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1.
J Neuroimmunol ; 388: 578312, 2024 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-38364528

RESUMO

OBJECTIVES: To describe papillitis as a clinical phenotype of IgLON5 autoimmunity. METHODS: We retrospectively reviewed patients with IgLON5 autoimmunity who had optic neuropathy, optic neuritis, or optic disc edema. Sera from patients with recurrent papillitis were tested for IgLON5 antibodies. RESULTS: We found two elderly males presenting with papillitis in the presence of IgLON5 antibodies. CSF pleocytosis was present and partial vision improvement occurred in one patient despite immunotherapy. Sera from 18 patients with recurrent papillitis were negative for IgLON5 antibodies. CONCLUSION: Papillitis could be a manifestation of IgLON5 disease, with or without accompanying cognitive, sleep, and movement disorders.


Assuntos
Neurite Óptica , Papiledema , Masculino , Humanos , Idoso , Autoimunidade , Estudos Retrospectivos , Neurite Óptica/complicações , Nervo Óptico , Moléculas de Adesão Celular Neuronais/uso terapêutico
2.
Metabolism ; 140: 155380, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36549436

RESUMO

BACKGROUND: Liver fibrogenesis is orchestrated by the paracrine signaling interaction between several resident cell types regulating the activation of hepatic stellate cells (HSCs). However, the molecular mechanisms underlying paracrine regulation are largely unknown. The aim of this study is to elucidate the role of Ninjurin2 in the crosstalk between hepatocytes and HSCs and better understand the implications of Ninjurin2 in liver fibrosis. METHODS: Ninj2 knockout mice (Ninj2-/-) and hepatocyte-specific Ninj2 overexpression mice (Ninj2Hep-tg) were constructed and followed by the induction of liver fibrosis using methionine- and choline-deficient (MCD) diet. The relationship between Ninjurin2 and liver fibrosis phenotype was evaluated in vivo by measurement of fibrotic markers and related genes. We used an in vitro transwell cell co-culture model to examine the impact of Ninjurin2 in hepatocytes on the crosstalk to HSCs. The interaction of Ninjurin2 and IGF1R and the regulation of PI3K-AKT-EGR1 were analyzed in vivo and in vitro. Finally, an inhibitory Ninjurin2 peptide was injected intravenously via the tail vein to investigate whether inhibiting of Ninjurin2 cascade can attenuate MCD diet-induced liver fibrosis in mice. RESULTS: We found that hepatic Ninjurin2 expression was significantly increased in fibrotic human liver and MCD diet-induced liver injury mouse models. In the mouse model, hepatocyte-specific overexpression of Ninj2 exacerbates MCD-induced liver fibrosis, while global Ninj2 knockout reverses the phenotype. To mimic hepatocyte-HSC crosstalk during liver fibrosis, we used co-culture systems containing hepatocytes and HSCs and determined that Ninjurin2 overexpression in hepatocytes directly activates HSCs in vitro. Mechanistically, Ninjurin2 directly interacts with insulin-like growth factor 1 receptor (IGF1R) and increases the hepatocyte secretion of the fibrogenic cytokine, platelet-derived growth factor-BB (PDGF-BB) through IGF1R-PI3K-AKT-EGR1 cascade. Inhibition of PDGFRB signaling in HSCs can abolish the profibrogenic effect of Ninjurin2. In addition, we demonstrated that a specific inhibitory Ninjurin2 peptide containing an N-terminal adhesion motif mitigates liver fibrosis and improves hepatic function in the mouse models by negatively regulating the sensitivity of IGF1R to IGF1 in hepatocytes. CONCLUSION: Hepatic Ninjurin2 plays a key role in liver fibrosis through paracrine regulation of PDGF-BB/PDGFRB signaling in HSCs, and the results suggesting Ninjurin2 may be a potential therapeutic target.


Assuntos
Moléculas de Adesão Celular Neuronais , Células Estreladas do Fígado , Fígado , Transdução de Sinais , Animais , Humanos , Camundongos , Becaplermina/metabolismo , Becaplermina/farmacologia , Becaplermina/uso terapêutico , Moléculas de Adesão Celular Neuronais/metabolismo , Moléculas de Adesão Celular Neuronais/farmacologia , Moléculas de Adesão Celular Neuronais/uso terapêutico , Modelos Animais de Doenças , Proteína 1 de Resposta de Crescimento Precoce/genética , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/farmacologia , Células Estreladas do Fígado/metabolismo , Hepatócitos/metabolismo , Fígado/patologia , Cirrose Hepática/metabolismo , Fibrose
3.
Neuroimmunomodulation ; 29(4): 515-519, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35354146

RESUMO

Anti-IgLON5 encephalopathy is a new and rare autoimmune encephalitis with unclear pathophysiology. In this study, we reported an unusual case of anti-IgLON5 encephalopathy with concomitant herpes virus encephalitis. A 51-year-old man with HLA-DQB1*05:01 and HLA-DRB1*10:01, who suffered from an episode of acute encephalitis, mental disorders, and memory impairment was admitted to our hospital. Human alpha herpes virus 1, human gamma herpes virus 4 (Epstein-Barr virus), and IgLON5-IgG were detected in the cerebrospinal fluid, indicating anti-IgLON5 encephalopathy with concomitant herpes virus encephalitis of this patient. Brain magnetic resonance imaging revealed T2 hyperintensities in the left temporal lobe and enhancement in the hippocampus. A mild sleep disorder was also found by video polysomnography. The patient was then treated with antiviral drugs, intravenous immunoglobulins, methylprednisolone, and protein A immunoadsorption. After treatment, the patient's clinical symptoms were partially improved. This is the first reported case of anti-IgLON5 encephalopathy with concomitant herpes virus encephalitis.


Assuntos
Encefalopatias , Encefalite , Infecções por Vírus Epstein-Barr , Doença de Hashimoto , Masculino , Humanos , Pessoa de Meia-Idade , Herpesvirus Humano 4 , Encefalite/complicações , Moléculas de Adesão Celular Neuronais/uso terapêutico
4.
Pharm Res ; 38(5): 803-817, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33982226

RESUMO

PURPOSE: Therapeutic strategies to treat ischemic stroke are limited due to the heterogeneity of cerebral ischemic injury and the mechanisms that contribute to the cell death. Since oxidative stress is one of the primary mechanisms that cause brain injury post-stroke, we hypothesized that therapeutic targets that modulate mitochondrial function could protect against reperfusion-injury after cerebral ischemia, with the focus here on a mitochondrial protein, mitoNEET, that modulates cellular bioenergetics. METHOD: In this study, we evaluated the pharmacology of the mitoNEET ligand NL-1 in an in vivo therapeutic role for NL-1 in a C57Bl/6 murine model of ischemic stroke. RESULTS: NL-1 decreased hydrogen peroxide production with an IC50 of 5.95 µM in neuronal cells (N2A). The in vivo activity of NL-1 was evaluated in a murine 1 h transient middle cerebral artery occlusion (t-MCAO) model of ischemic stroke. We found that mice treated with NL-1 (10 mg/kg, i.p.) at time of reperfusion and allowed to recover for 24 h showed a 43% reduction in infarct volume and 68% reduction in edema compared to sham-injured mice. Additionally, we found that when NL-1 was administered 15 min post-t-MCAO, the ischemia volume was reduced by 41%, and stroke-associated edema by 63%. CONCLUSION: As support of our hypothesis, as expected, NL-1 failed to reduce stroke infarct in a permanent photothrombotic occlusion model of stroke. This report demonstrates the potential therapeutic benefits of using mitoNEET ligands like NL-1 as novel mitoceuticals for treating reperfusion-injury with cerebral stroke.


Assuntos
Moléculas de Adesão Celular Neuronais/farmacologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Ataque Isquêmico Transitório/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Animais , Moléculas de Adesão Celular Neuronais/uso terapêutico , Modelos Animais de Doenças , Metabolismo Energético/efeitos dos fármacos , Humanos , Injeções Intraperitoneais , Proteínas de Ligação ao Ferro/metabolismo , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos
5.
Exp Neurol ; 216(2): 390-7, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19185570

RESUMO

Temporal lobe epilepsy (TLE) is often accompanied by granule cell dispersion (GCD), a migration defect of granule cells in the dentate gyrus. We have previously shown that a decrease in the expression of reelin, an extracellular matrix protein important for neuronal positioning, is associated with the development of GCD in TLE patients. Here, we used unilateral intrahippocampal injection of kainate (KA) in adult mice which is also associated with GCD formation and a decrease of reelin expression. In this mouse epilepsy model we aimed to prevent GCD development by the application of exogenous reelin. As a prerequisite we analyzed whether the reelin signaling transduction cascade was preserved in the KA-injected hippocampus. Using in situ hybridization and Western blot analysis we found that the expression of the reelin signaling components, apolipoprotein E receptor 2, the very-low-density lipoprotein receptor and the intracellular adaptor protein disabled 1, was maintained in dentate granule cells after KA injection. Next, recombinant reelin was infused into the KA-injected hippocampus by osmotic minipumps over a period of 2 weeks. Quantitative analysis of granule cell layer width revealed a significant reduction of GCD in reelin-treated, but not in saline-infused animals when compared to KA injection alone. Our findings highlight the crucial role of reelin for the maintenance of granule cell lamination in the dentate gyrus of adult mice and show that a reelin deficiency is causally involved in GCD development.


Assuntos
Moléculas de Adesão Celular Neuronais/uso terapêutico , Epilepsia/tratamento farmacológico , Epilepsia/patologia , Proteínas da Matriz Extracelular/uso terapêutico , Proteínas do Tecido Nervoso/uso terapêutico , Inibição Neural/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Serina Endopeptidases/uso terapêutico , Complexo 1 de Proteínas Adaptadoras/genética , Complexo 1 de Proteínas Adaptadoras/metabolismo , Análise de Variância , Animais , Moléculas de Adesão Celular Neuronais/metabolismo , Contagem de Células/métodos , Movimento Celular/efeitos dos fármacos , Giro Denteado/efeitos dos fármacos , Giro Denteado/patologia , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Epilepsia/induzido quimicamente , Agonistas de Aminoácidos Excitatórios/toxicidade , Proteínas da Matriz Extracelular/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Caínico/toxicidade , Proteínas Relacionadas a Receptor de LDL , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/metabolismo , RNA Mensageiro/metabolismo , Receptores de LDL/genética , Receptores de LDL/metabolismo , Receptores de Lipoproteínas/genética , Receptores de Lipoproteínas/metabolismo , Proteína Reelina , Serina Endopeptidases/metabolismo , Fatores de Tempo
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