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1.
Front Immunol ; 12: 624919, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33796100

RESUMO

Neuroinflammatory and neurodegenerative diseases are a major public health problem worldwide, especially with the increase of life-expectancy observed during the last decades. For many of these diseases, we still lack a full understanding of their etiology and pathophysiology. Nonetheless their association with mitochondrial dysfunction highlights this organelle as an important player during CNS homeostasis and disease. Markers of Parkinson (PD) and Alzheimer (AD) diseases are able to induce innate immune pathways induced by alterations in mitochondrial Ca2+ homeostasis leading to neuroinflammation. Additionally, exacerbated type I IFN responses triggered by mitochondrial DNA (mtDNA), failures in mitophagy, ER-mitochondria communication and mtROS production promote neurodegeneration. On the other hand, regulation of mitochondrial dynamics is essential for CNS health maintenance and leading to the induction of IL-10 and reduction of TNF-α secretion, increased cell viability and diminished cell injury in addition to reduced oxidative stress. Thus, although previously solely seen as power suppliers to organelles and molecular processes, it is now well established that mitochondria have many other important roles, including during immune responses. Here, we discuss the importance of these mitochondrial dynamics during neuroinflammation, and how they correlate either with the amelioration or worsening of CNS disease.


Assuntos
Encéfalo/metabolismo , Inflamação/metabolismo , Mitocôndrias/metabolismo , Dinâmica Mitocondrial , Doenças Neurodegenerativas/metabolismo , Neuroimunomodulação , Alarminas/metabolismo , Animais , Encéfalo/imunologia , Encéfalo/patologia , Citocinas/metabolismo , Humanos , Inflamação/imunologia , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Mitocôndrias/imunologia , Mitocôndrias/patologia , Degeneração Neural , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/patologia
2.
Curr Neurol Neurosci Rep ; 20(1): 1, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-32020300

RESUMO

PURPOSE OF REVIEW: Transcranial magnetic stimulation (TMS) is a method of Non-Invasive Brain Stimulation that is based on electro-physical principles discovered by Michael Faraday. A TMS device is made of one or two copper coils, positioned superficially to a site of interest in the brain, to non-invasively produce a brief magnetic pulse to an estimated depth from the surface of the scalp with the following axonal depolarization. This axonal depolarization activates cortical and subcortical networks with multiple effects. There are different methods of TMS used, all with different mechanisms of action. TMS is well tolerated with very few side effects. RECENT FINDINGS: TMS is now approved for major depression disorder and obsessive-compulsive disorder. There is significant data to consider approval of TMS for many neurological disorders. This is a review of the uses of TMS in diverse neurological conditions, including stroke and spasticity, migraine, and dementia. TMS is a device that utilizes non-invasive brain stimulation, and it has shown promising results with objective clinical and basic science data. Its ability to trigger neuronal plasticity and potentiating synaptic transmission gives it incredible therapeutic potential. There are diverse mechanisms of action, and this could be troublesome in elaborating clinical trials and standardization of therapy.


Assuntos
Encéfalo/fisiopatologia , Doenças do Sistema Nervoso/terapia , Estimulação Magnética Transcraniana/métodos , Humanos , Doenças do Sistema Nervoso/fisiopatologia , Plasticidade Neuronal/fisiologia
3.
Neuroreport ; 25(12): 954-9, 2014 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-24978397

RESUMO

Traumatic brain injury (TBI) is one of the leading causes of neurological disability and death in the USA across all age groups, ethnicities, and incomes. In addition to the short-term morbidity and mortality, TBI leads to epilepsy and severe neurocognitive symptoms, both of which are referenced to post-traumatic hippocampal dysfunction, although the mechanisms of such hippocampal dysfunction are incompletely understood. Here, we study the temporal profile of the transcription of three select immediate early gene (IEG) markers of neuronal hyperactivation, plasticity, and injury, c-fos, brain-derived neurotrophic factor (BDNF), and Bax, in the acute period following the epileptogenic lateral fluid percussion injury in a rodent TBI model. We found that lateral fluid percussion injury leads to enhanced expression of the selected IEGs within 24 h of TBI. Specifically, BDNF and c-fos increase maximally 1-6 h after TBI in the ipsilesional hippocampus, whereas Bax increases in the hippocampus bilaterally in this time window. Antagonism of the N-methyl-D-aspartate-type glutamate receptor by MK801 attenuates the increase in BDNF and Bax, which underscores a therapeutic role for N-methyl-D-aspartate-type glutamate receptor antagonism in the acute post-traumatic time period and suggests a value to a hippocampal IEG readout as an outcome after injury or acute therapeutic intervention.


Assuntos
Lesões Encefálicas/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteína X Associada a bcl-2/metabolismo , Doença Aguda , Animais , Lesões Encefálicas/tratamento farmacológico , Modelos Animais de Doenças , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Lateralidade Funcional , Hipocampo/efeitos dos fármacos , Masculino , RNA Mensageiro/metabolismo , Ratos Long-Evans , Reação em Cadeia da Polimerase em Tempo Real , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Fatores de Tempo , Transcrição Gênica/efeitos dos fármacos
4.
PLoS One ; 5(3): e9478, 2010 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-20221429

RESUMO

BACKGROUND: Jawed vertebrates generate their immune-receptor repertoire by a recombinatorial mechanism that has the potential to produce harmful autoreactive lymphocytes. In mammals, peripheral tolerance to self-antigens is enforced by Foxp3(+) regulatory T cells. Recombinatorial mechanisms also operate in teleosts, but active immunoregulation is thought to be a late incorporation to the vertebrate lineage. METHODS/PRINCIPAL FINDINGS: Here we report the characterization of adaptive autoimmunity and Foxp3-based immunoregulation in the zebrafish. We found that zebrafish immunization with an homogenate of zebrafish central nervous system (zCNS) triggered CNS inflammation and specific antibodies. We cloned the zebrafish ortholog for mammalian Foxp3 (zFoxp3) which induced a regulatory phenotype on mouse T cells and controlled IL-17 production in zebrafish embryos. CONCLUSIONS/SIGNIFICANCE: Our findings demonstrate the acquisition of active mechanisms of self-tolerance early in vertebrate evolution, suggesting that active regulatory mechanisms accompany the development of the molecular potential for adaptive autoimmunity. Moreover, they identify the zebrafish as a tool to study the molecular pathways controlling adaptive immunity.


Assuntos
Autoimunidade , Fatores de Transcrição Forkhead/fisiologia , Proteínas de Peixe-Zebra/fisiologia , Sequência de Aminoácidos , Animais , Linhagem da Célula , Sequência Conservada , Humanos , Sistema Imunitário , Interleucina-17/metabolismo , Camundongos , Estrutura Terciária de Proteína , Receptores de Hidrocarboneto Arílico/metabolismo , Homologia de Sequência de Aminoácidos , Linfócitos T/imunologia , Peixe-Zebra
5.
Proc Natl Acad Sci U S A ; 105(48): 18889-94, 2008 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-19028871

RESUMO

Multiple sclerosis (MS) is a chronic relapsing disease of the central nervous system (CNS) in which immune processes are believed to play a major role. To date, there is no reliable method by which to characterize the immune processes and their changes associated with different forms of MS and disease progression. We performed antigen microarray analysis to characterize patterns of antibody reactivity in MS serum against a panel of CNS protein and lipid autoantigens and heat shock proteins. Informatic analysis consisted of a training set that was validated on a blinded test set. The results were further validated on an independent cohort of relapsing-remitting (RRMS) samples. We found unique autoantibody patterns that distinguished RRMS, secondary progressive (SPMS), and primary progressive (PPMS) MS from both healthy controls and other neurologic or autoimmune driven diseases including Alzheimer's disease, adrenoleukodystropy, and lupus erythematosus. RRMS was characterized by autoantibodies to heat shock proteins that were not observed in PPMS or SPMS. In addition, RRMS, SPMS, and PPMS were characterized by unique patterns of reactivity to CNS antigens. Furthermore, we examined sera from patients with different immunopathologic patterns of MS as determined by brain biopsy, and we identified unique antibody patterns to lipids and CNS-derived peptides that were linked to each type of pathology. The demonstration of unique serum immune signatures linked to different stages and pathologic processes in MS provides an avenue to monitor MS and to characterize immunopathogenic mechanisms and therapeutic targets in the disease.


Assuntos
Autoanticorpos , Análise em Microsséries/métodos , Esclerose Múltipla/sangue , Esclerose Múltipla/imunologia , Animais , Autoanticorpos/sangue , Autoanticorpos/imunologia , Encéfalo/imunologia , Encéfalo/patologia , Colesterol/química , Colesterol/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/classificação , Esclerose Múltipla/fisiopatologia , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Soro/imunologia
6.
Nature ; 453(7191): 65-71, 2008 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-18362915

RESUMO

Regulatory T cells (T(reg)) expressing the transcription factor Foxp3 control the autoreactive components of the immune system. The development of T(reg) cells is reciprocally related to that of pro-inflammatory T cells producing interleukin-17 (T(H)17). Although T(reg) cell dysfunction and/or T(H)17 cell dysregulation are thought to contribute to the development of autoimmune disorders, little is known about the physiological pathways that control the generation of these cell lineages. Here we report the identification of the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) as a regulator of T(reg) and T(H)17 cell differentiation in mice. AHR activation by its ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin induced functional T(reg) cells that suppressed experimental autoimmune encephalomyelitis. On the other hand, AHR activation by 6-formylindolo[3,2-b]carbazole interfered with T(reg) cell development, boosted T(H)17 cell differentiation and increased the severity of experimental autoimmune encephalomyelitis in mice. Thus, AHR regulates both T(reg) and T(H)17 cell differentiation in a ligand-specific fashion, constituting a unique target for therapeutic immunomodulation.


Assuntos
Diferenciação Celular , Interleucina-17/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo , Animais , Carbazóis/metabolismo , Carbazóis/farmacologia , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/imunologia , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Humanos , Indóis/metabolismo , Indóis/farmacologia , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Dibenzodioxinas Policloradas/metabolismo , Dibenzodioxinas Policloradas/farmacologia , Receptores de Hidrocarboneto Arílico/genética , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Fator de Crescimento Transformador beta1/imunologia , Fator de Crescimento Transformador beta1/metabolismo
7.
Oncol Rep ; 16(3): 581-5, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16865259

RESUMO

We examined the epigenetic mechanisms involved in human T-cell lymphotropic virus type 1 (HTLV-1) Tax expression. Blockade of histone deacetylation with trichostatin A (TSA) resulted in Tax upregulation. Using a chromatin immunoprecipitation (ChIP) assay, we verified local histone hyperacetylation at the HTLV-1 LTR in response to TSA. In agreement, HDAC3 transfection led to reductions in both Tax expression and histone acetylation. HDAC3 mutations and deletions spanning the catalytic site had variable ability to repress Tax, but HDAC activity was not essential for repression. Immunoprecipitation studies revealed that Tax co-exists in a complex containing both histone deacetylase 1 (HDAC1) and 3 (HDAC3). Our results suggest that HDACs may actively participate in the repression of HTLV-1 Tax transcription.


Assuntos
Regulação da Expressão Gênica , Genes pX/genética , Histona Desacetilases/fisiologia , Proteínas Repressoras , Transcrição Gênica , Acetilação , Células Cultivadas , Imunoprecipitação da Cromatina , Inibidores Enzimáticos/farmacologia , Inibidores de Histona Desacetilases , Histona Desacetilases/farmacologia , Histonas , Vírus Linfotrópico T Tipo 1 Humano/metabolismo , Humanos , Ácidos Hidroxâmicos/farmacologia , Mutação , Regiões Promotoras Genéticas , Deleção de Sequência , Ativação Transcricional
8.
J Biol Chem ; 280(31): 28507-18, 2005 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-15927959

RESUMO

To effectively direct targeted repression, the class I histone deacetylases (HDACs) associate with many important regulatory proteins. In this paper we describe the molecular characterization of a member of the Jumonji domain 2 (JMJD2) family of proteins, and demonstrate its binding to both class I HDACs and the retinoblastoma protein (pRb). JMJD2 proteins are characterized by the presence of two leukemia-associated protein/plant homeodomain (LAP/PHD) zinc fingers, one JmjN, one JmjC (containing an internal retinoblastoma-binding protein 2 (RBBP2)-like sequence), and two Tudor domains. The first member of this group, JMJD2A, is widely expressed in human tissues and cell lines, and high endogenous expression of JMJD2A mRNA was found in several cell types, including human T-cell lymphotropic virus 1 (HTLV-1)-infected cell lines. JMJD2A and JMJD2B exhibit cell type-specific responses to the HDAC inhibitor trichostatin A. We show that the JMJD2A protein associates in vivo with pRb and class I HDACs, and mediates repression of E2F-regulated promoters. In HTLV-1 virus-infected cells, we find that JMJD2A binds to the viral Tax protein. Antibodies to JMJD2A recognize the native protein but also a half-sized protein fragment, the latter up-regulated in THP-1 cells during the G(2)/M phase of the cell cycle. The ability of JMJD2A to associate with pRb and HDACs and potentiate pRb-mediated repression of E2F-regulated promoters implies an important role for this protein in cell proliferation and oncogenesis.


Assuntos
Proteínas de Ligação a DNA/genética , Fatores de Transcrição/genética , Sequência de Aminoácidos , Sequência Conservada , Primers do DNA , DNA Complementar/genética , Eletroporação , Biblioteca Gênica , Histona Desacetilases/genética , Humanos , Histona Desmetilases com o Domínio Jumonji , Fígado/embriologia , Dados de Sequência Molecular , Proteínas de Neoplasias/genética , Oxirredutases N-Desmetilantes , Filogenia , Reação em Cadeia da Polimerase , Proteínas Recombinantes de Fusão/metabolismo , Transfecção
9.
J Neurochem ; 93(5): 1087-98, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15934930

RESUMO

Multiple molecular defects trigger cell death in amyotrophic lateral sclerosis (ALS). Among these, altered transcriptional activity may perturb many cellular functions, leading to a cascade of secondary pathological effects. We showed that pharmacological treatment, using the histone deacetylase inhibitor sodium phenylbutyrate, significantly extended survival and improved both the clinical and neuropathological phenotypes in G93A transgenic ALS mice. Phenylbutyrate administration ameliorated histone hypoacetylation observed in G93A mice and induced expression of nuclear factor-kappaB (NF-kappaB) p50, the phosphorylated inhibitory subunit of NF-kappaB (pIkappaB) and beta cell lymphoma 2 (bcl-2), but reduced cytochrome c and caspase expression. Curcumin, an NF-kappaB inhibitor, and mutation of the NF-kappaB responsive element in the bcl-2 promoter, blocked butyrate-induced bcl-2 promoter activity. We provide evidence that the pharmacological induction of NF-kappaB-dependent transcription and bcl-2 gene expression is neuroprotective in ALS mice by inhibiting programmed cell death. Phenylbutyrate acts to phosphorylate IkappaB, translocating NF-kappaB p50 to the nucleus, or to directly acetylate NF-kappaB p50. NF-kappaB p50 transactivates bcl-2 gene expression. Up-regulated bcl-2 blocks cytochrome c release and subsequent caspase activation, slowing motor neuron death. These transcriptional and post-translational pathways ultimately promote motor neuron survival and ameliorate disease progression in ALS mice. Phenylbutyrate may therefore provide a novel therapeutic approach for the treatment of patients with ALS.


Assuntos
Esclerose Lateral Amiotrófica/fisiopatologia , Apoptose/genética , Expressão Gênica/efeitos dos fármacos , Fenilbutiratos/farmacologia , Acetilação/efeitos dos fármacos , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/mortalidade , Esclerose Lateral Amiotrófica/patologia , Animais , Inibidores de Caspase , Sobrevivência Celular/efeitos dos fármacos , Curcumina/farmacologia , Citocromos c/antagonistas & inibidores , Progressão da Doença , Histonas/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Neurônios Motores/efeitos dos fármacos , NF-kappa B/metabolismo , Subunidade p50 de NF-kappa B , Regiões Promotoras Genéticas/efeitos dos fármacos , Precursores de Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Medula Espinal/patologia
10.
J Neuroimmunol ; 164(1-2): 10-21, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15885809

RESUMO

We demonstrate that the histone deacetylase (HDAC) inhibitor drug trichostatin A (TSA) reduces spinal cord inflammation, demyelination, neuronal and axonal loss and ameliorates disability in the relapsing phase of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). TSA up-regulates antioxidant, anti-excitotoxicity and pro-neuronal growth and differentiation mRNAs. TSA also inhibits caspase activation and down-regulates gene targets of the pro-apoptotic E2F transcription factor pathway. In splenocytes, TSA reduces chemotactic, pro-Th1 and pro-proliferative mRNAs. A transcriptional imbalance in MS may contribute to immune dysregulation and neurodegeneration, and we identify HDAC inhibition as a transcriptional intervention to ameliorate this imbalance.


Assuntos
Encefalomielite Autoimune Experimental/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Ácidos Hidroxâmicos/uso terapêutico , Inibidores da Síntese de Proteínas/uso terapêutico , Animais , Morte Celular/efeitos dos fármacos , Células Cultivadas , Córtex Cerebral/citologia , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Esquema de Medicação , Interações Medicamentosas , Embrião de Mamíferos , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/patologia , Feminino , Perfilação da Expressão Gênica/métodos , Glicoproteínas , Imuno-Histoquímica/métodos , Camundongos , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito , Neurônios/efeitos dos fármacos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Fragmentos de Peptídeos , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Índice de Gravidade de Doença , Baço/efeitos dos fármacos , Baço/metabolismo , Sais de Tetrazólio , Tiazóis , Fatores de Tempo
11.
J Neuroimmunol ; 150(1-2): 163-77, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15081262

RESUMO

We performed microarray analysis of peripheral blood mononuclear cells (PBMCs) from multiple sclerosis (MS) patients and detected a profile of immune cell activation, autoantigen upregulation, and enhanced E2F pathway transcription. Accordingly, E2f1-deficient mice manifested only mild disability upon induction of experimental autoimmune encephalomyelitis (EAE). Furthermore, PBMCs from Avonex-treated patients had lower expression of E2F targets. The profile was enriched in genes known to harbor MS-associated polymorphisms, or localized to MS susceptibility chromosomal regions. Our study shows that PBMC microarrays reflect MS pathobiology that can be validated in the EAE model.


Assuntos
Proteínas de Ciclo Celular , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Perfilação da Expressão Gênica , Leucócitos Mononucleares/metabolismo , Esclerose Múltipla Recidivante-Remitente/genética , Esclerose Múltipla Recidivante-Remitente/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Transdução de Sinais/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Adolescente , Adulto , Animais , Mapeamento Cromossômico , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/fisiologia , Fatores de Transcrição E2F , Fator de Transcrição E2F1 , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Feminino , Perfilação da Expressão Gênica/métodos , Perfilação da Expressão Gênica/estatística & dados numéricos , Humanos , Interferon beta-1a , Interferon beta/uso terapêutico , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Família Multigênica/efeitos dos fármacos , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/imunologia , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Análise de Sequência com Séries de Oligonucleotídeos/estatística & dados numéricos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Fatores de Transcrição/deficiência , Fatores de Transcrição/fisiologia
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