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1.
Nat Neurosci ; 22(11): 1892-1902, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31611708

RESUMO

Blood vessels in the CNS form a specialized and critical structure, the blood-brain barrier (BBB). We present a resource to understand the molecular mechanisms that regulate BBB function in health and dysfunction during disease. Using endothelial cell enrichment and RNA sequencing, we analyzed the gene expression of endothelial cells in mice, comparing brain endothelial cells with peripheral endothelial cells. We also assessed the regulation of CNS endothelial gene expression in models of stroke, multiple sclerosis, traumatic brain injury and seizure, each having profound BBB disruption. We found that although each is caused by a distinct trigger, they exhibit strikingly similar endothelial gene expression changes during BBB disruption, comprising a core BBB dysfunction module that shifts the CNS endothelial cells into a peripheral endothelial cell-like state. The identification of a common pathway for BBB dysfunction suggests that targeting therapeutic agents to limit it may be effective across multiple neurological disorders.


Assuntos
Barreira Hematoencefálica/metabolismo , Lesões Encefálicas Traumáticas/metabolismo , Células Endoteliais/metabolismo , Esclerose Múltipla/metabolismo , Convulsões/metabolismo , Acidente Vascular Cerebral/metabolismo , Transcriptoma/genética , Animais , Biotina/metabolismo , Encéfalo/metabolismo , Infarto da Artéria Cerebral Média , Ácido Caínico , Camundongos , Camundongos Transgênicos , Esclerose Múltipla/induzido quimicamente , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Peptídeos , Permeabilidade , Toxina Pertussis , Convulsões/induzido quimicamente , Transdução de Sinais
2.
Medicina (Kaunas) ; 55(10)2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31581595

RESUMO

Background and objectives: Macrophage Migration Inhibitory Factor (MIF) and D-Dopachrome Tautomerase (DDT) are two pleiotropic and primarily, but not exclusively, proinflammatory cytokines belonging to the MIF family of cytokines that have recently been shown to be implicated in the pathogenesis of progressive forms of human progressive Multiple Sclerosis (MS) and the experimental model counterpart in rodents. Materials and Methods: We have presently evaluated a transcriptomic analysis of the expression of MIF, DDT, their receptors CD74 and CD44, and MIF co-receptors CXCR2, CXCR4, and CXCR7 in peripheral blood of patients with Clinically Isolated Syndrome (CIS), with rapid progression to clinical defined MS. Results: Our analysis reveals that MIF, DDT, and CD44 are overexpressed in CD4+ T cells from patients with CIS, as compared to healthy controls. Accordingly, a significant overlap was observed between the genes overexpressed in CD4+ T cells from patients with CIS and the genes belonging to the MIF regulatory network. This upregulated expression appeared to be unique for CD4+T cells, as other immune cells including CD8+ T cells, B cells, and monocytes from these patients exhibited expression levels of these molecules that were superimposable to those observed in healthy controls. Conclusions: Overall, our data suggest that the overexpression MIF cytokine family signature may occur in CD4+ T cells from patients with CIS, and that this phenomenon may be implicated in the pathogenesis of the disease, offering the possibility to represent both a diagnostic marker and a therapeutic target.


Assuntos
Receptores de Hialuronatos/metabolismo , Oxirredutases Intramoleculares/metabolismo , Fatores Inibidores da Migração de Macrófagos/metabolismo , Esclerose Múltipla/metabolismo , Regulação para Cima , Adolescente , Adulto , Biomarcadores/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Feminino , Humanos , Masculino , Esclerose Múltipla/sangue , Adulto Jovem
3.
Int J Mol Sci ; 20(19)2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31574937

RESUMO

The transcription factor NURR1 is a constitutively active orphan receptor belonging to the steroid hormone receptor class NR4A. Although a genetic association between NURR1 and autoimmune inflammatory diseases has never emerged from genome-wide association studies (GWAS), alterations in the expression of NURR1 have been observed in various autoimmune diseases. Specifically, its role in autoimmune inflammatory diseases is mainly related to its capability to counteract inflammation. In fact, NURR1 exerts anti-inflammatory functions inhibiting the transcription of the molecules involved in proinflammatory pathways, not only in the peripheral blood compartment, but also in the cerebral parenchyma acting in microglial cells and astrocytes. In parallel, NURR1 has been also linked to dopamine-associated brain disorders, such as Parkinson's disease (PD) and schizophrenia, since it is involved in the development and in the maintenance of midbrain dopaminergic neurons (mDA). Considering its role in neuro- and systemic inflammatory processes, here we review the evidences supporting its contribution to multiple sclerosis (MS), a chronic inflammatory autoimmune disease affecting the central nervous system (CNS). To date, the specific role of NURR1 in MS is still debated and few authors have studied this topic. Here, we plan to clarify this issue analyzing the reported association between NURR1 and MS in human and murine model studies.


Assuntos
Suscetibilidade a Doenças , Esclerose Múltipla/etiologia , Esclerose Múltipla/metabolismo , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Animais , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental , Regulação da Expressão Gênica , Humanos , Camundongos , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
4.
Life Sci ; 238: 116924, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31606383

RESUMO

Multiple sclerosis (MS) is an autoimmune chronic inflammatory disease with distinctive features of focal demyelination, axonal loss, activation of glial cells, and immune cells infiltration. The precise molecular mechanism underlying the disease progression remains enigmatic despite of the rapid progression on experimental and clinical MS research. The focus of MS therapy relies on the repression of the pathogenic autoimmune response without compromising an adaptive immune response. High mobility group box-1 (HMGB1) protein is a ubiquitous nuclear protein driving pro-inflammatory responses as well as targeting innate immune signaling that initiates and mediates autoimmunity as well as sterile injury. A considerable amount of experimental and human studies suggests the contribution of HMGB1 in the pathogenesis of MS/experimental autoimmune encephalitis (EAE). In this regard, HMGB1 protein has gained increased attention, as an emerging possible therapeutic target against MS. This is more strengthened by the promising therapeutic outcome demonstrated by HMGB1 neutralizing agents in the experimental EAE model. Herein, we attempt to shed more light on the molecular crosstalk of HMGB1 protein in the pathogenesis of MS/EAE suggesting that HMGB1 blockade could impede the pro-inflammatory loop that drives MS autoimmunity.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Proteína HMGB1/antagonistas & inibidores , Esclerose Múltipla/tratamento farmacológico , Animais , Humanos , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia
5.
Int J Mol Sci ; 20(20)2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31614447

RESUMO

Ceramide and sphingosine display a unique profile during brain development, indicating their critical role in myelinogenesis. Employing advanced technology such as gas chromatography-mass spectrometry, high performance liquid chromatography, and immunocytochemistry, along with cell culture and molecular biology, we have found an accumulation of sphingosine in brain tissues of patients with multiple sclerosis (MS) and in the spinal cord of rats induced with experimental autoimmune encephalomyelitis. The elevated sphingosine leads to oligodendrocyte death and fosters demyelination. Ceramide elevation by serine palmitoyltransferse (SPT) activation was the primary source of the sphingosine elevation as myriocin, an inhibitor of SPT, prevented sphingosine elevation and protected oligodendrocytes. Supporting this view, fingolimod, a drug used for MS therapy, reduced ceramide generation, thus offering partial protection to oligodendrocytes. Sphingolipid synthesis and degradation in normal development is regulated by a series of microRNAs (miRNAs), and hence, accumulation of sphingosine in MS may be prevented by employing miRNA technology. This review will discuss the current knowledge of ceramide and sphingosine metabolism (synthesis and breakdown), and how their biosynthesis can be regulated by miRNA, which can be used as a therapeutic approach for MS.


Assuntos
Ceramidas/biossíntese , MicroRNAs/genética , Esclerose Múltipla/genética , Serina C-Palmitoiltransferase/metabolismo , Esfingosina/biossíntese , Animais , Encéfalo/metabolismo , Cloridrato de Fingolimode/farmacologia , Cloridrato de Fingolimode/uso terapêutico , Humanos , MicroRNAs/antagonistas & inibidores , Terapia de Alvo Molecular , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Bainha de Mielina/metabolismo , Ratos , Serina C-Palmitoiltransferase/antagonistas & inibidores
6.
Int J Mol Sci ; 20(20)2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31600882

RESUMO

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that involves the autoreactive T-cell attack on axonal myelin sheath. Lesions or plaques formed as a result of repeated damage and repair mechanisms lead to impaired relay of electrical impulses along the nerve, manifesting as clinical symptoms of MS. Evidence from studies in experimental autoimmune encephalomyelitis (EAE) models of MS strongly suggests that mitochondrial dysfunction presents at the onset of disease and throughout the disease course. The aim of this study was to determine if mitochondrial dysfunction occurs before clinical symptoms arise, and whether this is confined to the CNS. EAE was induced in C57B/L6 mice, and citrate synthase and mitochondrial respiratory chain (MRC) complex I-IV activities were assayed at presymptomatic (3 or 10 days post first immunisation (3 or 10 DPI)) and asymptomatic (17 days post first immunisation (17 DPI) time-points in central nervous system (CNS; spinal cord) and peripheral (liver and jaw muscle) tissues. Samples from animals immunised with myelin oligodendrocyte glycoprotein (MOG) as EAE models were compared with control animals immunised with adjuvant (ADJ) only. Significant changes in MOG compared to control ADJ animals in MRC complex I activity occurred only at presymptomatic stages, with an increase in the spinal cord at 10 DPI (87.9%), an increase at 3 DPI (25.6%) and decrease at 10 DPI (22.3%) in the jaw muscle, and an increase in the liver at 10 DPI (71.5%). MRC complex II/III activity changes occurred at presymptomatic and the asymptomatic stages of the disease, with a decrease occurring in the spinal cord at 3 DPI (87.6%) and an increase at 17 DPI (36.7%), increase in the jaw muscle at 10 DPI (25.4%), and an increase at 3 DPI (75.2%) and decrease at 17 DPI (95.7%) in the liver. Citrate synthase activity was also significantly decreased at 10 DPI (27.3%) in the liver. No significant changes were observed in complex IV across all three tissues assayed. Our findings reveal evidence that mitochondrial dysfunction is present at the asymptomatic stages in the EAE model of MS, and that the changes in MRC enzyme activities are tissue-specific and are not confined to the CNS.


Assuntos
Encefalomielite Autoimune Experimental/metabolismo , Mitocôndrias/metabolismo , Esclerose Múltipla/metabolismo , Animais , Biomarcadores , Modelos Animais de Doenças , Suscetibilidade a Doenças , Encefalomielite Autoimune Experimental/diagnóstico , Encefalomielite Autoimune Experimental/etiologia , Feminino , Camundongos , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/etiologia , Músculo Esquelético/metabolismo , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Índice de Gravidade de Doença
7.
DNA Cell Biol ; 38(10): 1025-1029, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31532239

RESUMO

Neutrophil trafficking into damaged or infected tissues is essential for the initiation of inflammation, clearance of pathogens and damaged cells, and ultimately tissue repair. Neutrophil recruitment is highly dependent on the stepwise induction of adhesion molecules and promigratory chemokines and cytokines. A number of studies in animal models have shown the efficacy of cannabinoid receptor 2 (CB2) agonists in limiting inflammation in a range of preclinical models of inflammation, including colitis, atherosclerosis, multiple sclerosis, and ischemia-reperfusion injury. Recent work in preclinical models of inflammation raises two questions: by what mechanisms do CB2 agonists provide anti-inflammatory effects during acute inflammation and what challenges exist in the translation of CB2 modulating therapeutics into the clinic.


Assuntos
Aterosclerose/genética , Colite/genética , Esclerose Múltipla/genética , Neutrófilos/metabolismo , Receptor CB2 de Canabinoide/genética , Traumatismo por Reperfusão/genética , Animais , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Aterosclerose/patologia , Agonistas de Receptores de Canabinoides/uso terapêutico , Antagonistas de Receptores de Canabinoides/uso terapêutico , Colite/tratamento farmacológico , Colite/metabolismo , Colite/patologia , Citocinas/metabolismo , Citocinas/farmacologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Inflamação , Ligantes , Camundongos , Camundongos Knockout , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Infiltração de Neutrófilos , Neutrófilos/efeitos dos fármacos , Neutrófilos/patologia , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/deficiência , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia
8.
Neurology ; 93(15): e1439-e1451, 2019 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-31501228

RESUMO

OBJECTIVES: To evaluate intrathecal immunoglobulin M (IgM) production, as compared to previously established risk factors, as risk factor for conversion from clinically isolated syndrome (CIS) to multiple sclerosis (MS) and to explore the association of intrathecal IgM production with onset age and radiologic and CSF findings in CIS/early MS. METHODS: Comprehensive CSF data, including oligoclonal immunoglobulin G (IgG) bands (OCB) and calculated intrathecal IgM and IgG production, were collected in a prospective study of 150 patients with CIS/early MS with regular clinical and MRI assessments. RESULTS: Intrathecal IgM production >0% occurred in 23.2% (33/142) of patients, who were on average 5 years younger at disease onset (p = 0.013) and more frequently had infratentorial lesions (18/32, 56.3%) than patients without intrathecal IgM production (33/104, 31.7%, p = 0.021). In multivariable Cox regression analyses, intrathecal IgM production in patients with a CIS (n = 93, median clinical and MRI follow-up 24 and 21 months) was strongly associated with conversion to MS according to the McDonald 2010 criteria (hazard ratio [95% confidence interval] 3.05 [1.45-6.44], p = 0.003) after adjustment for age (0.96 [0.93-1.00], p = 0.059), OCB (0.92 [0.33-2.61], p = 0.879), intrathecal IgG production (0.98 [0.48-1.99], p = 0.947), and radiologic evidence of dissemination in space (2.63 [1.11-6.22], p = 0.028). CONCLUSION: Intrathecal IgM production is a strong independent risk factor for early conversion to MS and may thus represent a clinically meaningful marker for predicting future disease activity in patients with a CIS.


Assuntos
Doenças Desmielinizantes/metabolismo , Imunoglobulina M/metabolismo , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Adulto , Idade de Início , Idoso , Doenças Desmielinizantes/patologia , Progressão da Doença , Feminino , Humanos , Imunoglobulina G/metabolismo , Masculino , Pessoa de Meia-Idade , Bandas Oligoclonais/metabolismo , Fatores de Risco , Índice de Gravidade de Doença
9.
Iran J Allergy Asthma Immunol ; 18(3): 230-250, 2019 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-31522431

RESUMO

Toll-like receptors (TLRs) play principle roles in recognition of autologous components which have been pointed as the danger-associated molecular patterns (DAMP) and microbial components which are identified as pathogen associated molecular patterns (PAMP).The infiltration of various inflammatory cells such as dendritic cells, lymphocytes (CD4+ T, CD8+ T as well as B cells), monocytes and macrophages occur into the central nervous sys-tem (CNS) during multiple sclerosis (MS) and its animal model named experimental autoimmune encephalomyelitis (EAE). The infiltrated leukocytes and residential cells of the CNS express several TLRs (especially TLR2) and their expression are elevated in MS and EAE. TLR2 recognizes a large variety DAMP and PAMP molecules due to its ability to create heterodimers with TLR1, TLR6 and probably TLR10. A wide spectrum of  DAMP molecules, including heat shock protein 60 (HSP60), HSP70, high mobility group box 1 (HMGB1), ß-defensin 3, surfactant protein A and D, eosinophil-derived neurotoxin, gangliosides, serum amyloid A, hyaluronic acid and biglycan are identified by TLR2, whose their expression is increased in MS patients. TLR2 may contribute in the development of MS and EAE diseases through the reinforcement of Th1/Th17 cell-related responses, downregulation of regulatory T cells, induction of IL-17+ γδ T cells, inhibition of oligodendrocyte maturation, induction of poly ADP-ribose polymerase-1 (PARP-1)-dependent pathway in microglia, macrophages and astrocytes and inhibition of type I interferons expression. The contribution of TLR2-related immunopathological responses in the MS and EAE pathogenesis and its possible targeting as promising therapeutic potentials are considered in this review.


Assuntos
Esclerose Múltipla/etiologia , Esclerose Múltipla/metabolismo , Receptor 2 Toll-Like/metabolismo , Animais , Comunicação Celular , Suscetibilidade a Doenças , Encefalomielite Autoimune Experimental/etiologia , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunomodulação , Ligantes , Macrófagos/imunologia , Macrófagos/metabolismo , Microglia/imunologia , Microglia/metabolismo , Terapia de Alvo Molecular , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologia , Bainha de Mielina/imunologia , Bainha de Mielina/metabolismo , Oligodendroglia/citologia , Oligodendroglia/imunologia , Oligodendroglia/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Receptor 2 Toll-Like/antagonistas & inibidores , Receptor 2 Toll-Like/genética
10.
Iran J Allergy Asthma Immunol ; 18(3): 300-309, 2019 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-31522437

RESUMO

Multiple sclerosis (MS) is an autoimmune disease that affects the central nervous system.MS creates a wide range of symptoms with lifelong debilitating consequences. The hallmark of the disease is the inflammation of the nervous system, which can lead to damage to the nerve tissue and loss of function of the neurons. IL-17 has a prominent role in the beginning of inflammatory reactions. Here, we analyzed a mouse model developed using anti-myelin antibodies. This mouse model mimics many symptoms of MS in humans. C57BL/6 mice were randomly divided into five groups. Mice were immunized subcutaneously with 50 µg, 100 µg, 150 µg and 200 µg myelin oligodendrocyte glycoprotein in complete Freund's adjuvant containing 4 mg/Ml Mycobacterium tuberculosis and two injections of 800 ng of pertussis toxin intraperitoneally, on day 0 and 2 post immunization. Serum level of IL-17 was measured, inflammation and demyelination of brain tissue were also evaluated. Mice with experimental autoimmune encephalomyelitis demonstrated inflammatory cell accumulation, different degrees of demyelination in the brain, and rising levels of serum IL-17 depending on the dose of the anti-myelin antibody. Our study demonstrates that level of IL-17 production is directly associated with inflammation and demyelination. In addition, different degrees of experimental autoimmune encephalomyelitis in mice can be utilized to test a wide range of therapeutic interventions for MS treatment.


Assuntos
Encéfalo/imunologia , Encéfalo/metabolismo , Doenças Desmielinizantes/imunologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Interleucina-17/sangue , Glicoproteína Mielina-Oligodendrócito/imunologia , Animais , Encéfalo/patologia , Citocinas/sangue , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/sangue , Encefalomielite Autoimune Experimental/diagnóstico , Feminino , Imuno-Histoquímica , Camundongos , Esclerose Múltipla/sangue , Esclerose Múltipla/imunologia , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Índice de Gravidade de Doença
11.
Nat Rev Neurol ; 15(12): 704-717, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31527807

RESUMO

Immune cells mediate critical inflammatory and neurodegenerative processes in the CNS in individuals with multiple sclerosis (MS). In MS, activated microglia, border-associated macrophages and monocyte-derived macrophages in the CNS can encounter T cells that have infiltrated the brain parenchyma from the circulation. Although microglia and T cells both contribute to normal CNS development and homeostasis, evidence suggests that the meeting of activated microglia and macrophages with encephalitogenic T cells exacerbates their capacity to inflict injury. This crosstalk involves many cell-surface molecules, cytokines and neurotoxic factors. In this Review, we summarize the mechanisms and consequences of T cell-microglia interactions as identified with in vitro experiments and animal models, and discuss the challenges that arise when translating this preclinical knowledge to MS in humans. We also consider therapeutic approaches to MS of which the mechanisms involve prevention or modulation of T cell and microglia responses and their interactions.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Microglia/imunologia , Esclerose Múltipla/imunologia , Linfócitos T/imunologia , Animais , Comunicação Celular/fisiologia , Encefalomielite Autoimune Experimental/metabolismo , Homeostase/fisiologia , Humanos , Microglia/metabolismo , Esclerose Múltipla/metabolismo , Linfócitos T/metabolismo
12.
BMC Immunol ; 20(1): 30, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31438837

RESUMO

BACKGROUND: The persistent the inflammatory condition in multiple sclerosis (MS) may due to the aberrant regulation of the elimination of the pathogenic autoreactive lymphocytes through apoptosis. Survivin, encoded by the BIRC5 gene, has been indicated to be involved in the regulation of apoptosis. This survey intended to investigate the genetic and microRNA mediated regulation of survivin in relapsing-remitting MS (RRMS) disease. RESULTS: It was observed that the C allele (OR = 1.38, 95% CI = 1.05-1.348, P = 0.022) and CC genotype (OR = 1.84, 95% CI = 1.06-3.19; P = 0.029) in the rs9904341 polymorphism increased the disease risk. Furthermore, miR-34a was significantly downregulated (Fold change = 0.41, P = 0.001) in the PBMCs from RRMS subjects. Survivin mRNA expression in PBMCs and serum survivin level were increased in RRMS patients in comparison to the controls. Downregulation of miR-34a was negatively correlated with increased survivin level. CONCLUSION: Although the genetic polymorphism of BIRC5 gene was associated with the disease risk, miR-34a was suggested to be involved in the regulation of survivin in the RRMS patients.


Assuntos
Epigênese Genética , Predisposição Genética para Doença , Esclerose Múltipla/genética , Polimorfismo de Nucleotídeo Único , Survivina/genética , Adulto , Alelos , Apoptose , Biomarcadores , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Leucócitos Mononucleares , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Esclerose Múltipla/metabolismo , Razão de Chances , Survivina/metabolismo
13.
Nat Rev Neurol ; 15(10): 582-593, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31420598

RESUMO

Activation of innate immune cells and other compartmentalized inflammatory cells in the brains and spinal cords of people with relapsing-remitting multiple sclerosis (MS) and progressive MS has been well described histopathologically. However, conventional clinical MRI is largely insensitive to this inflammatory activity. The past two decades have seen the introduction of quantitative dynamic MRI scanning with contrast agents that are sensitive to the reduction in blood-brain barrier integrity associated with inflammation and to the trafficking of inflammatory myeloid cells. New MRI imaging sequences provide improved contrast for better detection of grey matter lesions. Quantitative lesion volume measures and magnetic resonance susceptibility imaging are sensitive to the activity of macrophages in the rims of white matter lesions. PET and magnetic resonance spectroscopy methods can also be used to detect contributions from innate immune activation in the brain and spinal cord. Some of these advanced research imaging methods for visualization of chronic inflammation are practical for relatively routine clinical applications. Observations made with the use of these techniques suggest ways of stratifying patients with MS to improve their care. The imaging methods also provide new tools to support the development of therapies for chronic inflammation in MS.


Assuntos
Mediadores da Inflamação/metabolismo , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/metabolismo , Doença Crônica , Humanos , Inflamação/diagnóstico por imagem , Inflamação/metabolismo , Neuroimagem/tendências
14.
Molecules ; 24(16)2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31426440

RESUMO

Matrix metalloproteinases (MMPs) are a family of zinc- and calcium-dependent endopeptidases which are secreted or anchored in the cell membrane and are capable of degrading the multiple components of the extracellular matrix (ECM). MMPs are frequently overexpressed or highly activated in numerous human diseases. Owing to the important role of MMPs in human diseases, many MMP inhibitors (MMPIs) have been developed as novel therapeutics, and some of them have entered clinical trials. However, so far, only one MMPI (doxycycline) has been approved by the FDA. Therefore, the evaluation of the activity of a specific subset of MMPs in human diseases using clinically relevant imaging techniques would be a powerful tool for the early diagnosis and assessment of the efficacy of therapy. In recent years, numerous MMPIs labeled imaging agents have emerged. This article begins by providing an overview of the MMP subfamily and its structure and function. The latest advances in the design of subtype selective MMPIs and their biological evaluation are then summarized. Subsequently, the potential use of MMPI-labeled diagnostic agents in clinical imaging techniques are discussed, including positron emission tomography (PET), single-photon emission computed tomography (SPECT) and optical imaging (OI). Finally, this article concludes with future perspectives and clinical utility.


Assuntos
Aterosclerose/diagnóstico por imagem , Doenças Cardiovasculares/diagnóstico por imagem , Pneumopatias/diagnóstico por imagem , Inibidores de Metaloproteinases de Matriz/farmacocinética , Metaloproteinases da Matriz/química , Sondas Moleculares/farmacocinética , Neoplasias/diagnóstico por imagem , Osteoartrite/diagnóstico por imagem , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Domínio Catalítico/genética , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/diagnóstico por imagem , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Humanos , Pneumopatias/metabolismo , Pneumopatias/patologia , Inibidores de Metaloproteinases de Matriz/síntese química , Metaloproteinases da Matriz/genética , Metaloproteinases da Matriz/metabolismo , Imagem Molecular/métodos , Sondas Moleculares/síntese química , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Neoplasias/metabolismo , Neoplasias/patologia , Osteoartrite/metabolismo , Osteoartrite/patologia , Tomografia por Emissão de Pósitrons/métodos , Tomografia Computadorizada de Emissão de Fóton Único/métodos
15.
Nutrients ; 11(7)2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31284389

RESUMO

Multiple sclerosis (MS) is a complex disease of the central nervous system (CNS). The etiology of this multifactorial disease has not been clearly defined. Conventional medical treatment of MS has progressed, but is still based on symptomatic treatment. One of the key factors in the pathogenesis of MS is oxidative stress, enhancing inflammation and neurodegeneration. In MS, both reactive oxygen and nitrogen species are formed in the CNS mainly by activated macrophages and microglia structures, which can lead to demyelination and axon disruption. The course of MS is associated with the secretion of many inflammatory and oxidative stress mediators, including cytokines (IL-1b, IL-6, IL-17, TNF-α, INF-γ) and chemokines (MIP-1a, MCP-1, IP10). The early stage of MS (RRMS) lasts about 10 years, and is dominated by inflammatory processes, whereas the chronic stage is associated with neurodegenerative axon and neuron loss. Since oxidative damage has been known to be involved in inflammatory and autoimmune-mediated processes, antioxidant therapy could contribute to the reduction or even prevention of the progression of MS. Further research is needed in order to establish new aims for novel treatment and provide possible benefits to MS patients. The present review examines the roles of oxidative stress and non-pharmacological anti-oxidative therapies in MS.


Assuntos
Antioxidantes/uso terapêutico , Sistema Nervoso Central/efeitos dos fármacos , Esclerose Múltipla/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Animais , Anti-Inflamatórios/uso terapêutico , Antioxidantes/efeitos adversos , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/fisiopatologia , Citocinas/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Esclerose Múltipla/dietoterapia , Esclerose Múltipla/metabolismo , Esclerose Múltipla/fisiopatologia , Estado Nutricional , Transdução de Sinais , Resultado do Tratamento
16.
Neurology ; 93(6): e611-e623, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31285398

RESUMO

OBJECTIVE: Frequent administration of gadolinium-based contrast agents in multiple sclerosis (MS) may increase signal intensity (SI) unenhanced T1-weighted imaging MRI throughout the brain. We evaluated the association between lifetime cumulative doses of gadodiamide administration and increased SI within the dentate nucleus (DN), globus pallidus (GP), and thalamus in patients with early MS. METHODS: A total of 203 patients with MS (107 with baseline and follow-up MRI assessments) and 262 age- and sex-matched controls were included in this retrospective, longitudinal, 3T MRI-reader-blinded study. Patients with MS had disease duration <2 years at baseline and received exclusively gadodiamide at all MRI time points. SI ratio (SIR) to pons and CSF of lateral ventricle volume (CSF-LVV) were assessed. Analysis of covariance and correlation analyses, adjusted for age, sex, and region of interest volume, were used. RESULTS: The mean follow-up time was 55.4 months, and the mean number of gadolinium-based contrast agents administrations was 9.2. At follow-up, 49.3% of patients with MS and no controls showed DN T1 hyperintensity (p < 0.001). The mean SIR of DN (p < 0.001) and of GP (p = 0.005) to pons and the mean SIR of DN, GP, and thalamus to CSF-LVV were higher in patients with MS compared to controls (p < 0.001). SIR of DN to pons was associated with number of gadodiamide doses (p < 0.001). No associations between SIR of DN, GP, and thalamus and clinical and MRI outcomes of disease severity were detected over the follow-up. CONCLUSIONS: DN, GP, and thalamus gadolinium deposition in early MS is associated with lifetime cumulative gadodiamide administration without clinical or radiologic correlates of more aggressive disease.


Assuntos
Encéfalo/metabolismo , Meios de Contraste/farmacocinética , Gadolínio DTPA/farmacocinética , Gadolínio/metabolismo , Esclerose Múltipla/metabolismo , Adulto , Encéfalo/diagnóstico por imagem , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico por imagem , Estudos Retrospectivos
17.
Complement Ther Med ; 45: 275-279, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31331574

RESUMO

OBJECTIVES: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system. Several effector mechanisms are involved in the immunopathology of MS and a variety of medications such as beta interferons are applied to treat the disease. This study was conducted to evaluate the anti-inflammatory and immunomodulatory effects of sesame oil in combination with interferon beta-1a in MS treatment. METHODS: Ninety-three MS patients were enrolled in the study. The patients were randomly divided into two groups. The control group (n = 39) received 30 µg/week of interferon beta-1a intra-muscularly. The sesame oil-treated group (n = 54) received interferon beta-1a the same as the control group with the addition of 0.5 ml/kg/day of oral sesame oil for 6 months. RESULTS: After the 6-month study period, the interleukin (IL)-10 concentration in the sesame oil-treated group was significantly greater than that of the control group (p = 0.04). The concentrations of interferon-γ (IFN-γ), nitric oxide (NO), and tumor necrosis factor-α (TNF-α) in the sesame oil group after treatment were significantly less than those of the control group (p = 0.029, p = 0.0001, and p = 0.01, respectively). Lymphocyte proliferation in the sesame oil-treated group was significantly lower at the end of the study than at the beginning (p = 0.001). CONCLUSION: Sesame oil, through a decrease in IFN-γ secretion and anti-inflammatory and anti-oxidant activities, may have beneficial effects for MS patients.


Assuntos
Interferon beta-1a/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Óleo de Gergelim/uso terapêutico , Adolescente , Adulto , Idoso , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Interleucina-10/metabolismo , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/metabolismo , Óxido Nítrico/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Adulto Jovem
18.
Mediators Inflamm ; 2019: 8147803, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31346315

RESUMO

Peripheral blood biomarkers able to predict disease activity in multiple sclerosis (MS) patients have not been identified yet. Here, we analyzed the immune phenotype of T lymphocyte subpopulations in peripheral blood samples from 66 RRMS patients under DMF (n = 22) or fingolimod (n = 44) treatment, by flow cytometry. A correlation study between the percentage and absolute cell number of each lymphocyte subpopulation with the presence of relapses or new MRI lesions during 12-month follow-up was performed. Patients who had undergone relapses showed at baseline higher percentage of Th1CM cells (relapsed: 11.60 ± 4.17%vs. nonrelapsed: 9.25 ± 3.17%, p < 0.05) and Th1Th17CM cells (relapsed: 15.65 ± 6.15%vs. nonrelapsed: 10.14 ± 4.05%, p < 0.01) before initiating DMF or fingolimod treatment. Kaplan-Meier analysis revealed that patients with Th1Th17CM (CD4+CCR7+CD45RA-CCR6+CXCR3+) cells > 11.48% had a 50% relapse-free survival compared to patients with Th1Th17CMcells < 11.48% whose relapse-free survival was 88% (p = 0.013, log-rank test). Additionally, a high percentage of Th1Th17CM cells was also found in patients with MRI activity (MRI activity: 14.02 ± 5.87%vs. no MRI activity: 9.82 ± 4.06%, p < 0.01). Our results suggest that the percentage of Th1Th17CM lymphocytes at baseline is a predictive biomarker of activity during the first 12 months of treatment, regardless of the treatment.


Assuntos
Biomarcadores/metabolismo , Fumarato de Dimetilo/uso terapêutico , Cloridrato de Fingolimode/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Células Th17/metabolismo , Adulto , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Subpopulações de Linfócitos T/metabolismo
19.
Mult Scler Relat Disord ; 34: 47-58, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31228716

RESUMO

Multiple Sclerosis (MS) is a challenging and disabling condition particularly in the secondary progressive (SP) phase of this disease. The available treatments cannot ameliorate or stop disease progression in this phase, and there is an urgent need to focus on effective therapies and the molecular pathways involved SPMS. Given the significant impact of neurodegeneration, autoimmunity and metabolic alterations in MS, focusing on the molecules that target these different pathways could help in finding new treatments. Sirtuins (SIRTs) are NAD+ dependent epigenetic and metabolic regulators, which have critical roles in the physiology of central nervous system, immune system and metabolism. Based on these facts, SIRTs are crucial candidates of therapeutic targets in MS and collecting the information related to MS disease for each SIRT individually is noteworthy and highlights the lack of investigation in each part. In this review we summarized the role of different sirtuins as key regulator in neurodegeneration, autoimmunity and metabolism pathways. We also clarify the rationale behind selecting SIRTs as therapeutic targets in MS disease by collecting the researches showing alteration of these proteins in human samples of MS patients and animal model of MS, and also the improvement of modeled animals after SIRT-directed treatments.


Assuntos
Autoimunidade/fisiologia , Esclerose Múltipla/metabolismo , Degeneração Neural/metabolismo , Sirtuínas/metabolismo , Animais , Sistema Nervoso Central/metabolismo , Humanos
20.
Med Hypotheses ; 128: 25-27, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31203904

RESUMO

Nanobacteria or calcifying nanoparticles are 80-500 nm sized nano-organisms that are physically associated with carbonate apatite mineral formations. They have been indicated in various diseases, including kidney stone formation, Alzheimer's disease, and atherosclerosis. Nanoparticles contain calcium and apatite-binding protein fetuin-A, a calcification inhibitor. However, recent evidence indicates that fetuin-A can form nucleation seeds or nidi that grow in size through ion sedimentation to become larger amorphous nanoparticles in the presence of excess calcium and apatite ions. Fetuin-A also functions as an inhibitor of meprin, a metalloproteinase implicated in inflammation and neurodegenerative diseases. During inflammation, meprin functions to regulate chemokine activity of monocyte chemotactic protein 1, which is associated with chronic inflammatory diseases, including atherosclerosis, renal inflammatory diseases, and multiple sclerosis (MS). In addition, calcium phosphate nanocrystals that contain fetuin-A are pro-inflammatory to macrophages and promote vascular smooth muscle cell mineralization, potentiating a vicious cycle of inflammation and calcification. Thus, mineral stress and inflammation appear to be associated with each other. Furthermore, fetuin-A deficient mice exhibited reduced experimental autoimmune encephalomyelitis severity. Thus, fetuin-A plays a direct role in the neuroinflammatory response. Indeed, the level of fetuin-A in cerebrospinal fluid has been defined as a biomarker of disease activity in MS. MS is a chronic, inflammatory, demyelinating, and neurodegenerative disease of the central nervous system (CNS) with an unknown etiology. The "inside-out" model of MS, supported by recent data, states that the initial axonal degeneration in the CNS occurs before demyelination, which then stimulates an auto-immune attack. It was shown very recently that influx of calcium from the extracellular space through nanoscale ruptures of the axonal plasma membrane predict axon degeneration in neuroinflammation. Calcium is an activator of calpains, proteases that function to break down the cytoskeleton, leading to neurodegeneration. Nanoruptures of the plasma membrane were suggested to occur at the early stages of axon damage, especially at nodes of Ranvier, which are devoid of myelin. Here, I propose that calcifying nanoparticles may have a role in the etiology and/or pathophysiology of MS. The initial event causing neurodegeneration may be due to the nanoparticles that have been suggested to easily cross the blood-brain barrier. Following this, the nanoparticles may create nanoruptures in the axonal membrane and also increase the calcium concentration around and within the neurons by forming nidi for calcification, eventually causing neurodegeneration. Nanoparticles can self-replicate; hence, they may represent an infectious causative agent for the development of MS.


Assuntos
Nanopartículas Calcificantes/efeitos adversos , Calcinose/metabolismo , Esclerose Múltipla/etiologia , Animais , Apatitas/química , Barreira Hematoencefálica/metabolismo , Nanopartículas Calcificantes/química , Cálcio/química , Sistema Nervoso Central/metabolismo , Quimiocinas/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Humanos , Inflamação , Íons , Camundongos , Esclerose Múltipla/metabolismo , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/metabolismo , alfa-2-Glicoproteína-HS/química
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