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[PMID]:28457994
[Au] Autor:Kady N; Yan Y; Salazar T; Wang Q; Chakravarthy H; Huang C; Beli E; Navitskaya S; Grant M; Busik J
[Ad] Endereço:Department of Physiology, Michigan State University, East Lansing, MI, USA.
[Ti] Título:Increase in acid sphingomyelinase level in human retinal endothelial cells and CD34 circulating angiogenic cells isolated from diabetic individuals is associated with dysfunctional retinal vasculature and vascular repair process in diabetes.
[So] Source:J Clin Lipidol;11(3):694-703, 2017 May - Jun.
[Is] ISSN:1933-2874
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Diabetic retinopathy is a microvascular disease that results from retinal vascular degeneration and defective repair due to diabetes-induced endothelial progenitor dysfunction. OBJECTIVE: Understanding key molecular factors involved in vascular degeneration and repair is paramount for developing effective diabetic retinopathy treatment strategies. We propose that diabetes-induced activation of acid sphingomyelinase (ASM) plays essential role in retinal endothelial and CD34 circulating angiogenic cell (CAC) dysfunction in diabetes. METHODS: Human retinal endothelial cells (HRECs) isolated from control and diabetic donor tissue and human CD34 CACs from control and diabetic patients were used in this study. ASM messenger RNA and protein expression were assessed by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. To evaluate the effect of diabetes-induced ASM on HRECs and CD34 CACs function, tube formation, CAC incorporation into endothelial tubes, and diurnal release of CD34 CACs in diabetic individuals were determined. RESULTS: ASM expression level was significantly increased in HRECs isolated from diabetic compared with control donor tissue, as well as CD34 CACs and plasma of diabetic patients. A significant decrease in tube area was observed in HRECs from diabetic donors compared with control HRECs. The tube formation deficiency was associated with increased expression of ASM in diabetic HRECs. Moreover, diabetic CD34 CACs with high ASM showed defective incorporation into endothelial tubes. Diurnal release of CD34 CACs was disrupted with the rhythmicity lost in diabetic patients. CONCLUSION: Collectively, these findings support that diabetes-induced ASM upregulation has a marked detrimental effect on both retinal endothelial cells and CACs.
[Mh] Termos MeSH primário: Retinopatia Diabética/enzimologia
Células Endoteliais/metabolismo
Neovascularização Patológica/patologia
Retina/patologia
Vasos Retinianos/fisiopatologia
Esfingomielina Fosfodiesterase/metabolismo
[Mh] Termos MeSH secundário: Idoso
Antígenos CD34/metabolismo
Ritmo Circadiano
Retinopatia Diabética/sangue
Retinopatia Diabética/patologia
Retinopatia Diabética/fisiopatologia
Células Endoteliais/patologia
Feminino
Regulação Enzimológica da Expressão Gênica
Seres Humanos
Masculino
Meia-Idade
Vasos Retinianos/metabolismo
Esfingomielina Fosfodiesterase/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, CD34); EC 3.1.4.- (acid sphingomyelinase-1); EC 3.1.4.12 (Sphingomyelin Phosphodiesterase)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180307
[Lr] Data última revisão:
180307
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE


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[PMID]:29317203
[Au] Autor:Liu T; Duan W; Nizigiyimana P; Gao L; Liao Z; Xu B; Liu L; Lei M
[Ad] Endereço:Department of Endocrinology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Department of Endocrinology, Haikou People's Hospital, Haikou, Hainan, 570208, China.
[Ti] Título:Alpha-mangostin attenuates diabetic nephropathy in association with suppression of acid sphingomyelianse and endoplasmic reticulum stress.
[So] Source:Biochem Biophys Res Commun;496(2):394-400, 2018 02 05.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:AIMS: Diabetic nephropathy is a common complication of diabetes, but there are currently few treatment options. The aim of this study was to gain insight into the effect of alpha-mangostin on diabetic nephropathy and possible related mechanisms. METHODS: Goto-Kakizaki rats were used as a diabetic model and received alpha-mangostin or desipramine treatment with normal saline as a control. Ten age-matched Sprague Dawley rats were used as normal controls and treated with normal saline. At week 12, blood glucose, albuminuria, apoptosis and renal pathologic changes were assessed. Protein levels for acid sphingomyelinase, glucose-regulated protein 78, phosphorylated PKR-like ER-resident kinase, activated transcription factor 4, CCAAT/enhancer-binding protein, homologous protein), and cleaved-caspase12 were measured. RESULTS: The level of acid sphingomyelinase was significantly increased, and ER stress was activated in diabetic rat kidneys when compared to the control animals. When acid sphingomyelinase was inhibited by alpha-mangostin, the expression of ER stress-related proteins was down-regulated in association with decreased levels of diabetic kidney injury. CONCLUSIONS: Alpha-mangostin, an acid sphingomyelinase inhibitor plays a protective role in diabetic neuropathy by relieving ER stress induced-renal cell apoptosis.
[Mh] Termos MeSH primário: Diabetes Mellitus Experimental/tratamento farmacológico
Nefropatias Diabéticas/tratamento farmacológico
Inibidores Enzimáticos/farmacologia
Substâncias Protetoras/farmacologia
Esfingomielina Fosfodiesterase/antagonistas & inibidores
Xantonas/farmacologia
[Mh] Termos MeSH secundário: Fator 4 Ativador da Transcrição/genética
Fator 4 Ativador da Transcrição/metabolismo
Albuminúria/genética
Albuminúria/metabolismo
Albuminúria/patologia
Albuminúria/prevenção & controle
Animais
Apoptose/efeitos dos fármacos
Glicemia/metabolismo
Caspase 12/genética
Caspase 12/metabolismo
Desipramina/farmacologia
Diabetes Mellitus Experimental/induzido quimicamente
Diabetes Mellitus Experimental/genética
Diabetes Mellitus Experimental/patologia
Nefropatias Diabéticas/induzido quimicamente
Nefropatias Diabéticas/genética
Nefropatias Diabéticas/patologia
Estresse do Retículo Endoplasmático/efeitos dos fármacos
Regulação da Expressão Gênica
Proteínas de Choque Térmico/genética
Proteínas de Choque Térmico/metabolismo
Rim/efeitos dos fármacos
Rim/metabolismo
Rim/patologia
Masculino
Ratos
Ratos Sprague-Dawley
Esfingomielina Fosfodiesterase/genética
Esfingomielina Fosfodiesterase/metabolismo
Estreptozocina
eIF-2 Quinase/genética
eIF-2 Quinase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Atf4 protein, rat); 0 (Blood Glucose); 0 (Enzyme Inhibitors); 0 (Heat-Shock Proteins); 0 (Hspa5 protein, rat); 0 (Protective Agents); 0 (Xanthones); 145891-90-3 (Activating Transcription Factor 4); 5W494URQ81 (Streptozocin); EC 2.7.11.1 (PERK kinase); EC 2.7.11.1 (eIF-2 Kinase); EC 3.1.4.- (acid sphingomyelinase-1); EC 3.1.4.12 (Sphingomyelin Phosphodiesterase); EC 3.4.22.- (Casp12 protein, rat); EC 3.4.22.- (Caspase 12); TG537D343B (Desipramine); U6RIV93RU1 (mangostin)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180213
[Lr] Data última revisão:
180213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180111
[St] Status:MEDLINE


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[PMID]:28468968
[Au] Autor:Ocaña-Morgner C; Sales S; Rothe M; Shevchenko A; Jessberger R
[Ad] Endereço:Institute of Physiological Chemistry, Faculty of Medicine Carl Gustav Carus, Dresden University of Technology, Dresden 01307, Germany; and carlos.ocana-morgner@mailbox.tu-dresden.de rolf.jessberger@mailbox.tu-dresden.de.
[Ti] Título:Tolerogenic versus Immunogenic Lipidomic Profiles of CD11c Immune Cells and Control of Immunogenic Dendritic Cell Ceramide Dynamics.
[So] Source:J Immunol;198(11):4360-4372, 2017 06 01.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Lipids affect the membrane properties determining essential biological processes. Earlier studies have suggested a role of switch-activated protein 70 (SWAP-70) in lipid raft formation of dendritic cells. We used lipidomics combined with genetic and biochemical assays to analyze the role of SWAP-70 in lipid dynamics. TLR activation using LPS as a ligand represented a pathogenic immunogenic stimulus, physical disruption of cell-cell contacts a tolerogenic stimulus. Physical disruption, but not LPS, caused an increase of phosphatidylcholine ether and cholesteryl esters in CD11c immune cells. An increase of ceramide (Cer) was a hallmark for LPS activation. SWAP-70 was required for regulating the increase and localization of Cers in the cell membrane. SWAP-70 controls Cer accumulation through the regulation of pH-dependent acid-sphingomyelinase activity and of RhoA-dependent transport of endosomal contents to the plasma membrane. Poor accumulation of Cers in cells caused decreased apoptosis. This shows that two different pathways of activation, immunogenic and tolerogenic, induce different changes in the lipid composition of cultured CD11c cells, and highlights the important role of SWAP-70 in Cer dynamics in dendritic cells.
[Mh] Termos MeSH primário: Antígeno CD11c/imunologia
Ceramidas/metabolismo
Proteínas de Ligação a DNA/metabolismo
Células Dendríticas/imunologia
Fatores de Troca do Nucleotídeo Guanina/metabolismo
Tolerância Imunológica
Lipídeos/imunologia
Antígenos de Histocompatibilidade Menor/metabolismo
Proteínas Nucleares/metabolismo
[Mh] Termos MeSH secundário: Animais
Apoptose
Linhagem Celular
Células Cultivadas
Ceramidas/imunologia
Ésteres do Colesterol/genética
Ésteres do Colesterol/imunologia
Meios de Cultura/química
Citocinas/biossíntese
Citocinas/imunologia
Proteínas de Ligação a DNA/genética
Células Dendríticas/efeitos dos fármacos
Células Dendríticas/metabolismo
Fatores de Troca do Nucleotídeo Guanina/genética
Lipídeos/análise
Lipopolissacarídeos/imunologia
Camundongos
Antígenos de Histocompatibilidade Menor/genética
Proteínas Nucleares/genética
Esfingomielina Fosfodiesterase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (CD11c Antigen); 0 (Ceramides); 0 (Cholesterol Esters); 0 (Culture Media); 0 (Cytokines); 0 (DNA-Binding Proteins); 0 (Guanine Nucleotide Exchange Factors); 0 (Lipids); 0 (Lipopolysaccharides); 0 (Minor Histocompatibility Antigens); 0 (Nuclear Proteins); 0 (Swap70 protein, mouse); EC 3.1.4.12 (Sphingomyelin Phosphodiesterase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180127
[Lr] Data última revisão:
180127
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1601928


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[PMID]:28745666
[Au] Autor:Alesenko AV; Gavrilova SI; Gutner UA; Lebedeva AO; Shupik MA; Kolykhalov IV; Ponomareva EV; Selezneva ND; Fedorova YB
[Ad] Endereço:Emanuel Institute of Biochemical Physics of RAS, Moscow, Russia.
[Ti] Título:[Detection of effective treatment of amnestic mild cognitive impairement with cereton by testing of lipids markers].
[Ti] Título:Issledovanie éffektivnosti tseretona pri miagkom kognitivnom snizhenii amnesticheskogo tipa na osnove testirovaniia markerov lipidnoi prirody..
[So] Source:Zh Nevrol Psikhiatr Im S S Korsakova;117(6):21-27, 2017.
[Is] ISSN:1997-7298
[Cp] País de publicação:Russia (Federation)
[La] Idioma:rus
[Ab] Resumo:AIM: Determination of effectivity and safety of Cereton (Choline alfoscerate, production by Sotex) 1200 mg/day in the treatment of cognitive functioning disorders in patients with amnestic mild cognitive impairment (aMCI) and determining its influence in the process (after a 3 month course of taking the drug) and 3 months after the end of treatment of aMCI on the change in the content of phosphatidylcholine, sphingomyelin, ceramide-metabolite sphingolipids and the activity of genes controlling the synthesis of enzymes, which control ithe metabolism of sphingomyelin and ceramide (sphingomyelinase and ceramidase). MATERIAL AND METHODS: The study involved a group of elderly patients (20 people), consisting of 14 women and 6 men, aged 51 to 82 years (mean age 70.3±9.1 years). The patients' condition met the criteria for diagnosing aMCI syndrome. Analysis of phosphatidylcholine, sphingomyelin and ceramide in the blood plasma of patients was carried out by thin layer chromatography, expression of sphingomyelinase and ceramidase genes by RtPCR. RESULTS AND CONCLUSION: A sharp increase in the content of phosphatidylcholine and ceramide, the product of sphingomyelin hydrolysis, was detected. Expression of genes (acidic sphingomyelinase and ceramidase), controlling the metabolism of ceramide, is significantly reduced in the majority of patients in the treatment with ceretone. An increase in the level of phosphatidylcholine and a decrease in the expression level of the ceramide metabolism genes during treatment with ceretone and other drugs that affect the metabolism of phosphatidylchodine and sphingolipids can be used as markers of the effectiveness of therapy.
[Mh] Termos MeSH primário: Amnésia/tratamento farmacológico
Ceramidas/metabolismo
Disfunção Cognitiva/tratamento farmacológico
Glicerilfosforilcolina/uso terapêutico
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Biomarcadores/sangue
Biomarcadores/metabolismo
Ceramidases/sangue
Ceramidases/genética
Ceramidases/metabolismo
Ceramidas/sangue
Feminino
Expressão Gênica
Glicerilfosforilcolina/efeitos adversos
Seres Humanos
Masculino
Meia-Idade
Fosfatidilcolinas/sangue
Fosfatidilcolinas/metabolismo
Esfingomielina Fosfodiesterase/sangue
Esfingomielina Fosfodiesterase/genética
Esfingomielina Fosfodiesterase/metabolismo
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Ceramides); 0 (Phosphatidylcholines); 60M22SGW66 (Glycerylphosphorylcholine); EC 3.1.4.12 (Sphingomyelin Phosphodiesterase); EC 3.5.1.23 (Ceramidases)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171128
[Lr] Data última revisão:
171128
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170727
[St] Status:MEDLINE
[do] DOI:10.17116/jnevro20171176121-27


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[PMID]:28889482
[Au] Autor:Liu F; Li X; Yue H; Ji J; You M; Ding L; Fan H; Hou Y
[Ad] Endereço:The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, China.
[Ti] Título:TLR-Induced SMPD3 Defects Enhance Inflammatory Response of B Cell and Macrophage in the Pathogenesis of SLE.
[So] Source:Scand J Immunol;86(5):377-388, 2017 Nov.
[Is] ISSN:1365-3083
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:B lymphocyte and macrophages may contribute to SLE pathogenesis through cytokine production after TLR stimulation. Emerging evidences suggested that defects of sphingolipid metabolism were responsible for SLE pathogenesis. However, it is not clear whether these defects exist in B cells and macrophages under SLE condition and whether TLR signalling pathway was related to the dysfunction of sphingolipid metabolism in SLE. Here, we demonstrated that the enzymes involved in the sphingolipid metabolism expressed abnormally in B cells from SLE patients and lupus-prone mice. Moreover, we found that TLR signalling induced the abnormal expression of sphingomyelin phosphodiesterase 3 (SMPD3), sphingosine-1-phosphate phosphatase 2 (SGPP2), ceramide kinase (CERK) and UDP glycosyltransferase 8 (UGT8), which were involved in sphingolipid metabolism. TLR signalling also induced the transportation of SMPD3 from Golgi apparatus. Furthermore, the dysfunction of SMPD3 enhanced TLR-induced inflammatory response of B cells and macrophages in turn. Thus, these findings provide an innovative direction and a new target for research and treatment of SLE.
[Mh] Termos MeSH primário: Linfócitos B/imunologia
Lúpus Eritematoso Sistêmico/etiologia
Lúpus Eritematoso Sistêmico/imunologia
Macrófagos/imunologia
Esfingomielina Fosfodiesterase/metabolismo
Receptores Toll-Like/metabolismo
[Mh] Termos MeSH secundário: Animais
Apoptose
Linfócitos B/metabolismo
Modelos Animais de Doenças
Feminino
Expressão Gênica
Complexo de Golgi/metabolismo
Seres Humanos
Lúpus Eritematoso Sistêmico/metabolismo
Macrófagos/metabolismo
Macrófagos/patologia
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Endogâmicos MRL lpr
Modelos Biológicos
Transdução de Sinais
Esfingolipídeos/metabolismo
Esfingomielina Fosfodiesterase/antagonistas & inibidores
Esfingomielina Fosfodiesterase/genética
Receptores Toll-Like/agonistas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Sphingolipids); 0 (Toll-Like Receptors); EC 3.1.4.12 (SMPD3 protein, human); EC 3.1.4.12 (Smpd3 protein, mouse); EC 3.1.4.12 (Sphingomyelin Phosphodiesterase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171023
[Lr] Data última revisão:
171023
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170911
[St] Status:MEDLINE
[do] DOI:10.1111/sji.12611


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[PMID]:28697173
[Au] Autor:Kuzu OF; Gowda R; Noory MA; Robertson GP
[Ad] Endereço:Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
[Ti] Título:Modulating cancer cell survival by targeting intracellular cholesterol transport.
[So] Source:Br J Cancer;117(4):513-524, 2017 Aug 08.
[Is] ISSN:1532-1827
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Demand for cholesterol is high in certain cancers making them potentially sensitive to therapeutic strategies targeting cellular cholesterol homoeostasis. A potential approach involves disruption of intracellular cholesterol transport, which occurs in Niemann-Pick disease as a result of acid sphingomyelinase (ASM) deficiency. Hence, a class of lysosomotropic compounds that were identified as functional ASM inhibitors (FIASMAs) might exhibit chemotherapeutic activity by disrupting cancer cell cholesterol homoeostasis. METHODS: Here, the chemotherapeutic utility of ASM inhibition was investigated. The effect of FIASMAs on intracellular cholesterol levels, cholesterol homoeostasis, cellular endocytosis and signalling cascades were investigated. The in vivo efficacy of ASM inhibition was demonstrated using melanoma xenografts and a nanoparticle formulation was developed to overcome dose-limiting CNS-associated side effects of certain FIASMAs. RESULTS: Functional ASM inhibitors inhibited intracellular cholesterol transport leading to disruption of autophagic flux, cellular endocytosis and receptor tyrosine kinase signalling. Consequently, major oncogenic signalling cascades on which cancer cells were reliant for survival were inhibited. Two tested ASM inhibitors, perphenazine and fluphenazine that are also clinically used as antipsychotics, were effective in inhibiting xenografted tumour growth. Nanoliposomal encapsulation of the perphenazine enhanced its chemotherapeutic efficacy while decreasing CNS-associated side effects. CONCLUSIONS: This study suggests that disruption of intracellular cholesterol transport by targeting ASM could be utilised as a potential chemotherapeutic approach for treating cancer.
[Mh] Termos MeSH primário: Antidepressivos Tricíclicos/farmacologia
Antipsicóticos/farmacologia
Colesterol/metabolismo
Melanoma/tratamento farmacológico
Melanoma/metabolismo
Perfenazina/administração & dosagem
[Mh] Termos MeSH secundário: Administração Intravenosa
Administração Oral
Animais
Antidepressivos Tricíclicos/uso terapêutico
Antipsicóticos/administração & dosagem
Autofagia/efeitos dos fármacos
Transporte Biológico/efeitos dos fármacos
Transporte Biológico/genética
Sobrevivência Celular/efeitos dos fármacos
Desipramina/farmacologia
Desipramina/uso terapêutico
Endocitose/efeitos dos fármacos
Endossomos/metabolismo
Feminino
Flupentixol/farmacologia
Flupentixol/uso terapêutico
Flufenazina/farmacologia
Flufenazina/uso terapêutico
Regulação da Expressão Gênica/efeitos dos fármacos
Técnicas de Silenciamento de Genes
Células HCT116
Homeostase/efeitos dos fármacos
Homeostase/genética
Seres Humanos
Concentração Inibidora 50
Lipossomos
Lisossomos/metabolismo
Lisossomos/ultraestrutura
Células MCF-7
Melanoma/genética
Camundongos
Nortriptilina/farmacologia
Nortriptilina/uso terapêutico
Perfenazina/farmacologia
Fosfatidilinositol 3-Quinases/metabolismo
Proteínas Proto-Oncogênicas c-akt/metabolismo
Fator de Transcrição STAT3/metabolismo
Transdução de Sinais/efeitos dos fármacos
Esfingomielina Fosfodiesterase/genética
Proteína X Associada a bcl-2/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antidepressive Agents, Tricyclic); 0 (Antipsychotic Agents); 0 (Liposomes); 0 (STAT3 Transcription Factor); 0 (bcl-2-Associated X Protein); 97C5T2UQ7J (Cholesterol); BL03SY4LXB (Nortriptyline); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 3.1.4.12 (Sphingomyelin Phosphodiesterase); EC 3.1.4.12 (sphingomyelin phosphodiesterase 1, human); FA0UYH6QUO (Flupenthixol); FTA7XXY4EZ (Perphenazine); S79426A41Z (Fluphenazine); TG537D343B (Desipramine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170907
[Lr] Data última revisão:
170907
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170712
[St] Status:MEDLINE
[do] DOI:10.1038/bjc.2017.200


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[PMID]:28582448
[Au] Autor:Chami M; Halmer R; Schnoeder L; Anne Becker K; Meier C; Fassbender K; Gulbins E; Walter S
[Ad] Endereço:Department of Neurology, Saarland University Hospital, Homburg, Germany.
[Ti] Título:Acid sphingomyelinase deficiency enhances myelin repair after acute and chronic demyelination.
[So] Source:PLoS One;12(6):e0178622, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The cuprizone animal model, also known as the toxic demyelination model, is a well-reproducible model of demyelination- and remyelination in mice, and has been useful in studying important aspect of human demyelinating diseases, including multiple sclerosis. In this study, we investigated the role of acid sphingomyelinase in demyelination and myelin repair by inducing acute and chronic demyelination with 5- or 12-week cuprizone treatment, followed by a 2-week cuprizone withdrawal phase to allow myelin repair. Sphingolipids, in particular ceramide and the enzyme acid sphingomyelinase, which generates ceramide from sphingomyelin, seem to be involved in astrocyte activation and neuronal damage in multiple sclerosis. We used immunohistochemistry to study glial reaction and oligodendrocyte distribution in acid sphingomyelinase deficient mice and wild-type C57BL/6J littermates at various time intervals after demyelination and remyelination. Axonal injury was quantified using amyloid precursor protein and synaptophysin, and gene expression and protein levels were measured using gene analysis and Western blotting, respectively. Our results show that mice lacking acid sphingomyelinase had a significant increase in myelin recovery and a significantly higher oligodendrocyte cell count after 2 weeks remyelination compared to wild-type littermates. Detrimental astroglial distribution was also significantly reduced in acid sphingomyelinase deficient animals. We obtained similar results in experiments using amitriptyline to inhibit acid sphingomyelinase. These findings suggest that acid sphingomyelinase plays a significant role in myelin repair, and its inhibition by amitriptyline may constitute a novel therapeutic approach for multiple sclerosis patients.
[Mh] Termos MeSH primário: Amitriptilina/farmacologia
Doenças Desmielinizantes/prevenção & controle
Inibidores Enzimáticos/farmacologia
Esclerose Múltipla/prevenção & controle
Oligodendroglia/efeitos dos fármacos
Esfingomielina Fosfodiesterase/genética
[Mh] Termos MeSH secundário: Secretases da Proteína Precursora do Amiloide/genética
Secretases da Proteína Precursora do Amiloide/metabolismo
Animais
Astrócitos/efeitos dos fármacos
Astrócitos/enzimologia
Astrócitos/patologia
Axônios/efeitos dos fármacos
Axônios/enzimologia
Axônios/patologia
Contagem de Células
Cuprizona
Doenças Desmielinizantes/induzido quimicamente
Doenças Desmielinizantes/enzimologia
Doenças Desmielinizantes/patologia
Modelos Animais de Doenças
Regulação da Expressão Gênica
Seres Humanos
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Microglia/efeitos dos fármacos
Microglia/enzimologia
Microglia/patologia
Esclerose Múltipla/induzido quimicamente
Esclerose Múltipla/enzimologia
Esclerose Múltipla/patologia
Regeneração Nervosa/efeitos dos fármacos
Oligodendroglia/enzimologia
Oligodendroglia/patologia
Recuperação de Função Fisiológica/efeitos dos fármacos
Esfingomielina Fosfodiesterase/antagonistas & inibidores
Esfingomielina Fosfodiesterase/deficiência
Sinaptofisina/genética
Sinaptofisina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Synaptophysin); 0 (Syp protein, mouse); 1806D8D52K (Amitriptyline); 5N16U7E0AO (Cuprizone); EC 3.1.4.- (acid sphingomyelinase-1); EC 3.1.4.12 (Sphingomyelin Phosphodiesterase); EC 3.4.- (Amyloid Precursor Protein Secretases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170918
[Lr] Data última revisão:
170918
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170606
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0178622


  8 / 2725 MEDLINE  
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[PMID]:28577326
[Au] Autor:Yang CL; Chiou SH; Tai WC; Joseph NA; Chow KC
[Ad] Endereço:Graduate Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.
[Ti] Título:Trivalent chromium induces autophagy by activating sphingomyelin phosphodiesterase 2 and increasing cellular ceramide levels in renal HK2 cells.
[So] Source:Mol Carcinog;56(11):2424-2433, 2017 Nov.
[Is] ISSN:1098-2744
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In this study, we examined the role of autophagy in the initiation of lipid increases in renal epithelial HK2 cells. We found that trivalent chromium [Cr(III)] induced autophagy by activating sphingomyelin phosphodiesterase 2 (SMPD2). SMPD2 increases levels of ceramide and other lipids. Confocal immunofluorescence microscopy showed that signals of ceramide overlapped with LC3, suggesting that ceramide might play an important role in the formation of autophagosome. In conclusion, our data indicate that Cr(III) induces autophagy via structural aberration of organelle membrane, in particular by the increase of lipid compositions in addition to autophagy-associated proteins.
[Mh] Termos MeSH primário: Autofagia/efeitos dos fármacos
Ceramidas/metabolismo
Cromo/farmacologia
Ativação Enzimática/efeitos dos fármacos
Células Epiteliais/efeitos dos fármacos
Rim/efeitos dos fármacos
Esfingomielina Fosfodiesterase/metabolismo
[Mh] Termos MeSH secundário: Linhagem Celular
Células Epiteliais/metabolismo
Seres Humanos
Rim/citologia
Rim/metabolismo
Espécies Reativas de Oxigênio/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ceramides); 0 (Reactive Oxygen Species); 0R0008Q3JB (Chromium); EC 3.1.4.12 (Sphingomyelin Phosphodiesterase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171020
[Lr] Data última revisão:
171020
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170604
[St] Status:MEDLINE
[do] DOI:10.1002/mc.22689


  9 / 2725 MEDLINE  
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[PMID]:28551069
[Au] Autor:Dany M; Elston D
[Ad] Endereço:Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina, Charleston, South Carolina.
[Ti] Título:Gene expression of sphingolipid metabolism pathways is altered in hidradenitis suppurativa.
[So] Source:J Am Acad Dermatol;77(2):268-273.e6, 2017 Aug.
[Is] ISSN:1097-6787
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Hidradenitis suppurativa (HS) is a debilitating skin disease characterized by painful recurrent nodules and abscesses caused by chronic inflammation. Early events in the development of HS are believed to occur in the folliculopilosebaceous unit; however, the signaling pathways behind this mechanism are unknown. Sphingolipids, such as ceramide, are essential components of the skin and appendages and have important structural and signaling roles. OBJECTIVE: We sought to explore whether the gene expression of enzymes involved in sphingolipid metabolic pathways is altered in HS. METHODS: A microarray data set including 30 samples was used to compare the expression of sphingolipid-related enzymes in inflammatory skin lesions from HS patients (n = 17) with the expression in clinically healthy skin tissue (n = 13). Differential expression of sphingolipid metabolism-related genes was analyzed using Gene Expression Omnibus 2R. RESULTS: HS lesional skin samples have significantly decreased expression of enzymes generating ceramide and sphingomyelin, increased expression of enzymes catabolizing ceramide to sphingosine, and increased expression of enzymes converting ceramide to galactosylceramide and gangliosides. LIMITATIONS: Limitations of this study include assessing the expression of sphingolipid-related enzymes without assessing the levels of the related sphingolipids. CONCLUSION: Our study suggests that sphingolipid metabolism is altered in HS lesional skin compared with normal skin.
[Mh] Termos MeSH primário: Expressão Gênica
Hidradenite Supurativa/enzimologia
Hidradenite Supurativa/genética
Perilipinas/genética
Pele/enzimologia
Esfingolipídeos/metabolismo
[Mh] Termos MeSH secundário: Ceramidase Alcalina/genética
Estudos de Casos e Controles
Ceramidas/metabolismo
Proteínas Quinases Dependentes de AMP Cíclico/genética
Glucosilceramidase/genética
Glucosiltransferases/genética
Glicoesfingolipídeos/metabolismo
Hexosaminidases/genética
Seres Humanos
Lisofosfolipídeos/metabolismo
Proteínas de Membrana/genética
Redes e Vias Metabólicas/genética
Fosfotransferases (Aceptor do Grupo Álcool)/genética
Serina C-Palmitoiltransferase/genética
Transdução de Sinais/genética
Esfingolipídeos/biossíntese
Esfingomielina Fosfodiesterase/genética
Esfingomielinas/metabolismo
Esfingosina/análogos & derivados
Esfingosina/metabolismo
Esfingosina N-Aciltransferase/genética
Proteínas Supressoras de Tumor/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ceramides); 0 (Glycosphingolipids); 0 (Lysophospholipids); 0 (Membrane Proteins); 0 (Perilipins); 0 (Sphingolipids); 0 (Sphingomyelins); 0 (Tumor Suppressor Proteins); 26993-30-6 (sphingosine 1-phosphate); EC 2.3.1.24 (CERS2 protein, human); EC 2.3.1.24 (CERS5 protein, human); EC 2.3.1.24 (Sphingosine N-Acyltransferase); EC 2.3.1.50 (Serine C-Palmitoyltransferase); EC 2.4.1.- (Glucosyltransferases); EC 2.4.1.80 (ceramide glucosyltransferase); EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor)); EC 2.7.1.91 (sphingosine kinase 2, human); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases); EC 3.1.4.12 (Sphingomyelin Phosphodiesterase); EC 3.2.1.- (Hexosaminidases); EC 3.2.1.45 (Glucosylceramidase); EC 3.5.1.23 (Alkaline Ceramidase); NGZ37HRE42 (Sphingosine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170825
[Lr] Data última revisão:
170825
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170529
[St] Status:MEDLINE


  10 / 2725 MEDLINE  
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[PMID]:28420138
[Au] Autor:Chung HY; Kollmey AS; Schrepper A; Kohl M; Bläss MF; Stehr SN; Lupp A; Gräler MH; Claus RA
[Ad] Endereço:Center for Sepsis Control and Care, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany. Ha-yeun.Chung@med.uni-jena.de.
[Ti] Título:Adjustment of Dysregulated Ceramide Metabolism in a Murine Model of Sepsis-Induced Cardiac Dysfunction.
[So] Source:Int J Mol Sci;18(4), 2017 Apr 15.
[Is] ISSN:1422-0067
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Cardiac dysfunction, in particular of the left ventricle, is a common and early event in sepsis, and is strongly associated with an increase in patients' mortality. Acid sphingomyelinase (SMPD1)-the principal regulator for rapid and transient generation of the lipid mediator ceramide-is involved in both the regulation of host response in sepsis as well as in the pathogenesis of chronic heart failure. This study determined the degree and the potential role to which SMPD1 and its modulation affect sepsis-induced cardiomyopathy using both genetically deficient and pharmacologically-treated animals in a polymicrobial sepsis model. As surrogate parameters of sepsis-induced cardiomyopathy, cardiac function, markers of oxidative stress as well as troponin I levels were found to be improved in desipramine-treated animals, desipramine being an inhibitor of ceramide formation. Additionally, ceramide formation in cardiac tissue was dysregulated in SMPD1 as well as SMPD1 animals, whereas desipramine pretreatment resulted in stable, but increased ceramide content during host response. This was a result of elevated de novo synthesis. Strikingly, desipramine treatment led to significantly improved levels of surrogate markers. Furthermore, similar results in desipramine-pretreated SMPD1 littermates suggest an SMPD1-independent pathway. Finally, a pattern of differentially expressed transcripts important for regulation of apoptosis as well as antioxidative and cytokine response supports the concept that desipramine modulates ceramide formation, resulting in beneficial myocardial effects. We describe a novel, protective role of desipramine during sepsis-induced cardiac dysfunction that controls ceramide content. In addition, it may be possible to modulate cardiac function during host response by pre-conditioning with the Food and Drug Administration (FDA)-approved drug desipramine.
[Mh] Termos MeSH primário: Ceramidas/metabolismo
Cardiopatias/etiologia
Cardiopatias/fisiopatologia
Metabolismo dos Lipídeos
Sepse/complicações
Sepse/metabolismo
[Mh] Termos MeSH secundário: Animais
Biomarcadores
Débito Cardíaco/efeitos dos fármacos
Desipramina/metabolismo
Desipramina/farmacologia
Modelos Animais de Doenças
Feminino
Perfilação da Expressão Gênica
Regulação da Expressão Gênica
Cardiopatias/tratamento farmacológico
Cardiopatias/metabolismo
L-Lactato Desidrogenase/metabolismo
Masculino
Camundongos
Camundongos Knockout
Camundongos Transgênicos
Miocárdio/metabolismo
Estresse Oxidativo/efeitos dos fármacos
Sepse/genética
Sepse/microbiologia
Esfingomielina Fosfodiesterase/genética
Esfingomielina Fosfodiesterase/metabolismo
Troponina I/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Ceramides); 0 (Troponin I); EC 1.1.1.27 (L-Lactate Dehydrogenase); EC 3.1.4.12 (Sphingomyelin Phosphodiesterase); TG537D343B (Desipramine)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170629
[Lr] Data última revisão:
170629
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170420
[St] Status:MEDLINE



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