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1.
Eur J Med Res ; 29(1): 317, 2024 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-38849920

RESUMO

The brain-bone axis has emerged as a captivating field of research, unveiling the intricate bidirectional communication between the central nervous system (CNS) and skeletal metabolism. This comprehensive review delves into the current state of knowledge surrounding the brain-bone axis, exploring the complex mechanisms, key players, and potential clinical implications of this fascinating area of study. The review discusses the neural regulation of bone metabolism, highlighting the roles of the sympathetic nervous system, hypothalamic neuropeptides, and neurotransmitters in modulating bone remodeling. In addition, it examines the influence of bone-derived factors, such as osteocalcin and fibroblast growth factor 23, on brain function and behavior. The therapeutic potential of targeting the brain-bone axis in the context of skeletal and neurological disorders is also explored. By unraveling the complex interplay between the CNS and skeletal metabolism, this review aims to provide a comprehensive resource for researchers, clinicians, and students interested in the brain-bone axis and its implications for human health and disease.


Assuntos
Osso e Ossos , Encéfalo , Sistema Nervoso Central , Humanos , Osso e Ossos/metabolismo , Osso e Ossos/fisiologia , Encéfalo/metabolismo , Encéfalo/fisiologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/fisiologia , Animais , Remodelação Óssea/fisiologia , Sistema Nervoso Simpático/fisiologia , Sistema Nervoso Simpático/metabolismo
2.
J Neuroinflammation ; 21(1): 151, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38840215

RESUMO

BACKGROUND: Mounting evidence links glucose intolerance and diabetes as aspects of metabolic dysregulation that are associated with an increased risk of developing dementia. Inflammation and inflammasome activation have emerged as a potential link between these disparate pathologies. As diet is a key factor in both the development of metabolic disorders and inflammation, we hypothesize that long term changes in dietary factors can influence nervous system function by regulating inflammasome activity and that this phenotype would be sex-dependent, as sex hormones are known to regulate metabolism and immune processes. METHODS: 5-week-old male and female transgenic mice expressing a caspase-1 bioluminescent reporter underwent cranial window surgeries and were fed control (65% complex carbohydrates, 15% fat), high glycemic index (65% carbohydrates from sucrose, 15% fat), or ketogenic (1% complex carbohydrates, 79% fat) diet from 6 to 26 weeks of age. Glucose regulation was assessed with a glucose tolerance test following a 4-h morning fast. Bioluminescence in the brain was quantified using IVIS in vivo imaging. Blood cytokine levels were measured using cytokine bead array. 16S ribosomal RNA gene amplicon sequencing of mouse feces was performed to assess alterations in the gut microbiome. Behavior associated with these dietary changes was also evaluated. RESULTS: The ketogenic diet caused weight gain and glucose intolerance in both male and female mice. In male mice, the high glycemic diet led to increased caspase-1 biosensor activation over the course of the study, while in females the ketogenic diet drove an increase in biosensor activation compared to their respective controls. These changes correlated with an increase in inflammatory cytokines present in the serum of test mice and the emergence of anxiety-like behavior. The microbiome composition differed significantly between diets; however no significant link between diet, glucose tolerance, or caspase-1 signal was established. CONCLUSIONS: Our findings suggest that diet composition, specifically the source and quantity of carbohydrates, has sex-specific effects on inflammasome activation in the central nervous system and behavior. This phenotype manifested as increased anxiety in male mice, and future studies are needed to determine if this phenotype is linked to alterations in microbiome composition.


Assuntos
Caspase 1 , Dieta Cetogênica , Camundongos Transgênicos , Caracteres Sexuais , Animais , Feminino , Masculino , Camundongos , Caspase 1/metabolismo , Dieta Cetogênica/efeitos adversos , Carboidratos da Dieta/efeitos adversos , Carboidratos da Dieta/farmacologia , Sistema Nervoso Central/metabolismo , Microbioma Gastrointestinal/fisiologia , Camundongos Endogâmicos C57BL
3.
PLoS One ; 19(6): e0305120, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38848332

RESUMO

BACKGROUND: Tick-borne encephalitis (TBE) is a human viral infectious disease involving the central nervous system (CNS). It is caused by the tick-borne encephalitis virus (TBEV). At present, there is very limited information regarding the clinical importance and health burden of TBE infections without signs of CNS inflammation. Moreover, such cases are omitted from official TBE surveillances and there are no reports of population-based studies. METHODS AND FINDINGS: A nationwide population-based study was conducted in Latvia by intensively searching for symptomatic TBEV infections recorded in outpatient and hospital settings between 2007 and 2022. In total, 4,124 symptomatic TBEV infections were identified, of which 823 (20.0%) had no CNS involvement. Despite the lack of neurological symptoms, non-CNS TBE patients still experienced severe health conditions that required management in a hospital setting for a median duration of 7 days. Furthermore, lumbar puncture information was available for 708 of these patients, with 100 (14.1%) undergoing the procedure, suggesting a high suspicion of CNS involvement. CONCLUSIONS: Clearly, non-CNS TBE has the potential to negatively impact the health of patients. The actual burden of non-CNS TBEV cases may be higher than we think as these cases are omitted from official TBE surveillances and are challenging to recognize.


Assuntos
Vírus da Encefalite Transmitidos por Carrapatos , Encefalite Transmitida por Carrapatos , Humanos , Encefalite Transmitida por Carrapatos/epidemiologia , Encefalite Transmitida por Carrapatos/virologia , Letônia/epidemiologia , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Idoso , Adolescente , Adulto Jovem , Criança , Pré-Escolar , Sistema Nervoso Central/virologia , Sistema Nervoso Central/patologia , Idoso de 80 Anos ou mais
5.
Cells ; 13(9)2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38727275

RESUMO

ATP-binding cassette (ABC) transporters play a crucial role for the efflux of a wide range of substrates across different cellular membranes. In the central nervous system (CNS), ABC transporters have recently gathered significant attention due to their pivotal involvement in brain physiology and neurodegenerative disorders, such as Alzheimer's disease (AD). Glial cells are fundamental for normal CNS function and engage with several ABC transporters in different ways. Here, we specifically highlight ABC transporters involved in the maintenance of brain homeostasis and their implications in its metabolic regulation. We also show new aspects related to ABC transporter function found in less recognized diseases, such as Huntington's disease (HD) and experimental autoimmune encephalomyelitis (EAE), as a model for multiple sclerosis (MS). Understanding both their impact on the physiological regulation of the CNS and their roles in brain diseases holds promise for uncovering new therapeutic options. Further investigations and preclinical studies are warranted to elucidate the complex interplay between glial ABC transporters and physiological brain functions, potentially leading to effective therapeutic interventions also for rare CNS disorders.


Assuntos
Transportadores de Cassetes de Ligação de ATP , Sistema Nervoso Central , Neuroglia , Humanos , Transportadores de Cassetes de Ligação de ATP/metabolismo , Neuroglia/metabolismo , Animais , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Doenças do Sistema Nervoso Central/metabolismo , Doenças do Sistema Nervoso Central/patologia
6.
Sci Adv ; 10(18): eadn5861, 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38701218

RESUMO

Enzymes of the ten-eleven translocation (TET) family play a key role in the regulation of gene expression by oxidizing 5-methylcytosine (5mC), a prominent epigenetic mark in many species. Yet, TET proteins also have less characterized noncanonical modes of action, notably in Drosophila, whose genome is devoid of 5mC. Here, we show that Drosophila TET activates the expression of genes required for larval central nervous system (CNS) development mainly in a catalytic-independent manner. Genome-wide profiling shows that TET is recruited to enhancer and promoter regions bound by Polycomb group complex (PcG) proteins. We found that TET interacts and colocalizes on chromatin preferentially with Polycomb repressor complex 1 (PRC1) rather than PRC2. Furthermore, PRC1 but not PRC2 is required for the activation of TET target genes. Last, our results suggest that TET and PRC1 binding to activated genes is interdependent. These data highlight the importance of TET noncatalytic function and the role of PRC1 for gene activation in the Drosophila larval CNS.


Assuntos
Proteínas de Drosophila , Complexo Repressor Polycomb 1 , Animais , Sistema Nervoso Central/metabolismo , Cromatina/metabolismo , Cromatina/genética , Drosophila/metabolismo , Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Regulação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Larva/metabolismo , Larva/genética , Complexo Repressor Polycomb 1/metabolismo , Complexo Repressor Polycomb 1/genética , Regiões Promotoras Genéticas , Ligação Proteica
7.
J Neuroinflammation ; 21(1): 127, 2024 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-38741181

RESUMO

HIV-associated neurocognitive disorders (HAND) are a spectrum of cognitive impairments that continue to affect approximately half of all HIV-positive individuals despite effective viral suppression through antiretroviral therapy (ART). White matter pathologies have persisted in the ART era, and the degree of white matter damage correlates with the degree of neurocognitive impairment in patients with HAND. The HIV protein Nef has been implicated in HAND pathogenesis, but its effect on white matter damage has not been well characterized. Here, utilizing in vivo, ex vivo, and in vitro methods, we demonstrate that Nef-containing extracellular vesicles (Nef EVs) disrupt myelin sheaths and inflict damage upon oligodendrocytes within the murine central nervous system. Intracranial injection of Nef EVs leads to reduced myelin basic protein (MBP) staining and a decreased number of CC1 + oligodendrocytes in the corpus callosum. Moreover, cerebellar slice cultures treated with Nef EVs exhibit diminished MBP expression and increased presence of unmyelinated axons. Primary mixed brain cultures and enriched oligodendrocyte precursor cell cultures exposed to Nef EVs display a decreased number of O4 + cells, indicative of oligodendrocyte impairment. These findings underscore the potential contribution of Nef EV-mediated damage to oligodendrocytes and myelin maintenance in the pathogenesis of HAND.


Assuntos
Vesículas Extracelulares , HIV-1 , Camundongos Endogâmicos C57BL , Oligodendroglia , Produtos do Gene nef do Vírus da Imunodeficiência Humana , Animais , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Oligodendroglia/virologia , Camundongos , Vesículas Extracelulares/metabolismo , Produtos do Gene nef do Vírus da Imunodeficiência Humana/metabolismo , HIV-1/metabolismo , Bainha de Mielina/metabolismo , Bainha de Mielina/patologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Sistema Nervoso Central/virologia , Células Cultivadas , Humanos , Masculino
8.
J Morphol ; 285(6): e21710, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38760949

RESUMO

Lithornithidae, an assemblage of volant Palaeogene fossil birds, provide our clearest insights into the early evolutionary history of Palaeognathae, the clade that today includes the flightless ratites and volant tinamous. The neotype specimen of Lithornis vulturinus, from the early Eocene (approximately 53 million years ago) of Europe, includes a partial neurocranium that has never been thoroughly investigated. Here, we describe these cranial remains including the nearly complete digital endocasts of the brain and bony labyrinth. The telencephalon of Lithornis is expanded and its optic lobes are ventrally shifted, as is typical for crown birds. The foramen magnum is positioned caudally, rather than flexed ventrally as in some crown birds, with the optic lobes, cerebellum, and foramen magnum shifted further ventrally. The overall brain shape is similar to that of tinamous, the only extant clade of flying palaeognaths, suggesting that several aspects of tinamou neuroanatomy may have been evolutionarily conserved since at least the early Cenozoic. The estimated ratio of the optic lobe's surface area relative to the total brain suggests a diurnal ecology. Lithornis may provide the clearest insights to date into the neuroanatomy of the ancestral crown bird, combining an ancestrally unflexed brain with a caudally oriented connection with the spinal cord, a moderately enlarged telencephalon, and ventrally shifted, enlarged optic lobes.


Assuntos
Evolução Biológica , Fósseis , Paleógnatas , Crânio , Animais , Fósseis/anatomia & histologia , Paleógnatas/anatomia & histologia , Crânio/anatomia & histologia , Sistema Nervoso Central/anatomia & histologia , Encéfalo/anatomia & histologia , Aves/anatomia & histologia , Paleontologia , Filogenia
9.
Sci Immunol ; 9(95): eadj9730, 2024 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-38728414

RESUMO

Chimeric antigen receptor (CAR) T cell immunotherapy for the treatment of neurological autoimmune diseases is promising, but CAR T cell kinetics and immune alterations after treatment are poorly understood. Here, we performed single-cell multi-omics sequencing of paired cerebrospinal fluid (CSF) and blood samples from patients with neuromyelitis optica spectrum disorder (NMOSD) treated with anti-B cell maturation antigen (BCMA) CAR T cells. Proliferating cytotoxic-like CD8+ CAR T cell clones were identified as the main effectors in autoimmunity. Anti-BCMA CAR T cells with enhanced features of chemotaxis efficiently crossed the blood-CSF barrier, eliminated plasmablasts and plasma cells in the CSF, and suppressed neuroinflammation. The CD44-expressing early memory phenotype in infusion products was potentially associated with CAR T cell persistence in autoimmunity. Moreover, CAR T cells from patients with NMOSD displayed distinctive features of suppressed cytotoxicity compared with those from hematological malignancies. Thus, we provide mechanistic insights into CAR T cell function in patients with neurological autoimmune disease.


Assuntos
Imunoterapia Adotiva , Receptores de Antígenos Quiméricos , Análise de Célula Única , Humanos , Imunoterapia Adotiva/métodos , Receptores de Antígenos Quiméricos/imunologia , Autoimunidade/imunologia , Neuromielite Óptica/imunologia , Neuromielite Óptica/terapia , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Sistema Nervoso Central/imunologia
10.
Pathologica ; 116(2): 134-139, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38767545

RESUMO

Primary angiitis of the central nervous system (CNS) is an uncommon inflammatory disorder, with highly variable clinical presentation. It needs to be differentiated from several mimickers, such as CNS involvement in systemic vasculitides, connective tissue disorders, infectious disease, and leukodystrophy as well as neoplastic diseases. The diagnosis requires a combination of clinical and laboratory investigations, multimodal imaging, and histopathological examination, which should be available for confirmation. In the present paper, the histopathological features of primary angiitis of the CNS are described and highlighted to help pathologists avoid misdiagnosis of a treatable acquired disease.


Assuntos
Vasculite do Sistema Nervoso Central , Humanos , Vasculite do Sistema Nervoso Central/diagnóstico , Vasculite do Sistema Nervoso Central/patologia , Diagnóstico Diferencial , Sistema Nervoso Central/patologia , Sistema Nervoso Central/diagnóstico por imagem
12.
Cell ; 187(10): 2465-2484.e22, 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38701782

RESUMO

Remyelination failure in diseases like multiple sclerosis (MS) was thought to involve suppressed maturation of oligodendrocyte precursors; however, oligodendrocytes are present in MS lesions yet lack myelin production. We found that oligodendrocytes in the lesions are epigenetically silenced. Developing a transgenic reporter labeling differentiated oligodendrocytes for phenotypic screening, we identified a small-molecule epigenetic-silencing-inhibitor (ESI1) that enhances myelin production and ensheathment. ESI1 promotes remyelination in animal models of demyelination and enables de novo myelinogenesis on regenerated CNS axons. ESI1 treatment lengthened myelin sheaths in human iPSC-derived organoids and augmented (re)myelination in aged mice while reversing age-related cognitive decline. Multi-omics revealed that ESI1 induces an active chromatin landscape that activates myelinogenic pathways and reprograms metabolism. Notably, ESI1 triggered nuclear condensate formation of master lipid-metabolic regulators SREBP1/2, concentrating transcriptional co-activators to drive lipid/cholesterol biosynthesis. Our study highlights the potential of targeting epigenetic silencing to enable CNS myelin regeneration in demyelinating diseases and aging.


Assuntos
Epigênese Genética , Bainha de Mielina , Oligodendroglia , Remielinização , Animais , Bainha de Mielina/metabolismo , Humanos , Camundongos , Remielinização/efeitos dos fármacos , Oligodendroglia/metabolismo , Sistema Nervoso Central/metabolismo , Camundongos Endogâmicos C57BL , Rejuvenescimento , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Organoides/metabolismo , Organoides/efeitos dos fármacos , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/genética , Diferenciação Celular/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Masculino , Regeneração/efeitos dos fármacos , Esclerose Múltipla/metabolismo , Esclerose Múltipla/genética , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologia
13.
Biomolecules ; 14(5)2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38785943

RESUMO

In the present study, we conducted a scoping review to provide an overview of the existing literature on the carbocyanine dye DiI, in human neuroanatomical tract tracing. The PubMed, Scopus, and Web of Science databases were systematically searched. We identified 61 studies published during the last three decades. While studies incorporated specimens across human life from the embryonic stage onwards, the majority of studies focused on adult human tissue. Studies that utilized peripheral nervous system (PNS) tissue were a minority, with the majority of studies focusing on the central nervous system (CNS). The most common topic of interest in previous tract tracing investigations was the connectivity of the visual pathway. DiI crystals were more commonly applied. Nevertheless, several studies utilized DiI in a paste or dissolved form. The maximum tracing distance and tracing speed achieved was, respectively, 70 mm and 1 mm/h. We identified studies that focused on optimizing tracing efficacy by varying parameters such as fixation, incubation temperature, dye re-application, or the application of electric fields. Additional studies aimed at broadening the scope of DiI use by assessing the utility of archival tissue and compatibility of tissue clearing in DiI applications. A combination of DiI tracing and immunohistochemistry in double-labeling studies have been shown to provide the means for assessing connectivity of phenotypically defined human CNS and PNS neuronal populations.


Assuntos
Técnicas de Rastreamento Neuroanatômico , Humanos , Técnicas de Rastreamento Neuroanatômico/métodos , Carbocianinas/química , Sistema Nervoso Central , Sistema Nervoso Periférico , Corantes Fluorescentes/química
14.
Cancer Cell ; 42(6): 985-1002.e18, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38821061

RESUMO

Tumors employ various strategies to evade immune surveillance. Central nervous system (CNS) has multiple features to restrain immune response. Whether tumors and CNS share similar programs of immunosuppression is elusive. Here, we analyze multi-omics data of tumors from HER2+ breast cancer patients receiving trastuzumab and anti-PD-L1 antibody and find that CNS-enriched N-acetyltransferase 8-like (NAT8L) and its metabolite N-acetylaspartate (NAA) are overexpressed in resistant tumors. In CNS, NAA is released during brain inflammation. NAT8L attenuates brain inflammation and impairs anti-tumor immunity by inhibiting cytotoxicity of natural killer (NK) cells and CD8+ T cells via NAA. NAA disrupts the formation of immunological synapse by promoting PCAF-induced acetylation of lamin A-K542, which inhibits the integration between lamin A and SUN2 and impairs polarization of lytic granules. We uncover that tumor cells mimic the anti-inflammatory mechanism of CNS to evade anti-tumor immunity and NAT8L is a potential target to enhance efficacy of anti-cancer agents.


Assuntos
Sinapses Imunológicas , Humanos , Sinapses Imunológicas/metabolismo , Animais , Camundongos , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/imunologia , Feminino , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linhagem Celular Tumoral , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/tratamento farmacológico
15.
Sci Rep ; 14(1): 12486, 2024 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-38816506

RESUMO

Affections of the central nervous system (CNS) rarely occur in Lyme neuroborreliosis (LNB). CNS manifestations can have residual neurological symptoms despite antibiotic treatment. We explored the spectrum of CNS affections in patients with LNB in a tertiary care center in a region endemic for Lyme borreliosis. We retrospectively included patients treated at a tertiary care center from January 2020-December 2021 fulfilling the case criteria for LNB as stated in the current German guideline on LNB. Clinical data, cerebrospinal fluid (CSF) findings and MRI imaging were collected. We included 35 patients with LNB, 24 with early manifestations and 11 with CNS-LNB. CNS-LNB patients had encephalomyelitis (n = 6) or cerebral vasculitis (n = 5). Patients with early LNB and CNS-LNB differed regarding albumin CSF/serum quotient and total protein in CSF. Duration from onset of symptoms until diagnosis was statistically significantly longer in patients with encephalomyelitis. MRI findings were heterogeneous and showed longitudinal extensive myelitis, perimedullar leptomeningeal enhancement, pontomesencephalic lesions or cerebral vasculitis. CNS-LNB can present with a variety of clinical syndromes and MRI changes. No clear pattern of MRI findings in CNS-LNB could be identified. The role of MRI consists in ruling out other causes of neurological symptoms.


Assuntos
Neuroborreliose de Lyme , Imageamento por Ressonância Magnética , Humanos , Neuroborreliose de Lyme/diagnóstico por imagem , Neuroborreliose de Lyme/líquido cefalorraquidiano , Neuroborreliose de Lyme/diagnóstico , Imageamento por Ressonância Magnética/métodos , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Estudos Retrospectivos , Idoso , Sistema Nervoso Central/diagnóstico por imagem , Sistema Nervoso Central/patologia , Encefalomielite/diagnóstico por imagem , Encefalomielite/líquido cefalorraquidiano , Adulto Jovem , Vasculite do Sistema Nervoso Central/diagnóstico por imagem
16.
Biomaterials ; 309: 122594, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38701641

RESUMO

Therapeutic outcomes of local biomolecule delivery to the central nervous system (CNS) using bulk biomaterials are limited by inadequate drug loading, neuropil disruption, and severe foreign body responses. Effective CNS delivery requires addressing these issues and developing well-tolerated, highly-loaded carriers that are dispersible within local neural parenchyma. Here, we synthesized biodegradable trehalose-based polyelectrolyte oligomers using facile A2:B3:AR thiol-ene Michael addition reactions that form complex coacervates upon mixing of oppositely charged oligomers. Coacervates permit high concentration loading and controlled release of bioactive growth factors, enzymes, and antibodies, with modular formulation parameters that confer tunable release kinetics. Coacervates are cytocompatible with cultured neural cells in vitro and can be formulated to either direct intracellular protein delivery or sequester media containing proteins and remain extracellular. Coacervates serve as effective vehicles for precisely delivering biomolecules, including bioactive neurotrophins, to the mouse striatum following intraparenchymal injection. These results support the use of trehalose-based coacervates as part of therapeutic protein delivery strategies for CNS disorders.


Assuntos
Sistema Nervoso Central , Trealose , Trealose/química , Animais , Camundongos , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Camundongos Endogâmicos C57BL , Proteínas/química
17.
Int Immunopharmacol ; 134: 112246, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38759372

RESUMO

BACKGROUND: A wide array of histone deacetylase (HDAC) inhibitors and aryl hydrocarbon receptor (AHR) agonists commonly arrest experimental autoimmune encephalomyelitis (EAE). However, it is not known whether HDAC inhibition is linked to the AHR signaling pathway in EAE. METHODS: We investigated how the pan-HDAC inhibitor SB939 (pracinostat) exerted immunoregulatory action in the myelin oligodendrocyte glycoprotein 35-55 (MOG35-55)-induced EAE mouse model by evaluating changes in of signal transducer and activator of transcription 3 (STAT3) acetylation and the expression of indoleamine 2,3-dioxygenase 1 (IDO1) and AHR in inflamed spinal cords during EAE evolution. We proved the involvement of IDO1 and the AHR in SB939-mediated immunosuppression using Ido1-/- and Ahr-/- mice. RESULTS: Administration with SB939 halted EAE progression, which depended upon IDO1 expression in neurons of the central nervous system (CNS). Our in vitro and in vivo studies demonstrated that SB939 sustained the interleukin-6-induced acetylation of STAT3, resulting in the stable transcriptional activation of Ido1. The therapeutic effect of SB939 also required the AHR, which is expressed mainly in CD4+ T cells and macrophages in CNS disease lesions. Finally, SB939 was shown to markedly reduce the proliferation of CD4+ T cells in inflamed neuronal tissues but not in the spleen or draining lymph nodes. CONCLUSIONS: Overall, our results suggest that IDO1 tryptophan metabolites produced by neuronal cells may act on AHR in pathogenic CD4+ T cells in a paracrine fashion in the CNS and that the specific induction of IDO1 expression in neurons at disease-afflicted sites can be considered a therapeutic approach to block the progression of multiple sclerosis without affecting systemic immunity.


Assuntos
Encefalomielite Autoimune Experimental , Inibidores de Histona Desacetilases , Indolamina-Pirrol 2,3,-Dioxigenase , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios , Fator de Transcrição STAT3 , Animais , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/imunologia , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Fator de Transcrição STAT3/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/metabolismo , Camundongos , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Feminino , Medula Espinal/patologia , Medula Espinal/metabolismo , Medula Espinal/imunologia , Medula Espinal/efeitos dos fármacos , Glicoproteína Mielina-Oligodendrócito/imunologia , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Progressão da Doença , Histona Desacetilases/metabolismo , Histona Desacetilases/genética , Fragmentos de Peptídeos/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Interleucina-6/metabolismo , Interleucina-6/genética
18.
Viruses ; 16(5)2024 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-38793545

RESUMO

Initially reported as pneumonia of unknown origin, COVID-19 is increasingly being recognized for its impact on the nervous system, despite nervous system invasions being extremely rare. As a result, numerous studies have been conducted to elucidate the mechanisms of nervous system damage and propose appropriate coping strategies. This review summarizes the mechanisms by which SARS-CoV-2 invades and damages the central nervous system, with a specific focus on aspects apart from the immune response and inflammatory storm. The latest research findings on these mechanisms are presented, providing new insights for further in-depth research.


Assuntos
COVID-19 , Sistema Nervoso Central , Síndrome da Liberação de Citocina , SARS-CoV-2 , Animais , Humanos , Sistema Nervoso Central/virologia , Sistema Nervoso Central/imunologia , COVID-19/imunologia , COVID-19/virologia , Síndrome da Liberação de Citocina/imunologia , Inflamação/imunologia , Inflamação/virologia , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade
19.
Zoolog Sci ; 41(3): 281-289, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38809867

RESUMO

Platyhelminthes are a phylum of simple bilaterian invertebrates with prototypic body systems. Compared with non-bilaterians such as cnidarians, the bilaterians are likely to exhibit integrated free-moving behaviors, which require a concentrated nervous system "brain" rather than the distributed nervous system of radiatans. Marine flatworms have an early cephalized 'central' nervous system compared not only with non-bilaterians but also with parasitic flatworms or freshwater planarians. In this study, we used the marine flatworm Stylochoplana pusilla as an excellent model organism in Platyhelminthes because of the early cephalized central nervous system. Here, we investigated the three-dimensional structures of the flatworm central nervous system by the use of X-ray micro-computed tomography (micro-CT) in a synchrotron radiation facility. We found that the obtained tomographic images were sufficient to discriminate some characteristic structures of the nervous system, including nerve cords around the cephalic ganglion, mushroom body-like structures, and putative optic nerves forming an optic commissure-like structure. Through the micro-CT imaging, we could obtain undistorted serial section images, permitting us to visualize precise spatial relationships of neuronal subpopulations and nerve tracts. 3-D micro-CT is very effective in the volume analysis of the nervous system at the cellular level; the methodology is straightforward and could be applied to many other non-model organisms.


Assuntos
Sistema Nervoso Central , Platelmintos , Microtomografia por Raio-X , Animais , Microtomografia por Raio-X/veterinária , Platelmintos/anatomia & histologia , Platelmintos/classificação , Sistema Nervoso Central/diagnóstico por imagem , Sistema Nervoso Central/anatomia & histologia
20.
Cell Biochem Funct ; 42(4): e4056, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38812104

RESUMO

Previous studies suggested that central nervous system injury is often accompanied by the activation of Toll-like receptor 4/NF-κB pathway, which leads to the upregulation of proapoptotic gene expression, causes mitochondrial oxidative stress, and further aggravates the inflammatory response to induce cell apoptosis. Subsequent studies have shown that NF-κB and IκBα can directly act on mitochondria. Therefore, elucidation of the specific mechanisms of NF-κB and IκBα in mitochondria may help to discover new therapeutic targets for central nervous system injury. Recent studies have suggested that NF-κB (especially RelA) in mitochondria can inhibit mitochondrial respiration or DNA expression, leading to mitochondrial dysfunction. IκBα silencing will cause reactive oxygen species storm and initiate the mitochondrial apoptosis pathway. Other research results suggest that RelA can regulate mitochondrial respiration and energy metabolism balance by interacting with p53 and STAT3, thus initiating the mitochondrial protection mechanism. IκBα can also inhibit apoptosis in mitochondria by interacting with VDAC1 and other molecules. Regulating the biological role of NF-κB signaling pathway in mitochondria by targeting key proteins such as p53, STAT3, and VDAC1 may help maintain the balance of mitochondrial respiration and energy metabolism, thereby protecting nerve cells and reducing inflammatory storms and death caused by ischemia and hypoxia.


Assuntos
Mitocôndrias , NF-kappa B , Transdução de Sinais , Receptor 4 Toll-Like , Humanos , Mitocôndrias/metabolismo , Receptor 4 Toll-Like/metabolismo , NF-kappa B/metabolismo , Animais , Apoptose , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Sistema Nervoso Central/lesões
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