Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Pharmacol Sci ; 150(1): 1-8, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35926944

RESUMO

Ceramide, a central molecule of sphingolipid metabolism, is phosphorylated to ceramide-1-phosphate (C1P) by ceramide kinase (CerK). The CerK/C1P pathway regulates many cellular functions, but its roles in immune/inflammation-related (IIR) diseases in vivo are not well known. Sepsis is an acute systemic inflammatory disease accompanied by damage/dysfunction in multiple organs. In the present study, we investigated the effects of CerK knockout on the onset/progression of sepsis-related events in lipopolysaccharide (LPS)-treated sepsis-model mice. In CerK-null mice, the lethality at 48 h after i.v. injection of LPS was significantly increased compared with that in wild-type (WT) mice. The increased lethality by CerK knockout was reproduced in mice treated with i.p. injections of LPS. Changes in serum levels of 23 IIR molecules, including cytokines and chemokines, were measured. In WT mice, levels of these molecules increased 4 and/or 20 h after i.v. injection of LPS. Although the basal levels of IIR molecules were not affected, LPS-induced increases in interleukin-17 (IL-17), C-C motif chemokine ligands (CCL-2 and CCL-11), and tumor necrosis factor-α were significantly up-regulated, whereas IL-2 levels were slightly down-regulated by CerK knockout. Putative mechanisms for the CerK/C1P pathway-mediated regulation of IIR molecules and increased lethality in LPS-treated mice are discussed.


Assuntos
Lipopolissacarídeos , Sepse , Animais , Ceramidas/metabolismo , Quimiocinas , Citocinas , Deleção de Genes , Camundongos , Camundongos Knockout , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Sepse/genética
2.
Life Sci ; 296: 120446, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35245521

RESUMO

Changes in sphingolipid metabolism regulate and/or alter many cellular functions in the brain. Ceramide, a central molecule of sphingolipid metabolism, is phosphorylated to ceramide-1-phosphate (C1P) by ceramide kinase (CerK). CerK and C1P were reported to regulate many cellular responses, but their roles in immune-related diseases in vivo have not been well elucidated. Thus, we investigated the effects of CerK knockout on the onset/progression of multiple sclerosis (MS), which is a chronic neurodegenerative disease accompanied by the loss of myelin sheaths in the brain. MS-model mice were prepared using a diet containing the copper chelator cuprizone (CPZ). Treatment of 8-week-old mice with 0.2% CPZ for 8 weeks resulted in motor dysfunction based on the Rota-rod test, and caused the loss of myelin-related proteins (MRPs) in the brain and demyelination in the corpus callosum without affecting synaptophysin levels. CerK knockout, which did not affect developmental changes in MRPs, ameliorated the motor dysfunction, loss of MRPs, and demyelination in the brain in CPZ-treated mice. Loss of tail tonus, another marker of motor dysfunction, was detected at 1 week without demyelination after CPZ treatment in a CerK knockout-independent manner. CPZ-induced loss of tail tonus progressed, specifically in female mice, to 6-8 weeks, and the loss was ameliorated by CerK knockout. Activities of ceramide metabolic enzymes including CerK in the lysates of the brain were not affected by CPZ treatment. Inhibition of CerK as a candidate for MS treatment was discussed.


Assuntos
Corpo Caloso/fisiopatologia , Esclerose Múltipla/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fatores Etários , Animais , Comportamento Animal/fisiologia , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Corpo Caloso/efeitos dos fármacos , Cuprizona/toxicidade , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/etiologia , Doenças Desmielinizantes/genética , Modelos Animais de Doenças , Feminino , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Esclerose Múltipla/induzido quimicamente , Esclerose Múltipla/etiologia , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Proteínas/genética , Proteínas/metabolismo , Cauda/efeitos dos fármacos , Cauda/fisiopatologia
3.
Biochim Biophys Acta Mol Cell Res ; 1867(7): 118714, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32246947

RESUMO

Ceramide kinase (CerK) phosphorylates ceramide to ceramide-1-phosphate (C1P). CerK is highly expressed in the brain, and its association with the neuronal function has been reported. Previous reports showed that the activity of CerK is regulated by post-translational modifications including phosphorylation, whereas the cellular fate of CerK protein and its role in neuronal functions have not been clearly elucidated. Therefore, we investigated these issues in PC12 cells. Treatment with nerve growth factor (NGF) for 6 h increased the formation of C1P but not CerK mRNA. Knockdown of CerK and overexpression of HA-tagged CerK down- and up-regulated the formation of C1P, respectively. In PC12-CerK-HA cells, serum withdrawal caused ubiquitination of CerK-HA protein and down-regulated both CerK-HA protein and C1P formation within 6 h, and these down-regulations were abolished by co-treatments with NGF or proteasome inhibitors such as MG132 and clasto-lactacystin. Microscopic analysis showed that treatment with the proteasome inhibitors increased CerK-HA in puncture structures, possibly endosomes and/or vesicles, in cells. Treatment with the lysosome inhibitors reduced serum withdrawal-induced down-regulation of CerK-HA protein but not C1P formation. When knockdown or overexpression of CerK was performed, Ca2+-induced release of [3H] noradrenaline was reduced or enhanced, respectively, but neurite extension was not modified. There was a positive correlation between noradrenaline release and formation of C1P and/or CerK-HA levels in NGF- and clasto-lactacystin-treated cells. These results suggest that levels of CerK were down-regulated by the ubiquitin/proteasome and lysosome pathways and the former pathway-sensitive pool of CerK was suggested to be linked with exocytosis in PC12 cells.


Assuntos
Exocitose/genética , Fator de Crescimento Neural/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Animais , Ciclo Celular , Proliferação de Células , Ceramidas , Lisossomos/genética , Lisossomos/metabolismo , Redes e Vias Metabólicas/genética , Fator de Crescimento Neural/metabolismo , Células PC12 , Fosforilação , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Ratos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...