
17.
Food Chem ; 358: 129888, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33933969

RESUMO

Present study aimed to prepare and identify antioxidative peptides from selenium-containing soybeans, and to investigate their bioavailability and protective effects against oxidative stress-related diseases. Selenium-containing soybean antioxidative peptides (Mw < 1 kDa, SePPs) hydrolyzed by Neutrase and Alcalase reached the highest cellular antioxidant activity (EC50 value 320.5 ± 39.71 µg/L). SePPs could be efficiently absorbed through Caco-2 monolayer, and then significantly reverse the tumor necrosis factor-α (TNF-α)-induced inflammatory cytokine, phosphorylated c-Jun N-terminal kinases (p-JNK) and nuclear factor-kappa B (NF-κB) levels in EA. hy926 cells (p < 0.05). d-galactose-induced aging mice model showed that liver superoxidase dismutase (SOD) and glutathione peroxidase-1 (GPx-1) were enhanced, while aspartate aminotransferase (AST), alanine aminotransferase (ALT) and NF-κB were decreased by SePPs significantly (p < 0.05). SePPs could inhibit brain oxidative stress via regulating MAPK/NF-κB pathway. Comparing with Na2SeO3, selenomethionine (SeMet) and selenium-free peptides, SePPs was found to present synergistic effects of selenium and peptides in antioxidant activity.


Assuntos
Antioxidantes/farmacologia , Peptídeos/farmacologia , Selênio/farmacologia , Proteínas de Soja/farmacologia , Animais , Antioxidantes/química , Antioxidantes/farmacocinética , Disponibilidade Biológica , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células CACO-2 , Citocinas/metabolismo , Suplementos Nutricionais , Enzimas/metabolismo , Feminino , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos Endogâmicos ICR , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Peptídeos/química , Selênio/química , Selênio/farmacocinética , Proteínas de Soja/química , Fator de Necrose Tumoral alfa/metabolismo
18.
Int J Mol Sci ; 22(9)2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946340

RESUMO

During brain development, the genome must be repeatedly reconfigured in order to facilitate neuronal and glial differentiation. A host of chromatin remodeling complexes facilitates this process. At the genetic level, the non-redundancy of these complexes suggests that neurodevelopment may require a lexicon of remodelers with different specificities and activities. Here, we focus on the nucleosome remodeling and deacetylase (NuRD) complex. We review NuRD biochemistry, genetics, and functions in neural progenitors and neurons.


Assuntos
Encéfalo/crescimento & desenvolvimento , Montagem e Desmontagem da Cromatina , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/metabolismo , Animais , Encéfalo/embriologia , Encéfalo/metabolismo , Humanos , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/genética , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Neurogênese , Neurônios/citologia , Neurônios/metabolismo
20.
Front Immunol ; 12: 665300, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33981312

RESUMO

The irruption of SARS-CoV-2 during 2020 has been of pandemic proportions due to its rapid spread and virulence. COVID-19 patients experience respiratory, digestive and neurological symptoms. Distinctive symptom as anosmia, suggests a potential neurotropism of this virus. Amongst the several pathways of entry to the nervous system, we propose an alternative pathway from the infection of the gut, involving Toll-like receptor 4 (TLR4), zonulin, protease-activated receptor 2 (PAR2) and zonulin brain receptor. Possible use of zonulin antagonists could be investigated to attenuate neurological manifestations caused by SARS-CoV-19 infection.


Assuntos
/complicações , Haptoglobinas/metabolismo , Doenças do Sistema Nervoso/complicações , Precursores de Proteínas/metabolismo , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/virologia , Encéfalo/metabolismo , Encéfalo/virologia , /virologia , Proteínas do Sistema Complemento/metabolismo , Gastroenteropatias/complicações , Gastroenteropatias/metabolismo , Gastroenteropatias/virologia , Humanos , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/virologia , /patogenicidade , Receptor 4 Toll-Like/metabolismo
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