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[PMID]:29428127
[Au] Autor:Liao J; Liu X; Gao M; Wang M; Wang Y; Wang F; Huang W; Liu G
[Ad] Endereço:Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian 116011, China; Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center,
[Ti] Título:Dyslipidemia, steatohepatitis and atherogenesis in lipodystrophic apoE deficient mice with Seipin deletion.
[So] Source:Gene;648:82-88, 2018 Mar 30.
[Is] ISSN:1879-0038
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:SEIPIN is an integral membrane protein located in the endoplasmic reticulum, regulating adipocytes differentiation and lipolysis. Deficiency of Seipin in mice causes severe general lipodystrophy, accompanied by insulin resistance, postprandial hypertriglyceridemia and steatohepatitis. In atherosclerosis-prone Ldlr null (Ldlr ) mice, lipodystrophy caused by Seipin deletion even led to severe hypercholesteremia and accelerated atherogenesis, when challenged with an atherogenic diet. However, whether the phenotypes observed in Seipin Ldlr mice were a common consequence due to lipodystrophy, rather than genetic background restricted or diet dependent, was unknown. Herein we explored the lipodystrophy-related dyslipidemia, steatohepatitis and atherogenesis in another atherosclerosis-prone murine model, apolipoprotein E null (apoE ) mice. Besides, we also compared phenotypes between sexes in apoE mice with Seipin deletion (Seipin apoE ). We found that compared with apoE controls, Seipin apoE mice also developed severe general lipodystrophy with hyperlipidemia, steatohepatitis and increased atherogenesis. Although the severity of adipose loss in female and male Seipin apoE mice were similar, hyperlipidemia, steatohepatitis and atherosclerosis were less severe in females than in males. Therefore, we demonstrated that lipodystrophy-related metabolic disorders, caused by Seipin deletion, were independent of genetic background and experimental diet, as seen in Ldlr and apoE mice. However, gender factor affected the disease progression, with females more resistant to developing lipodystrophy-related metabolic consequences.
[Mh] Termos MeSH primário: Apolipoproteínas E/genética
Aterosclerose/genética
Dislipidemias/genética
Fígado Gorduroso/genética
Proteínas Heterotriméricas de Ligação ao GTP/genética
Lipodistrofia/genética
[Mh] Termos MeSH secundário: Animais
Apolipoproteínas E/deficiência
Aterosclerose/metabolismo
Aterosclerose/patologia
Progressão da Doença
Dislipidemias/metabolismo
Dislipidemias/patologia
Fígado Gorduroso/metabolismo
Fígado Gorduroso/patologia
Feminino
Proteínas Heterotriméricas de Ligação ao GTP/deficiência
Lipodistrofia/metabolismo
Lipodistrofia/patologia
Masculino
Camundongos Endogâmicos C57BL
Camundongos Knockout
Receptores de LDL/deficiência
Receptores de LDL/genética
Índice de Gravidade de Doença
Fatores Sexuais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Apolipoproteins E); 0 (Bscl2 protein, mouse); 0 (Receptors, LDL); EC 3.6.5.1 (Heterotrimeric GTP-Binding Proteins)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180212
[St] Status:MEDLINE


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[PMID]:29342149
[Au] Autor:Lindegaard B; Hvid T; Wolsk Mygind H; Hartvig-Mortensen O; Grøndal T; Abildgaard J; Gerstoft J; Pedersen BK; Baranowski M
[Ad] Endereço:The Centre of Inflammation and Metabolism and The Centre of Physical Activity Research, Rigshospital, Copenhagen, Denmark.
[Ti] Título:Low expression of IL-18 and IL-18 receptor in human skeletal muscle is associated with systemic and intramuscular lipid metabolism-Role of HIV lipodystrophy.
[So] Source:PLoS One;13(1):e0186755, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Interleukin (IL)-18 is involved in regulation of lipid and glucose metabolism. Mice lacking whole-body IL-18 signalling are prone to develop weight gain and insulin resistance, a phenotype which is associated with impaired fat oxidation and ectopic skeletal muscle lipid deposition. IL-18 mRNA is expressed in human skeletal muscle but a role for IL-18 in muscle has not been identified. Patients with HIV-infection and lipodystrophy (LD) are characterized by lipid and glucose disturbances and increased levels of circulating IL-18. We hypothesized that skeletal muscle IL-18 and IL-18 receptor (R) expression would be altered in patients with HIV-lipodystrophy. DESIGN AND METHODS: Twenty-three HIV-infected patients with LD and 15 age-matched healthy controls were included in a cross-sectional study. Biopsies from the vastus lateralis muscle were obtained and IL-18 and IL-18R mRNA expression were measured by real-time PCR and sphingolipids (ceramides, sphingosine, sphingosine-1-Phosphate, sphinganine) were measured by HPLC. Insulin resistance was assessed by HOMA and the insulin response during an OGTT. RESULTS: Patients with HIV-LD had a 60% and 54% lower level of muscular IL-18 and IL-18R mRNA expression, respectively, compared to age-matched healthy controls. Patients with HIV-LD had a trend towards increased levels of ceramide (18.3±4.7 versus 14.8±3.0,p = 0.06) and sphingosine (0.41±0.13 versus 0.32±0.07, and lower level of sphinganine (p = 0.06). Low levels of muscle IL-18 mRNA correlated to high levels of ceramides (r = -0.31, p = 0.038) and sphingosine-1P (r = -0.29, p = 0.046) in skeletal muscle, whereas such a correlation was not found in healthy controls. Low expression of IL-18 mRNA in skeletal muscle correlated to elevated concentration of circulating triglycerides (Rp = -0.73, p<0.0001). Neither muscle expression of IL-18 mRNA or ceramide correlated to parameters of insulin resistance. CONCLUSION: IL-18 (mRNA) in skeletal muscle appears to be involved in the regulation of intramuscular lipid metabolism and hypertriglyceridemia.
[Mh] Termos MeSH primário: Infecções por HIV/metabolismo
Interleucina-18/metabolismo
Metabolismo dos Lipídeos
Lipodistrofia/metabolismo
Músculo Esquelético/metabolismo
Receptores de Interleucina-18/metabolismo
[Mh] Termos MeSH secundário: Adulto
Infecções por HIV/complicações
Seres Humanos
Lipodistrofia/complicações
Masculino
Meia-Idade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Interleukin-18); 0 (Receptors, Interleukin-18)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180129
[Lr] Data última revisão:
180129
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180118
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0186755


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[PMID]:28841605
[Au] Autor:Gassman AA; Pezeshk R; Scheuer JF; Sieber DA; Campbell CF; Rohrich RJ
[Ad] Endereço:Philadelphia, Pa.; and Dallas, Texas From the Department of Surgery, Division of Plastic Surgery, Temple University; and the Department of Plastic Surgery, University of Texas Southwestern Medical Center.
[Ti] Título:Anatomical and Clinical Implications of the Deep and Superficial Fat Compartments of the Neck.
[So] Source:Plast Reconstr Surg;140(3):405e-414e, 2017 Sep.
[Is] ISSN:1529-4242
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Anatomical study has proven vital to the understanding and improvement of rejuvenation techniques of the face and neck. The microscopic septa responsible for individual facial fat compartments are also present in the neck. The authors' anatomical studies of the neck, including supraplatysmal and subplatysmal elements, have influenced their surgical and nonsurgical techniques. Careful muscular resuspension and modification of both deep and superficial fat compartments can lead to impressive and lasting aesthetic outcomes. The authors present their algorithm and approach to both surgical and noninvasive methods for aesthetic neck contouring. The discussion contained here is augmented by video footage of injected, fresh cadaver dissection that highlights the anatomical relationships of neck fat compartments discussed in this article.
[Mh] Termos MeSH primário: Pescoço/anatomia & histologia
Ritidoplastia/métodos
Gordura Subcutânea/anatomia & histologia
[Mh] Termos MeSH secundário: Algoritmos
Cadáver
Estética
Face/cirurgia
Seres Humanos
Lipodistrofia/cirurgia
Músculo Esquelético/anatomia & histologia
Pescoço/cirurgia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170918
[Lr] Data última revisão:
170918
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170826
[St] Status:MEDLINE
[do] DOI:10.1097/PRS.0000000000003618


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[PMID]:28698261
[Au] Autor:Lee SY; Lee HY; Song JH; Kim GT; Jeon S; Song YJ; Lee JS; Hur JH; Oh HH; Park SY; Shim SM; Yoo HJ; Lee BC; Jiang XC; Choi CS; Park TS
[Ad] Endereço:Department of Life Science, Gachon University, Sungnam, Korea.
[Ti] Título:Adipocyte-Specific Deficiency of De Novo Sphingolipid Biosynthesis Leads to Lipodystrophy and Insulin Resistance.
[So] Source:Diabetes;66(10):2596-2609, 2017 Oct.
[Is] ISSN:1939-327X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Sphingolipids have been implicated in the etiology of chronic metabolic diseases. Here, we investigated whether sphingolipid biosynthesis is associated with the development of adipose tissues and metabolic diseases. SPTLC2, a subunit of serine palmitoyltransferase, was transcriptionally upregulated in the adipose tissues of obese mice and in differentiating adipocytes. Adipocyte-specific SPTLC2-deficient (aSPTLC2 KO) mice had markedly reduced adipose tissue mass. Fatty acids that were destined for the adipose tissue were instead shunted to liver and caused hepatosteatosis. This impaired fat distribution caused systemic insulin resistance and hyperglycemia, indicating severe lipodystrophy. Mechanistically, sphingosine 1-phosphate (S1P) was reduced in the adipose tissues of aSPTLC2 KO mice, and this inhibited adipocyte proliferation and differentiation via the downregulation of S1P receptor 1 and decreased activity of the peroxisome proliferator-activator receptor γ. In addition, downregulation of SREBP (sterol regulatory element-binding protein)-1c prevented adipogenesis of aSPTLC2 KO adipocytes. Collectively, our observations suggest that the tight regulation of de novo sphingolipid biosynthesis and S1P signaling plays an important role in adipogenesis and hepatosteatosis.
[Mh] Termos MeSH primário: Adipócitos/citologia
Adipócitos/metabolismo
Lipodistrofia/etiologia
Lipodistrofia/metabolismo
[Mh] Termos MeSH secundário: Adipogenia/genética
Adipogenia/fisiologia
Tecido Adiposo/citologia
Tecido Adiposo/metabolismo
Animais
Diferenciação Celular/genética
Diferenciação Celular/fisiologia
Proliferação Celular/genética
Proliferação Celular/fisiologia
Resistência à Insulina/genética
Resistência à Insulina/fisiologia
Lisofosfolipídeos/metabolismo
Masculino
Camundongos
Camundongos Knockout
Serina C-Palmitoiltransferase/genética
Serina C-Palmitoiltransferase/metabolismo
Esfingosina/análogos & derivados
Esfingosina/metabolismo
Proteína de Ligação a Elemento Regulador de Esterol 1/genética
Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Lysophospholipids); 0 (Sterol Regulatory Element Binding Protein 1); 26993-30-6 (sphingosine 1-phosphate); EC 2.3.1.50 (Serine C-Palmitoyltransferase); EC 2.3.1.50 (Sptlc2 protein, mouse); NGZ37HRE42 (Sphingosine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170713
[St] Status:MEDLINE
[do] DOI:10.2337/db16-1232


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[PMID]:28552196
[Au] Autor:Tachmazidou I; Süveges D; Min JL; Ritchie GRS; Steinberg J; Walter K; Iotchkova V; Schwartzentruber J; Huang J; Memari Y; McCarthy S; Crawford AA; Bombieri C; Cocca M; Farmaki AE; Gaunt TR; Jousilahti P; Kooijman MN; Lehne B; Malerba G; Männistö S; Matchan A; Medina-Gomez C; Metrustry SJ; Nag A; Ntalla I; Paternoster L; Rayner NW; Sala C; Scott WR; Shihab HA; Southam L; St Pourcain B; Traglia M; Trajanoska K; Zaza G; Zhang W; Artigas MS; Bansal N; Benn M; Chen Z; Danecek P; Lin WY; Locke A; Luan J; Manning AK; Mulas A; Sidore C; Tybjaerg-Hansen A; Varbo A; SpiroMeta Consortium; GoT2D Consortium; arcOGEN Consortium; Understanding Society Scientific Group; UK10K Consortium
[Ad] Endereço:The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.
[Ti] Título:Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits.
[So] Source:Am J Hum Genet;100(6):865-884, 2017 Jun 01.
[Is] ISSN:1537-6605
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Deep sequence-based imputation can enhance the discovery power of genome-wide association studies by assessing previously unexplored variation across the common- and low-frequency spectra. We applied a hybrid whole-genome sequencing (WGS) and deep imputation approach to examine the broader allelic architecture of 12 anthropometric traits associated with height, body mass, and fat distribution in up to 267,616 individuals. We report 106 genome-wide significant signals that have not been previously identified, including 9 low-frequency variants pointing to functional candidates. Of the 106 signals, 6 are in genomic regions that have not been implicated with related traits before, 28 are independent signals at previously reported regions, and 72 represent previously reported signals for a different anthropometric trait. 71% of signals reside within genes and fine mapping resolves 23 signals to one or two likely causal variants. We confirm genetic overlap between human monogenic and polygenic anthropometric traits and find signal enrichment in cis expression QTLs in relevant tissues. Our results highlight the potential of WGS strategies to enhance biologically relevant discoveries across the frequency spectrum.
[Mh] Termos MeSH primário: Antropometria
Genoma Humano
Estudo de Associação Genômica Ampla
Locos de Características Quantitativas/genética
Análise de Sequência de DNA/métodos
[Mh] Termos MeSH secundário: Estatura/genética
Estudos de Coortes
Metilação de DNA/genética
Bases de Dados Genéticas
Feminino
Variação Genética
Seres Humanos
Lipodistrofia/genética
Masculino
Metanálise como Assunto
Obesidade/genética
Mapeamento Físico do Cromossomo
Caracteres Sexuais
Síndrome
Reino Unido
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170731
[Lr] Data última revisão:
170731
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170530
[St] Status:MEDLINE


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[PMID]:28521875
[Au] Autor:Elouej S; Beleza-Meireles A; Caswell R; Colclough K; Ellard S; Desvignes JP; Béroud C; Lévy N; Mohammed S; De Sandre-Giovannoli A
[Ad] Endereço:Aix Marseille Univ, INSERM, GMGF, Marseille, France.
[Ti] Título:Exome sequencing reveals a de novo POLD1 mutation causing phenotypic variability in mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL).
[So] Source:Metabolism;71:213-225, 2017 Jun.
[Is] ISSN:1532-8600
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL) is an autosomal dominant systemic disorder characterized by prominent loss of subcutaneous fat, a characteristic facial appearance and metabolic abnormalities. This syndrome is caused by heterozygous de novo mutations in the POLD1 gene. To date, 19 patients with MDPL have been reported in the literature and among them 14 patients have been characterized at the molecular level. Twelve unrelated patients carried a recurrent in-frame deletion of a single codon (p.Ser605del) and two other patients carried a novel heterozygous mutation in exon 13 (p.Arg507Cys). Additionally and interestingly, germline mutations of the same gene have been involved in familial polyposis and colorectal cancer (CRC) predisposition. PATIENTS AND METHODS: We describe a male and a female patient with MDPL respectively affected with mild and severe phenotypes. Both of them showed mandibular hypoplasia, a beaked nose with bird-like facies, prominent eyes, a small mouth, growth retardation, muscle and skin atrophy, but the female patient showed such a severe and early phenotype that a first working diagnosis of Hutchinson-Gilford Progeria was made. The exploration was performed by direct sequencing of POLD1 gene exon 15 in the male patient with a classical MDPL phenotype and by whole exome sequencing in the female patient and her unaffected parents. RESULTS: Exome sequencing identified in the latter patient a de novo heterozygous undescribed mutation in the POLD1 gene (NM_002691.3: c.3209T>A), predicted to cause the missense change p.Ile1070Asn in the ZnF2 (Zinc Finger 2) domain of the protein. This mutation was not reported in the 1000 Genome Project, dbSNP and Exome sequencing databases. Furthermore, the Isoleucine1070 residue of POLD1 is highly conserved among various species, suggesting that this substitution may cause a major impairment of POLD1 activity. For the second patient, affected with a typical MDPL phenotype, direct sequencing of POLD1 exon 15 revealed the recurrent in-frame deletion (c.1812_1814del, p.S605del). CONCLUSION: Our work highlights that mutations in different POLD1 domains can lead to phenotypic variability, ranging from dominantly inherited cancer predisposition syndromes, to mild MDPL phenotypes without lifespan reduction, to very severe MDPL syndromes with major premature aging features. These results also suggest that POLD1 gene testing should be considered in patients presenting with severe progeroid features.
[Mh] Termos MeSH primário: DNA Polimerase III/genética
Surdez/genética
Exoma/genética
Lipodistrofia/genética
Mutação
Progéria/genética
[Mh] Termos MeSH secundário: Idade de Início
Criança
Surdez/patologia
Surdez/psicologia
Éxons/genética
Feminino
Deleção de Genes
Seres Humanos
Lipodistrofia/patologia
Lipodistrofia/psicologia
Masculino
Fenótipo
Progéria/patologia
Progéria/psicologia
Análise de Sequência de Proteína
Síndrome
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.7.7.- (DNA Polymerase III); EC 2.7.7.- (POLD1 protein, human)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170814
[Lr] Data última revisão:
170814
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170520
[St] Status:MEDLINE


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[PMID]:28521869
[Au] Autor:Gallego-Escuredo JM; Lamarca MK; Villarroya J; Domingo JC; Mateo MG; Gutierrez MDM; Vidal F; Villarroya F; Domingo P; Giralt M
[Ad] Endereço:Institut de Recerca Biomèdica (IRB) de Lleida, Lleida, Spain; Departament de Bioquímica i Biomedicina Molecular and Institut de Biomedicina (IBUB), Universitat de Barcelona, and CIBER Fisiopatología de la Obesidad y Nutrición, Barcelona, Spain.
[Ti] Título:High FGF21 levels are associated with altered bone homeostasis in HIV-1-infected patients.
[So] Source:Metabolism;71:163-170, 2017 Jun.
[Is] ISSN:1532-8600
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Fibroblast growth factor-21 (FGF21) has emerged as an important regulator of glucose, lipid, and body weight homeostasis. However, recent experimental studies have reported that increased FGF21 levels may lead to bone loss. OBJECTIVE: To assess the relationship of serum FGF21 levels and altered bone homeostasis in HIV-1-infected patients. DESIGN: Cross-sectional study of 137 HIV-1-infected patients and 35 healthy controls conducted at the Hospital de la Santa Creu i Sant Pau, Barcelona. Among HIV-1-infected patients, 35 were untreated (naïve), 43 were treated with antiretrovirals (HIV-1/ART) with no lipodystrophy, and 59 patients were HIV-1/ART and experienced lipodystrophy. Bone mineral density (BMD) and content (BMC) were assessed using dual-energy X-ray absorptiometry. Serum levels of FGF21, receptor activator of nuclear factor (NF)-KB ligand (RANKL), and C-telopeptide of type-I collagen (CTX-1) were measured by enzyme-linked immunosorbent assays. Serum levels of osteocalcin, osteoprotegerin, leptin, tumor necrosis factor-α, interleukin-6, interleukin-8, and monocyte chemoattractant protein-1 were determined using an antibody-linked, fluorescently labeled microsphere bead-based multiplex analysis system. RESULTS: Alterations in bone parameters and bone homeostasis marker levels were consistent with higher turnover and bone loss in HIV-1 infected patients. FGF21 correlated negatively with BMD and BMC. FGF21 correlated positively with serum levels of osteoprotegerin and CTX-1, as well as with the CTX-1/osteocalcin ratio. CONCLUSIONS: Elevated FGF21 levels are associated with poor bone homeostasis in HIV-1-infected patients. Increases in FGF21 serum level may be an indicator not only of metabolic derangement but it may also serve as a biomarker of altered bone homeostasis in HIV-1 infected patients.
[Mh] Termos MeSH primário: Osso e Ossos/metabolismo
Fatores de Crescimento de Fibroblastos/sangue
Infecções por HIV/sangue
Infecções por HIV/metabolismo
HIV-1
[Mh] Termos MeSH secundário: Absorciometria de Fóton
Adulto
Terapia Antirretroviral de Alta Atividade
Composição Corporal
Densidade Óssea
Estudos de Coortes
Estudos Transversais
Feminino
Infecções por HIV/patologia
Homeostase
Seres Humanos
Lipodistrofia/sangue
Lipodistrofia/complicações
Fígado/patologia
Masculino
Meia-Idade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (fibroblast growth factor 21); 62031-54-3 (Fibroblast Growth Factors)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170814
[Lr] Data última revisão:
170814
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170520
[St] Status:MEDLINE


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[PMID]:28490631
[Au] Autor:Varnum MM; Clayton KA; Yoshii-Kitahara A; Yonemoto G; Koro L; Ikezu S; Ikezu T
[Ad] Endereço:From the Departments of Pharmacology and Experimental Therapeutics and.
[Ti] Título:A split-luciferase complementation, real-time reporting assay enables monitoring of the disease-associated transmembrane protein TREM2 in live cells.
[So] Source:J Biol Chem;292(25):10651-10663, 2017 Jun 23.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Triggering receptor expressed on myeloid cells 2 (TREM2) is a single transmembrane molecule uniquely expressed in microglia. TREM2 mutations are genetically linked to Nasu-Hakola disease and associated with multiple neurodegenerative disorders, including Alzheimer's disease. TREM2 may regulate microglial inflammation and phagocytosis through coupling to the adaptor protein TYRO protein-tyrosine kinase-binding protein (TYROBP). However, there is no functional system for monitoring this protein-protein interaction. We developed a luciferase-based modality for real-time monitoring of TREM2-TYROBP coupling in live cells that utilizes split-luciferase complementation technology based on TREM2 and TYROBP fusion to the C- or N-terminal portion of the luciferase gene. Transient transfection of human embryonic kidney 293 cells with this reporter vector increased luciferase activity upon stimulation with an anti-TREM2 antibody, which induces their homodimerization. This was confirmed by ELISA-based analysis of the TREM2-TYROBP interaction. Antibody-mediated TREM2 stimulation enhanced spleen tyrosine kinase (SYK) activity and uptake of in microglial cell line BV-2 in a kinase-dependent manner. Interestingly, the TREM2 T66M mutation significantly enhanced luciferase activity without stimulation, indicating constitutive coupling to TYROBP. Finally, flow cytometry analyses indicated significantly lower surface expression of T66M TREM2 variant than wild type or other TREM2 variants. These results demonstrate that our TREM2 reporter vector is a novel tool for monitoring the TREM2-TYROBP interaction in real time.
[Mh] Termos MeSH primário: Citometria de Fluxo/métodos
Teste de Complementação Genética/métodos
Luciferases de Renilla/metabolismo
Glicoproteínas de Membrana/metabolismo
Microglia/metabolismo
Receptores Imunológicos/metabolismo
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transdução de Sinal/genética
Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Doença de Alzheimer/genética
Doença de Alzheimer/metabolismo
Animais
Linhagem Celular
Seres Humanos
Lipodistrofia/genética
Lipodistrofia/metabolismo
Glicoproteínas de Membrana/genética
Proteínas de Membrana/genética
Proteínas de Membrana/metabolismo
Camundongos
Osteocondrodisplasias/genética
Osteocondrodisplasias/metabolismo
Receptores Imunológicos/genética
Panencefalite Esclerosante Subaguda/genética
Panencefalite Esclerosante Subaguda/metabolismo
Quinase Syk/genética
Quinase Syk/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (Membrane Glycoproteins); 0 (Membrane Proteins); 0 (Receptors, Immunologic); 0 (TREM2 protein, human); 0 (TYROBP protein, human); 0 (Trem2 protein, mouse); 0 (Tyrobp protein, mouse); EC 1.13.12.5 (Luciferases, Renilla); EC 2.7.10.2 (SYK protein, human); EC 2.7.10.2 (Syk Kinase); EC 2.7.10.2 (Syk protein, mouse)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170714
[Lr] Data última revisão:
170714
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170512
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.759159


  9 / 2731 MEDLINE  
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[PMID]:28371314
[Au] Autor:Kimura L; Alvarez G; Li N; Pawlikowska-Haddal A; Moore TB; Casillas J; Lee KW
[Ad] Endereço:Department of Pediatric Endocrinology, UCLA Mattel Children's Hospital, Los Angeles, California.
[Ti] Título:Temporary resolution of insulin requirement in acquired partial lipodystrophy associated with chronic graft-versus-host disease.
[So] Source:Pediatr Blood Cancer;64(7), 2017 Jul.
[Is] ISSN:1545-5017
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:This is a case presentation describing a high insulin requirement that suddenly resolved in a patient with acute lymphoblastic leukemia treated with stem cell transplantation complicated by chronic graft-versus-host disease. The patient was diagnosed with acquired partial lipodystrophy that did not require alternative therapies such as leptin or insulin-like growth factor 1.
[Mh] Termos MeSH primário: Doença Enxerto-Hospedeiro/complicações
Transplante de Células-Tronco Hematopoéticas/efeitos adversos
Lipodistrofia/etiologia
Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia
[Mh] Termos MeSH secundário: Criança
Doença Crônica
Feminino
Seres Humanos
Hipertrigliceridemia/etiologia
Hipoglicemiantes/uso terapêutico
Insulina/uso terapêutico
Lipodistrofia/tratamento farmacológico
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Hypoglycemic Agents); 0 (Insulin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170914
[Lr] Data última revisão:
170914
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170404
[St] Status:MEDLINE
[do] DOI:10.1002/pbc.26427


  10 / 2731 MEDLINE  
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[PMID]:28330852
[Au] Autor:Abulizi A; Perry RJ; Camporez JPG; Jurczak MJ; Petersen KF; Aspichueta P; Shulman GI
[Ad] Endereço:Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
[Ti] Título:A controlled-release mitochondrial protonophore reverses hypertriglyceridemia, nonalcoholic steatohepatitis, and diabetes in lipodystrophic mice.
[So] Source:FASEB J;31(7):2916-2924, 2017 Jul.
[Is] ISSN:1530-6860
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Lipodystrophy is a rare disorder characterized by complete or partial loss of adipose tissue. Patients with lipodystrophy exhibit hypertriglyceridemia, severe insulin resistance, type 2 diabetes, and nonalcoholic steatohepatitis (NASH). Efforts to ameliorate NASH in lipodystrophies with pharmacologic agents have met with limited success. We examined whether a controlled-release mitochondrial protonophore (CRMP) that produces mild liver-targeted mitochondrial uncoupling could decrease hypertriglyceridemia and reverse NASH and diabetes in a mouse model (fatless AZIP/F-1 mice) of severe lipodystrophy and diabetes. After 4 wk of oral CRMP (2 mg/kg body weight per day) or vehicle treatment, mice underwent hyperinsulinemic-euglycemic clamps combined with radiolabeled glucose to assess liver and muscle insulin responsiveness and tissue lipid measurements. CRMP treatment reversed hypertriglyceridemia and insulin resistance in liver and skeletal muscle. Reversal of insulin resistance could be attributed to reductions in diacylglycerol content and reduced PKC-ε and PKC-θ activity in liver and muscle respectively. CRMP treatment also reversed NASH as reflected by reductions in plasma aspartate aminotransferase and alanine aminotransferase concentrations; hepatic steatosis; and hepatic expression of IL-1α, -ß, -2, -4, -6, -10, -12, CD69, and caspase 3 and attenuated activation of the IRE-1α branch of the unfolded protein response. Taken together, these results provide proof of concept for the development of liver-targeted mitochondrial uncoupling agents as a potential novel therapy for lipodystrophy-associated hypertriglyceridemia, NASH and diabetes.-Abulizi, A., Perry, R. J., Camporez, J. P. G., Jurczak, M. J., Petersen, K. F., Aspichueta, P., Shulman, G. I. A controlled-release mitochondrial protonophore reverses hypertriglyceridemia, nonalcoholic steatohepatitis, and diabetes in lipodystrophic mice.
[Mh] Termos MeSH primário: Diabetes Mellitus Tipo 2/tratamento farmacológico
Hipertrigliceridemia/tratamento farmacológico
Lipodistrofia/tratamento farmacológico
Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico
Ionóforos de Próton/uso terapêutico
[Mh] Termos MeSH secundário: Animais
Preparações de Ação Retardada
Ingestão de Alimentos/efeitos dos fármacos
Metabolismo Energético/efeitos dos fármacos
Resistência à Insulina
Masculino
Camundongos
Mitocôndrias Hepáticas/efeitos dos fármacos
Ionóforos de Próton/administração & dosagem
Distribuição Aleatória
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Delayed-Action Preparations); 0 (Proton Ionophores)
[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:170324
[St] Status:MEDLINE
[do] DOI:10.1096/fj.201700001R



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