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  1 / 2031 MEDLINE  
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[PMID]:28450571
[Au] Autor:Weinreb NJ
[Ad] Endereço:UNIVERSITY OF MIAMI.
[Ti] Título:Encore! Oral therapy for type 1 Gaucher disease.
[So] Source:Blood;129(17):2337-2338, 2017 04 27.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Doença de Gaucher
Glucosilceramidase
[Mh] Termos MeSH secundário: Terapia de Reposição de Enzimas
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; COMMENT
[Nm] Nome de substância:
EC 3.2.1.45 (Glucosylceramidase)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180116
[Lr] Data última revisão:
180116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2017-02-769034


  2 / 2031 MEDLINE  
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[PMID]:28453301
[Au] Autor:Najarian DR; Hilton K; McCauley T; Qiu Y
[Ad] Endereço:Bioanalytical & Biomarker Development, 300 Shire Way, Lexington, MA 02421, USA.
[Ti] Título:A comparison study of bioanalytical methods for detection and characterization of anti-velaglucerase alfa antibodies.
[So] Source:Bioanalysis;9(10):775-786, 2017 May.
[Is] ISSN:1757-6199
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:AIM: To provide more efficient and timely immunogenicity testing service to support routine patient care, the original complex testing algorithm for evaluation of anti-velaglucerase alfa antibodies has been simplified and individual methods (screen, confirm, titer, neutralizing antibody [NAb] and IgE) have been redeveloped/optimized and validated. RESULTS: To compare the performance of different methods, 50 velaglucerase alfa-treated patient samples were analyzed using both old and new methods for the presence of antidrug antibodies (ADAs) and 31 ADA-positive samples were analyzed for neutralizing capacity. The ADA and NAb statuses are almost identical from both methods and both ADA and NAb titer results are highly correlated with a Spearman's correlation of 0.96 and 0.86, respectively. CONCLUSION: The original and new testing methods can be considered interchangeable for the measurement of total and neutralizing anti-velaglucerase alfa antibodies.
[Mh] Termos MeSH primário: Anticorpos Neutralizantes/sangue
Anticorpos Neutralizantes/imunologia
Análise Química do Sangue/métodos
Glucosilceramidase/imunologia
[Mh] Termos MeSH secundário: Doença de Gaucher/tratamento farmacológico
Doença de Gaucher/enzimologia
Glucosilceramidase/uso terapêutico
Seres Humanos
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Neutralizing); EC 3.2.1.45 (Glucosylceramidase); EC 3.2.1.45 (Velaglucerase alfa, human)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171225
[Lr] Data última revisão:
171225
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.4155/bio-2016-0274


  3 / 2031 MEDLINE  
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[PMID]:28969384
[Au] Autor:Migdalska-Richards A; Wegrzynowicz M; Rusconi R; Deangeli G; Di Monte DA; Spillantini MG; Schapira AHV
[Ad] Endereço:Department of Clinical Neurosciences, Institute of Neurology, University College London, London NW3 2PF, UK.
[Ti] Título:The L444P Gba1 mutation enhances alpha-synuclein induced loss of nigral dopaminergic neurons in mice.
[So] Source:Brain;140(10):2706-2721, 2017 Oct 01.
[Is] ISSN:1460-2156
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Mutations in glucocerebrosidase 1 (GBA1) represent the most prevalent risk factor for Parkinson's disease. The molecular mechanisms underlying the link between GBA1 mutations and Parkinson's disease are incompletely understood. We analysed two aged (24-month-old) Gba1 mouse models, one carrying a knock-out mutation and the other a L444P knock-in mutation. A significant reduction of glucocerebrosidase activity was associated with increased total alpha-synuclein accumulation in both these models. Gba1 mutations alone did not alter the number of nigral dopaminergic neurons nor striatal dopamine levels. We then investigated the effect of overexpression of human alpha-synuclein in the substantia nigra of aged (18 to 21-month-old) L444P Gba1 mice. Following intraparenchymal injections of human alpha-synuclein carrying viral vectors, pathological accumulation of phosphorylated alpha-synuclein occurred within the transduced neurons. Stereological counts of nigral dopaminergic neurons revealed a significantly greater cell loss in Gba1-mutant than wild-type mice. These results indicate that Gba1 deficiency enhances neuronal vulnerability to neurodegenerative processes triggered by increased alpha-synuclein expression.
[Mh] Termos MeSH primário: Dopamina/metabolismo
Glucosilceramidase/genética
Mutação/genética
Neurônios/patologia
Substância Negra/patologia
alfa-Sinucleína/metabolismo
[Mh] Termos MeSH secundário: Fatores Etários
Animais
Encéfalo/metabolismo
Encéfalo/patologia
Glucosilceramidase/deficiência
Seres Humanos
Leucina/genética
Camundongos
Camundongos Transgênicos
Neurônios/metabolismo
Prolina/genética
Desempenho Psicomotor/fisiologia
Olfato/genética
Substância Negra/metabolismo
Transdução Genética
Tirosina 3-Mono-Oxigenase/metabolismo
beta-N-Acetil-Hexosaminidases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (alpha-Synuclein); 9DLQ4CIU6V (Proline); EC 1.14.16.2 (Tyrosine 3-Monooxygenase); EC 3.2.1.45 (Glucosylceramidase); EC 3.2.1.52 (beta-N-Acetylhexosaminidases); GMW67QNF9C (Leucine); VTD58H1Z2X (Dopamine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171006
[Lr] Data última revisão:
171006
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171004
[St] Status:MEDLINE
[do] DOI:10.1093/brain/awx221


  4 / 2031 MEDLINE  
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[PMID]:28857617
[Au] Autor:Arenz C
[Ad] Endereço:Institute for Chemistry, Humboldt Universität zu Berlin, Brook-Taylor-Str. 2, 12489 Berlin, Germany.
[Ti] Título:Recent advances and novel treatments for sphingolipidoses.
[So] Source:Future Med Chem;9(14):1685-1698, 2017 Sep.
[Is] ISSN:1756-8927
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Sphingolipidoses are genetically inherited diseases in which genetic mutations lead to functional deficiencies in the enzymes needed for lysosomal degradation of sphingolipid substrates. As a consequence, nondegradable lipids enrich in the lysosomes and lead to fatal pathological phenotypes in affected individuals. In this review, different drug-based treatment strategies including enzyme replacement therapy and substrate reduction therapy are discussed. A special focus is on the concept of pharmacological chaperones, one of which recently acquired clinical approval within the EU. On the basis of the different limitations for each approach, possible future directions of research are discussed.
[Mh] Termos MeSH primário: Enzimas/uso terapêutico
Esfingolipidoses/tratamento farmacológico
[Mh] Termos MeSH secundário: Terapia de Reposição de Enzimas
Enzimas/genética
Enzimas/metabolismo
Doença de Fabry/tratamento farmacológico
Doença de Gaucher/tratamento farmacológico
Glucosilceramidase/genética
Glucosilceramidase/metabolismo
Glucosilceramidase/uso terapêutico
Seres Humanos
Lisossomos/metabolismo
Proteínas Recombinantes/biossíntese
Proteínas Recombinantes/isolamento & purificação
Proteínas Recombinantes/uso terapêutico
Esfingolipidoses/genética
Esfingolipidoses/patologia
Esfingolipídeos/metabolismo
alfa-Galactosidase/genética
alfa-Galactosidase/metabolismo
alfa-Galactosidase/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Enzymes); 0 (Recombinant Proteins); 0 (Sphingolipids); EC 3.2.1.22 (alpha-Galactosidase); EC 3.2.1.45 (Glucosylceramidase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171025
[Lr] Data última revisão:
171025
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170901
[St] Status:MEDLINE
[do] DOI:10.4155/fmc-2017-0065


  5 / 2031 MEDLINE  
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[PMID]:28847804
[Au] Autor:Taguchi YV; Liu J; Ruan J; Pacheco J; Zhang X; Abbasi J; Keutzer J; Mistry PK; Chandra SS
[Ad] Endereço:Department of Cell Biology.
[Ti] Título:Glucosylsphingosine Promotes α-Synuclein Pathology in Mutant GBA-Associated Parkinson's Disease.
[So] Source:J Neurosci;37(40):9617-9631, 2017 Oct 04.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Glucocerebrosidase 1 ( ) mutations responsible for Gaucher disease (GD) are the most common genetic risk factor for Parkinson's disease (PD). Although the genetic link between GD and PD is well established, the underlying molecular mechanism(s) are not well understood. We propose that glucosylsphingosine, a sphingolipid accumulating in GD, mediates PD pathology in -associated PD. We show that, whereas GD-related sphingolipids (glucosylceramide, glucosylsphingosine, sphingosine, sphingosine-1-phosphate) promote α-synuclein aggregation , glucosylsphingosine triggers the formation of oligomeric α-synuclein species capable of templating in human cells and neurons. Using newly generated GD/PD mouse lines of either sex [ mutant (N370S, L444P, KO) crossed to α-synuclein transgenics], we show that mutations predispose to PD through a loss-of-function mechanism. We further demonstrate that glucosylsphingosine specifically accumulates in young GD/PD mouse brain. With age, brains exhibit glucosylceramide accumulations colocalized with α-synuclein pathology. These findings indicate that glucosylsphingosine promotes pathological aggregation of α-synuclein, increasing PD risk in GD patients and carriers. Parkinson's disease (PD) is a prevalent neurodegenerative disorder in the aging population. Glucocerebrosidase 1 mutations, which cause Gaucher disease, are the most common genetic risk factor for PD, underscoring the importance of delineating the mechanisms underlying mutant -associated PD. We show that lipids accumulating in Gaucher disease, especially glucosylsphingosine, play a key role in PD pathology in the brain. These data indicate that ASAH1 (acid ceramidase 1) and GBA2 (glucocerebrosidase 2) enzymes that mediate glucosylsphingosine production and metabolism are attractive therapeutic targets for treating mutant -associated PD.
[Mh] Termos MeSH primário: Glucosilceramidase/biossíntese
Mutação/fisiologia
Doença de Parkinson/metabolismo
Psicosina/análogos & derivados
alfa-Sinucleína/biossíntese
[Mh] Termos MeSH secundário: Animais
Encéfalo/metabolismo
Encéfalo/patologia
Feminino
Glucosilceramidase/genética
Células HEK293
Seres Humanos
Masculino
Camundongos
Camundongos Transgênicos
Doença de Parkinson/genética
Doença de Parkinson/patologia
Psicosina/biossíntese
Psicosina/genética
alfa-Sinucleína/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (alpha-Synuclein); 2238-90-6 (Psychosine); 52050-17-6 (sphingosyl beta-glucoside); EC 3.2.1.45 (Glucosylceramidase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171021
[Lr] Data última revisão:
171021
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170830
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.1525-17.2017


  6 / 2031 MEDLINE  
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[PMID]:28762527
[Au] Autor:Mistry PK; Lukina E; Ben Turkia H; Shankar SP; Baris H; Ghosn M; Mehta A; Packman S; Pastores G; Petakov M; Assouline S; Balwani M; Danda S; Hadjiev E; Ortega A; Gaemers SJM; Tayag R; Peterschmitt MJ
[Ad] Endereço:Department of Internal Medicine and Pediatrics, Yale University School of Medicine, New Haven, CT, USA.
[Ti] Título:Outcomes after 18 months of eliglustat therapy in treatment-naïve adults with Gaucher disease type 1: The phase 3 ENGAGE trial.
[So] Source:Am J Hematol;92(11):1170-1176, 2017 Nov.
[Is] ISSN:1096-8652
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Eliglustat, an oral substrate reduction therapy, is a first-line treatment for adults with Gaucher disease type 1 (GD1) who are poor, intermediate, or extensive CYP2D6 metabolizers (>90% of patients). In the primary analysis of the Phase 3 ENGAGE trial (NCT00891202), eliglustat treatment for 9 months resulted in significant reductions in spleen and liver volumes and increases in hemoglobin concentration and platelet count compared with placebo. We report 18-month outcomes of patients who entered the trial extension period, in which all patients received eliglustat. Of 40 trial patients, 39 entered the extension period, and 38 completed 18 months. Absolute values and percent change over time were determined for spleen and liver volume, hemoglobin concentration, platelet count, bone mineral density, bone marrow burden, and Gaucher disease biomarkers. For patients randomized to eliglustat in the double-blind period, continuing treatment with eliglustat for 9 more months resulted in incremental improvement of all disease parameters. For patients randomized to placebo in the double-blind period, eliglustat treatment during the 9-month, open-label period resulted in significant decrease of spleen and liver volumes and significant increase of hemoglobin and platelets, with a similar rate of change to patients who had received eliglustat in the double-blind period. Eliglustat treatment was also associated with improvement in bone marrow burden score, bone mineral density, and established biomarkers of Gaucher disease, including reduction of the bioactive lipid, glucosylsphingosine. These findings underscore the efficacy of eliglustat in treatment-naïve patients. Eliglustat was well-tolerated, and there were no new safety concerns with longer-term exposure.
[Mh] Termos MeSH primário: Inibidores Enzimáticos/uso terapêutico
Terapia de Reposição de Enzimas
Doença de Gaucher/tratamento farmacológico
Pirrolidinas/uso terapêutico
[Mh] Termos MeSH secundário: Inibidores Enzimáticos/administração & dosagem
Inibidores Enzimáticos/efeitos adversos
Seguimentos
Doença de Gaucher/diagnóstico
Doença de Gaucher/enzimologia
Glucosilceramidase/antagonistas & inibidores
Seres Humanos
Fígado/patologia
Tamanho do Órgão
Pirrolidinas/administração & dosagem
Pirrolidinas/efeitos adversos
Baço/patologia
Resultado do Tratamento
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE III; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Pyrrolidines); DR40J4WA67 (eliglustat); EC 3.2.1.45 (Glucosylceramidase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171103
[Lr] Data última revisão:
171103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170802
[St] Status:MEDLINE
[do] DOI:10.1002/ajh.24877


  7 / 2031 MEDLINE  
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[PMID]:28617219
[Au] Autor:Lee YH; Choi H; Park S; Lee B; Yi GS
[Ad] Endereço:Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, South Korea.
[Ti] Título:Drug repositioning for enzyme modulator based on human metabolite-likeness.
[So] Source:BMC Bioinformatics;18(Suppl 7):226, 2017 May 31.
[Is] ISSN:1471-2105
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Recently, the metabolite-likeness of the drug space has emerged and has opened a new possibility for exploring human metabolite-like candidates in drug discovery. However, the applicability of metabolite-likeness in drug discovery has been largely unexplored. Moreover, there are no reports on its applications for the repositioning of drugs to possible enzyme modulators, although enzyme-drug relations could be directly inferred from the similarity relationships between enzyme's metabolites and drugs. METHODS: We constructed a drug-metabolite structural similarity matrix, which contains 1,861 FDA-approved drugs and 1,110 human intermediary metabolites scored with the Tanimoto similarity. To verify the metabolite-likeness measure for drug repositioning, we analyzed 17 known antimetabolite drugs that resemble the innate metabolites of their eleven target enzymes as the gold standard positives. Highly scored drugs were selected as possible modulators of enzymes for their corresponding metabolites. Then, we assessed the performance of metabolite-likeness with a receiver operating characteristic analysis and compared it with other drug-target prediction methods. We set the similarity threshold for drug repositioning candidates of new enzyme modulators based on maximization of the Youden's index. We also carried out literature surveys for supporting the drug repositioning results based on the metabolite-likeness. RESULTS: In this paper, we applied metabolite-likeness to repurpose FDA-approved drugs to disease-associated enzyme modulators that resemble human innate metabolites. All antimetabolite drugs were mapped with their known 11 target enzymes with statistically significant similarity values to the corresponding metabolites. The comparison with other drug-target prediction methods showed the higher performance of metabolite-likeness for predicting enzyme modulators. After that, the drugs scored higher than similarity score of 0.654 were selected as possible modulators of enzymes for their corresponding metabolites. In addition, we showed that drug repositioning results of 10 enzymes were concordant with the literature evidence. CONCLUSIONS: This study introduced a method to predict the repositioning of known drugs to possible modulators of disease associated enzymes using human metabolite-likeness. We demonstrated that this approach works correctly with known antimetabolite drugs and showed that the proposed method has better performance compared to other drug target prediction methods in terms of enzyme modulators prediction. This study as a proof-of-concept showed how to apply metabolite-likeness to drug repositioning as well as potential in further expansion as we acquire more disease associated metabolite-target protein relations.
[Mh] Termos MeSH primário: Reposicionamento de Medicamentos
Enzimas/metabolismo
[Mh] Termos MeSH secundário: Antimetabólitos/metabolismo
Área Sob a Curva
Bases de Dados Factuais
Enzimas/química
Doença de Gaucher/tratamento farmacológico
Doença de Gaucher/enzimologia
Doença de Gaucher/patologia
Glucosilceramidase/uso terapêutico
Seres Humanos
Curva ROC
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antimetabolites); 0 (Enzymes); EC 3.2.1.45 (Glucosylceramidase)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171102
[Lr] Data última revisão:
171102
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170616
[St] Status:MEDLINE
[do] DOI:10.1186/s12859-017-1637-5


  8 / 2031 MEDLINE  
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[PMID]:28569047
[Au] Autor:Mistry PK; Batista JL; Andersson HC; Balwani M; Burrow TA; Charrow J; Kaplan P; Khan A; Kishnani PS; Kolodny EH; Rosenbloom B; Scott CR; Weinreb N
[Ad] Endereço:Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
[Ti] Título:Transformation in pretreatment manifestations of Gaucher disease type 1 during two decades of alglucerase/imiglucerase enzyme replacement therapy in the International Collaborative Gaucher Group (ICGG) Gaucher Registry.
[So] Source:Am J Hematol;92(9):929-939, 2017 Sep.
[Is] ISSN:1096-8652
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:This study tests the hypothesis that the prevalence of severe clinical manifestations in Gaucher disease type 1 (GD1) patients at the time of treatment initiation has changed since alglucerase/imiglucerase enzyme replacement therapy (ERT) was approved in the United States (US) in 1991. US alglucerase/imiglucerase-treated GD1 patients from the International Collaborative Gaucher Group Gaucher Registry clinicaltrials.gov NCT00358943 were stratified by age at ERT initiation (<18, 18 to <50, ≥50 years), era of ERT initiation (1991-1995, 1996-2000, 2001-2005, 2006-2009), and splenectomy status pre-ERT. Prevalence of splenectomy decreased dramatically across the eras among all age groups. Bone manifestations were more prevalent in splenectomized patients than non-splenectomized patients in all age groups. Prevalence of bone manifestations differed across eras in certain age groups: non-splenectomized patients had a lower prevalence of ischemic bone events (pediatric patients) and bone crisis (pediatric patients and adults 18 to <50 years) in later eras; splenectomized adult (18 to <50 years) patients had a lower prevalence of ischemic bone events and bone crisis in later eras. Over two decades after the introduction of ERT, the prevalence of splenectomy and associated skeletal complications has declined dramatically. Concomitantly, the interval between diagnosis and initiation of ERT has decreased, most strikingly in pediatric patients who have the most severe disease. Together, these findings suggest that since the introduction of alglucerase/imiglucerase ERT, optimal standard of care has become established in the US to prevent destructive complications of GD1.
[Mh] Termos MeSH primário: Terapia de Reposição de Enzimas
Doença de Gaucher/tratamento farmacológico
Glucosilceramidase/uso terapêutico
[Mh] Termos MeSH secundário: Adolescente
Adulto
Feminino
Seguimentos
Seres Humanos
Masculino
Meia-Idade
Prevalência
Sistema de Registros
Esplenectomia
[Pt] Tipo de publicação:CLINICAL TRIAL; JOURNAL ARTICLE; MULTICENTER STUDY
[Nm] Nome de substância:
27T56C7KK0 (alglucerase); EC 3.2.1.45 (Glucosylceramidase); Q6U6J48BWY (imiglucerase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170602
[St] Status:MEDLINE
[do] DOI:10.1002/ajh.24801


  9 / 2031 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


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[PMID]:28328014
[Au] Autor:Sevsek A; Srot L; Rihter J; Celan M; van Ufford LQ; Moret EE; Martin NI; Pieters RJ
[Ad] Endereço:Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P.O. Box 3508 TB, 3508, TB, Utrecht, The Netherlands.
[Ti] Título:N-Guanidino Derivatives of 1,5-Dideoxy-1,5-imino-d-xylitol are Potent, Selective, and Stable Inhibitors of ß-Glucocerebrosidase.
[So] Source:ChemMedChem;12(7):483-486, 2017 Apr 06.
[Is] ISSN:1860-7187
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:A series of lipidated guanidino and urea derivatives of 1,5-dideoxy-1,5-imino-d-xylitol were prepared from d-xylose using a concise synthetic protocol. Inhibition assays with a panel of glycosidases revealed that the guanidino analogues display potent inhibition against human recombinant ß-glucocerebrosidase with IC values in the low nanomolar range. Related urea analogues of 1,5-dideoxy-1,5-imino-d-xylitol were also synthesized and evaluated in the same fashion and found to be selective for ß-galactosidase from bovine liver. No inhibition of human recombinant ß-glucocerebrosidase was observed for the urea analogues. Computational studies provided insight into the potent activity of analogues bearing the substituted guanidine moiety in the inhibition of lysosomal glucocerebrosidase (GBA).
[Mh] Termos MeSH primário: Inibidores Enzimáticos/química
Glucosilceramidase/antagonistas & inibidores
Guanidina/química
Xilitol/química
[Mh] Termos MeSH secundário: Animais
Sítios de Ligação
Bovinos
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/metabolismo
Glucosilceramidase/genética
Glucosilceramidase/metabolismo
Seres Humanos
Fígado/enzimologia
Simulação de Acoplamento Molecular
Ligação Proteica
Estrutura Terciária de Proteína
Proteínas Recombinantes/biossíntese
Proteínas Recombinantes/química
Proteínas Recombinantes/isolamento & purificação
Relação Estrutura-Atividade
Xilitol/síntese química
Xilitol/metabolismo
beta-Galactosidase/antagonistas & inibidores
beta-Galactosidase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Recombinant Proteins); EC 3.2.1.23 (beta-Galactosidase); EC 3.2.1.45 (Glucosylceramidase); JU58VJ6Y3B (Guanidine); VCQ006KQ1E (Xylitol)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170519
[Lr] Data última revisão:
170519
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170323
[St] Status:MEDLINE
[do] DOI:10.1002/cmdc.201700050



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