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Pesquisa : D12.776.543.750.705.852.150.200 [Categoria DeCS]
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  1 / 1966 MEDLINE  
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[PMID]:28945754
[Au] Autor:Kallenberger SM; Unger AL; Legewie S; Lymperopoulos K; Klingmüller U; Eils R; Herten DP
[Ad] Endereço:Department for Bioinformatics and Functional Genomics, Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Heidelberg University, Heidelberg, Germany.
[Ti] Título:Correlated receptor transport processes buffer single-cell heterogeneity.
[So] Source:PLoS Comput Biol;13(9):e1005779, 2017 Sep.
[Is] ISSN:1553-7358
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cells typically vary in their response to extracellular ligands. Receptor transport processes modulate ligand-receptor induced signal transduction and impact the variability in cellular responses. Here, we quantitatively characterized cellular variability in erythropoietin receptor (EpoR) trafficking at the single-cell level based on live-cell imaging and mathematical modeling. Using ensembles of single-cell mathematical models reduced parameter uncertainties and showed that rapid EpoR turnover, transport of internalized EpoR back to the plasma membrane, and degradation of Epo-EpoR complexes were essential for receptor trafficking. EpoR trafficking dynamics in adherent H838 lung cancer cells closely resembled the dynamics previously characterized by mathematical modeling in suspension cells, indicating that dynamic properties of the EpoR system are widely conserved. Receptor transport processes differed by one order of magnitude between individual cells. However, the concentration of activated Epo-EpoR complexes was less variable due to the correlated kinetics of opposing transport processes acting as a buffering system.
[Mh] Termos MeSH primário: Transporte Biológico/fisiologia
Modelos Biológicos
Receptores de Superfície Celular/metabolismo
Análise de Célula Única/métodos
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Biologia Computacional
Corantes Fluorescentes/análise
Corantes Fluorescentes/química
Corantes Fluorescentes/metabolismo
Seres Humanos
Processamento de Imagem Assistida por Computador/métodos
Cinética
Microscopia Confocal
Receptores de Superfície Celular/análise
Receptores de Superfície Celular/química
Receptores da Eritropoetina
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Fluorescent Dyes); 0 (Receptors, Cell Surface); 0 (Receptors, Erythropoietin)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171110
[Lr] Data última revisão:
171110
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170926
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pcbi.1005779


  2 / 1966 MEDLINE  
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[PMID]:28600471
[Au] Autor:Yokoro M; Nakayama Y; Yamagishi SI; Ando R; Sugiyama M; Ito S; Yano J; Taguchi K; Kaida Y; Saigusa D; Kimoto M; Abe T; Ueda S; Fukami K
[Ad] Endereço:Division of Nephrology, Department of Medicine, and.
[Ti] Título:Asymmetric Dimethylarginine Contributes to the Impaired Response to Erythropoietin in CKD-Anemia.
[So] Source:J Am Soc Nephrol;28(9):2670-2680, 2017 Sep.
[Is] ISSN:1533-3450
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Erythropoietin-resistant anemia is associated with adverse cardiovascular events in patients with ESRD, but the underlying mechanism remains unclear. Here, we evaluated the role of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA). In 54 patients with advanced CKD, erythrocyte but not plasma ADMA levels independently associated with low hemoglobin values, although levels of both types of ADMA were elevated compared with those in healthy volunteers. Furthermore, erythrocyte ADMA level associated with the erythropoietin resistance index in patients receiving a weekly injected dose of erythropoiesis-stimulating agents standardized for hemoglobin levels and body weight, whereas it correlated with the erythropoietin demand index (plasma erythropoietin units divided by the hemoglobin value) in patients not receiving erythropoiesis-stimulating agents. Compared with sham-operated controls, wild-type mice with 5/6 subtotal nephrectomy (Nx), a remnant kidney model with advanced CKD, had decreased hemoglobin, hematocrit, and mean corpuscular volume values but increased erythrocyte and plasma ADMA and plasma erythropoietin levels. In comparison, dimethylarginine dimethlaminohydrolase-1 transgenic (DDAH-1 Tg) mice, which efficiently metabolized ADMA, had significant improvements in all of the values except those for erythropoietin after 5/6 Nx. Additionally, wild-type Nx mice, but not DDAH-1 Tg Nx mice, had reduced splenic gene expression of erythropoietin receptor and erythroferrone, which regulates iron metabolism in response to erythropoietin. This study suggests that erythrocyte ADMA accumulation contributes to impaired response to erythropoietin in predialysis patients and advanced CKD mice suppression of erythropoietin receptor expression.
[Mh] Termos MeSH primário: Anemia/tratamento farmacológico
Arginina/análogos & derivados
Eritrócitos/metabolismo
Eritropoetina/uso terapêutico
Hematínicos/uso terapêutico
Plasma/metabolismo
Insuficiência Renal Crônica/sangue
[Mh] Termos MeSH secundário: Idoso
Amidoidrolases/genética
Anemia/sangue
Anemia/etiologia
Animais
Arginina/sangue
Citocinas/genética
Resistência a Medicamentos
Índices de Eritrócitos
Feminino
Expressão Gênica
Hematócrito
Hemoglobinas/metabolismo
Seres Humanos
Masculino
Camundongos
Meia-Idade
Proteínas Musculares/genética
Nefrectomia
Receptores da Eritropoetina/genética
Insuficiência Renal Crônica/complicações
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CTRP15 protein, mouse); 0 (Cytokines); 0 (Hematinics); 0 (Hemoglobins); 0 (Muscle Proteins); 0 (Receptors, Erythropoietin); 11096-26-7 (Erythropoietin); 63CV1GEK3Y (N,N-dimethylarginine); 94ZLA3W45F (Arginine); EC 3.5.- (Amidohydrolases); EC 3.5.3.18 (dimethylargininase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170611
[St] Status:MEDLINE
[do] DOI:10.1681/ASN.2016111184


  3 / 1966 MEDLINE  
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[PMID]:28504707
[Au] Autor:Liu X; Zhang Y; Ni M; Cao H; Signer RAJ; Li D; Li M; Gu Z; Hu Z; Dickerson KE; Weinberg SE; Chandel NS; DeBerardinis RJ; Zhou F; Shao Z; Xu J
[Ad] Endereço:Children's Medical Center Research Institute, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
[Ti] Título:Regulation of mitochondrial biogenesis in erythropoiesis by mTORC1-mediated protein translation.
[So] Source:Nat Cell Biol;19(6):626-638, 2017 Jun.
[Is] ISSN:1476-4679
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Advances in genomic profiling present new challenges of explaining how changes in DNA and RNA are translated into proteins linking genotype to phenotype. Here we compare the genome-scale proteomic and transcriptomic changes in human primary haematopoietic stem/progenitor cells and erythroid progenitors, and uncover pathways related to mitochondrial biogenesis enhanced through post-transcriptional regulation. Mitochondrial factors including TFAM and PHB2 are selectively regulated through protein translation during erythroid specification. Depletion of TFAM in erythroid cells alters intracellular metabolism, leading to elevated histone acetylation, deregulated gene expression, and defective mitochondria and erythropoiesis. Mechanistically, mTORC1 signalling is enhanced to promote translation of mitochondria-associated transcripts through TOP-like motifs. Genetic and pharmacological perturbation of mitochondria or mTORC1 specifically impairs erythropoiesis in vitro and in vivo. Our studies support a mechanism for post-transcriptional control of erythroid mitochondria and may have direct relevance to haematologic defects associated with mitochondrial diseases and ageing.
[Mh] Termos MeSH primário: Eritropoese
Células-Tronco Hematopoéticas/enzimologia
Mitocôndrias/enzimologia
Complexos Multiproteicos/metabolismo
Biogênese de Organelas
Biossíntese de Proteínas
Serina-Treonina Quinases TOR/metabolismo
[Mh] Termos MeSH secundário: Acetilação
Animais
Células Cultivadas
Proteínas de Ligação a DNA/genética
Proteínas de Ligação a DNA/metabolismo
Perfilação da Expressão Gênica/métodos
Proteínas de Grupo de Alta Mobilidade/genética
Proteínas de Grupo de Alta Mobilidade/metabolismo
Histonas/metabolismo
Seres Humanos
Alvo Mecanístico do Complexo 1 de Rapamicina
Camundongos Knockout
Proteínas Mitocondriais/genética
Proteínas Mitocondriais/metabolismo
Complexos Multiproteicos/genética
PTEN Fosfo-Hidrolase/genética
PTEN Fosfo-Hidrolase/metabolismo
Fenótipo
Proteômica/métodos
RNA/genética
RNA/metabolismo
Interferência de RNA
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
Receptores da Eritropoetina/genética
Receptores da Eritropoetina/metabolismo
Proteínas Repressoras/genética
Proteínas Repressoras/metabolismo
Transdução de Sinais
Serina-Treonina Quinases TOR/genética
Fatores de Transcrição/genética
Fatores de Transcrição/metabolismo
Transfecção
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA-Binding Proteins); 0 (High Mobility Group Proteins); 0 (Histones); 0 (Mitochondrial Proteins); 0 (Multiprotein Complexes); 0 (RNA, Messenger); 0 (RNA, mitochondrial); 0 (Receptors, Erythropoietin); 0 (Repressor Proteins); 0 (TFAM protein, human); 0 (Tfam protein, mouse); 0 (Transcription Factors); 0 (prohibitin); 63231-63-0 (RNA); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1); EC 3.1.3.67 (PTEN Phosphohydrolase); EC 3.1.3.67 (Pten protein, mouse)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170516
[St] Status:MEDLINE
[do] DOI:10.1038/ncb3527


  4 / 1966 MEDLINE  
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[PMID]:28352153
[Au] Autor:Beh CY; How CW; Foo JB; Foong JN; Selvarajah GT; Rasedee A
[Ad] Endereço:Laboratory of Vaccines and Immunotherapeutics, Institute of Bioscience, Universiti Putra Malaysia, Serdang.
[Ti] Título:Development of erythropoietin receptor-targeted drug delivery system against breast cancer using tamoxifen-loaded nanostructured lipid carriers.
[So] Source:Drug Des Devel Ther;11:771-782, 2017.
[Is] ISSN:1177-8881
[Cp] País de publicação:New Zealand
[La] Idioma:eng
[Ab] Resumo:Tamoxifen (TAM) has been used in the treatment of breast cancers and is supplemented with erythropoietin (EPO) to alleviate the cancer-related anemia. The purported deleterious effects caused by the use of EPO with chemotherapeutic agents in the treatment of cancer-related anemia vary across studies and remain controversial. The use of nanoparticles as a drug delivery system has the potential to improve the specificity of anticancer drugs. In this study, we simultaneously incorporated two pharmacological active ingredients in one nanocarrier to develop EPO-conjugated TAM-loaded lipid nanoparticles (EPO-TAMNLC), a targeted delivery system, to enhance the cytotoxic activity while reducing the side effects of the ingredients. The effect of temperature in modulating the thermodynamic parameters associated with the binding of EPO and TAMNLC was assessed using isothermal titration calorimetry, while the unfolding of EPO structure was determined using fluorescence-quenching approach. The association efficiency of EPO and TAMNLC was 55.43%. Unlike binding of albumin to TAMNLC, the binding of EPO to TAMNLC occurred through endothermic and entropy-driven reaction. The EPO-TAMNLC formulation was stable because of the hydrophobic interaction and the high free energy, suggesting the spontaneity of the interactions between EPO and TAMNLC. The EPO-TAMNLC enhanced the in vitro cytotoxicity of TAM to MCF-7 cells. The EPO surface-functionalized TAMNLC could sequentially deliver EPO and TAM as well as improving site-specific delivery of these therapeutic compounds.
[Mh] Termos MeSH primário: Antineoplásicos Hormonais/administração & dosagem
Neoplasias da Mama/tratamento farmacológico
Neoplasias da Mama/metabolismo
Portadores de Fármacos/química
Lipídeos/química
Nanoestruturas/química
Receptores da Eritropoetina/metabolismo
Tamoxifeno/administração & dosagem
[Mh] Termos MeSH secundário: Anemia/tratamento farmacológico
Anemia/patologia
Antineoplásicos Hormonais/metabolismo
Antineoplásicos Hormonais/farmacocinética
Antineoplásicos Hormonais/farmacologia
Neoplasias da Mama/patologia
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Feminino
Seres Humanos
Células MCF-7
Relação Estrutura-Atividade
Tamoxifeno/metabolismo
Tamoxifeno/farmacocinética
Tamoxifeno/farmacologia
Termodinâmica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents, Hormonal); 0 (Drug Carriers); 0 (Lipids); 0 (Receptors, Erythropoietin); 094ZI81Y45 (Tamoxifen)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170515
[Lr] Data última revisão:
170515
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170330
[St] Status:MEDLINE
[do] DOI:10.2147/DDDT.S123939


  5 / 1966 MEDLINE  
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[PMID]:28302753
[Au] Autor:Purroy C; Fairchild RL; Tanaka T; Baldwin WM; Manrique J; Madsen JC; Colvin RB; Alessandrini A; Blazar BR; Fribourg M; Donadei C; Maggiore U; Heeger PS; Cravedi P
[Ad] Endereço:Department of Medicine, Translational Transplant Research Center, Recanati Miller Transplant Institute and.
[Ti] Título:Erythropoietin Receptor-Mediated Molecular Crosstalk Promotes T Cell Immunoregulation and Transplant Survival.
[So] Source:J Am Soc Nephrol;28(8):2377-2392, 2017 Aug.
[Is] ISSN:1533-3450
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Although spontaneous kidney transplant acceptance/tolerance occurs in mice and occasionally in humans, mechanisms remain unclear. Herein we test the hypothesis that EPO, a hormone predominantly produced by the adult kidney, has immunomodulating properties that are required for spontaneous kidney graft acceptance. , in a manner dependent on the EPO receptor and CD131 on antigen-presenting cells, EPO induced the secretion of active TGF by antigen-presenting cells, which in turn converted naïve CD4 T cells into functional Foxp3 regulatory T cells (Treg). In murine transplant models, pharmacologic downregulation of kidney-derived EPO prevented spontaneous Treg generation. In a controlled, prospective cohort clinical study, EPO administration at doses used to correct anemia augmented the frequency of peripheral CD4 CD25 CD127 T cells in humans with CKD. Furthermore, EPO directly inhibited conventional T cell proliferation tyrosine phosphatase SHP-1-dependent uncoupling of IL-2R signaling. Conversely, EPO-initiated signals facilitated Treg proliferation by augmenting IL-2R signaling and maintaining constitutively quenched IL-2R signaling. In additional murine transplant models, recombinant EPO administration prolonged heart allograft survival, whereas pharmacologic downregulation of kidney-derived EPO reduced the expression of TGF mRNA and abrogated kidney allograft acceptance. Together, our findings delineate the protolerogenic properties of EPO in inhibiting conventional T cells while simultaneously promoting Treg induction, and suggest that manipulating the EPO/EPO receptor signaling axis could be exploited to prevent and/or treat T cell-mediated pathologies, including transplant rejection.
[Mh] Termos MeSH primário: Sobrevivência de Enxerto/imunologia
Transplante de Rim
Receptor Cross-Talk
Receptores da Eritropoetina/fisiologia
Linfócitos T Reguladores/imunologia
[Mh] Termos MeSH secundário: Animais
Seres Humanos
Camundongos
Estudos Prospectivos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Erythropoietin)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170318
[St] Status:MEDLINE
[do] DOI:10.1681/ASN.2016101100


  6 / 1966 MEDLINE  
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[PMID]:28283542
[Au] Autor:Zhang Y; Rogers HM; Zhang X; Noguchi CT
[Ad] Endereço:Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
[Ti] Título:Sex difference in mouse metabolic response to erythropoietin.
[So] Source:FASEB J;31(6):2661-2673, 2017 Jun.
[Is] ISSN:1530-6860
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Erythropoietin (EPO) is the cytokine that regulates red blood cell production. Less understood is the nonerythroid action of EPO, including metabolic regulation of fat accumulation and glucose homeostasis. Although EPO treatment increased hematocrit and improved glucose tolerance in male and female mice, we observed a gender difference in EPO effects in weight control. EPO treatment reduced diet-induced weight gain from 9.6 ± 1.5 to 4.2 ± 1.4 g in male mice ( < 0.001), while the weight gain in female mice was similar (4.7 ± 2.0 g with PBS treatment and 3.3 ± 2.1 g with EPO treatment). EPO treatment also reduced weight gain in ovariectomized female mice, while the effect was abrogated with estradiol supplementation, suggesting that the sex-differential response to EPO was associated with estrogen. Furthermore, mice with targeted deletion of EPO receptor in white adipose tissue exhibited sex-differential phenotype in weight control and glucose sensitivity, and EPO receptor gene expression was reduced in wild-type female mice, suggesting that white adipose tissue plays an integral role in mediating the metabolic effects of EPO. Our data provide evidence for a sex-differential response to EPO in weight control in mice and underscore the potential for gender specific EPO action beyond erythropoiesis.-Zhang, Y., Rogers, H. M., Zhang, X., Noguchi, C. T. Sex difference in mouse metabolic response to erythropoietin.
[Mh] Termos MeSH primário: Metabolismo Energético/efeitos dos fármacos
Eritropoetina/farmacologia
[Mh] Termos MeSH secundário: Animais
Estrogênios/metabolismo
Feminino
Regulação da Expressão Gênica
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Ovariectomia
Receptores da Eritropoetina/genética
Receptores da Eritropoetina/metabolismo
Fatores Sexuais
Perda de Peso/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Estrogens); 0 (Receptors, Erythropoietin); 11096-26-7 (Erythropoietin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170912
[Lr] Data última revisão:
170912
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170312
[St] Status:MEDLINE
[do] DOI:10.1096/fj.201601223RRR


  7 / 1966 MEDLINE  
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[PMID]:28283061
[Au] Autor:Kim AR; Ulirsch JC; Wilmes S; Unal E; Moraga I; Karakukcu M; Yuan D; Kazerounian S; Abdulhay NJ; King DS; Gupta N; Gabriel SB; Lander ES; Patiroglu T; Ozcan A; Ozdemir MA; Garcia KC; Piehler J; Gazda HT; Klein DE; Sankaran VG
[Ad] Endereço:Division of Hematology/Oncology, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard
[Ti] Título:Functional Selectivity in Cytokine Signaling Revealed Through a Pathogenic EPO Mutation.
[So] Source:Cell;168(6):1053-1064.e15, 2017 Mar 09.
[Is] ISSN:1097-4172
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cytokines are classically thought to stimulate downstream signaling pathways through monotonic activation of receptors. We describe a severe anemia resulting from a homozygous mutation (R150Q) in the cytokine erythropoietin (EPO). Surprisingly, the EPO R150Q mutant shows only a mild reduction in affinity for its receptor but has altered binding kinetics. The EPO mutant is less effective at stimulating erythroid cell proliferation and differentiation, even at maximally potent concentrations. While the EPO mutant can stimulate effectors such as STAT5 to a similar extent as the wild-type ligand, there is reduced JAK2-mediated phosphorylation of select downstream targets. This impairment in downstream signaling mechanistically arises from altered receptor dimerization dynamics due to extracellular binding changes. These results demonstrate how variation in a single cytokine can lead to biased downstream signaling and can thereby cause human disease. Moreover, we have defined a distinct treatable form of anemia through mutation identification and functional studies.
[Mh] Termos MeSH primário: Anemia de Diamond-Blackfan/genética
Anemia de Diamond-Blackfan/patologia
Eritropoetina/genética
Mutação de Sentido Incorreto
Transdução de Sinais
[Mh] Termos MeSH secundário: Anemia de Diamond-Blackfan/terapia
Criança
Consanguinidade
Ativação Enzimática
Eritropoese
Eritropoetina/química
Feminino
Seres Humanos
Janus Quinase 2/metabolismo
Cinética
Masculino
Receptores da Eritropoetina/química
Receptores da Eritropoetina/genética
Receptores da Eritropoetina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (EPO protein, human); 0 (Receptors, Erythropoietin); 11096-26-7 (Erythropoietin); EC 2.7.10.2 (JAK2 protein, human); EC 2.7.10.2 (Janus Kinase 2)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170606
[Lr] Data última revisão:
170606
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170312
[St] Status:MEDLINE


  8 / 1966 MEDLINE  
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[PMID]:28257780
[Au] Autor:Tamura T; Aoyama M; Ukai S; Kakita H; Sobue K; Asai K
[Ad] Endereço:Department of Molecular Neurobiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; Department of Anesthesiology and Intensive Care Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. Electronic address: tetsuharuhina1226@yahoo.co.jp.
[Ti] Título:Neuroprotective erythropoietin attenuates microglial activation, including morphological changes, phagocytosis, and cytokine production.
[So] Source:Brain Res;1662:65-74, 2017 May 01.
[Is] ISSN:1872-6240
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Erythropoietin (EPO), a hematopoietic hormonal cytokine induced in response to hypoxia, has neuroprotective effects. EPO receptor (EPOR) is expressed in microglia, resident immune cells in the brain. However, the effect of EPO on microglial activation is not clear. In the present study, we demonstrated that the EPOR is highly expressed in microglia, rather than in neurons or astrocytes, in in vitro experiments. Therefore, we investigated whether EPO could attenuate lipopolysaccharide (LPS)-mediated activation of microglia in vitro. The BV-2 microglial cell line was treated with LPS in the absence or presence of EPO. In the presence of EPO, microglial expression of LPS-induced inflammatory cytokine genes was significantly decreased. In addition, EPO suppressed the LPS-induced phagocytic activity of BV-2 cells towards fluorescent beads, as well as induction of inducible nitric oxide synthase. In in vivo experiments, EPO significantly decreased the LPS-induced expression of inflammatory cytokine genes in mouse brains. Furthermore, morphological analysis of cortical microglia in the brains of mice stimulated with LPS revealed that combined treatment with EPO alleviated LPS-induced morphological changes in the microglia. These data indicate that EPO attenuates microglial activation, including morphological changes in vivo, phagocytosis in vitro, and the production of inflammatory cytokines in vivo and in vitro. Further investigation of EPO modulation of LPS-induced microglial activation may contribute to the development of novel neuroprotective therapies.
[Mh] Termos MeSH primário: Eritropoetina/metabolismo
Microglia/fisiologia
Receptores da Eritropoetina/metabolismo
[Mh] Termos MeSH secundário: Animais
Astrócitos/fisiologia
Encéfalo/metabolismo
Técnicas de Cultura de Células
Citocinas
Eritropoetina/uso terapêutico
Inflamação/metabolismo
Lipopolissacarídeos/farmacologia
Ativação de Macrófagos
Camundongos
Microglia/efeitos dos fármacos
Neurônios/fisiologia
Fármacos Neuroprotetores/metabolismo
Óxido Nítrico/metabolismo
Óxido Nítrico Sintase Tipo II/metabolismo
Fagocitose/efeitos dos fármacos
Ratos
Receptores da Eritropoetina/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytokines); 0 (Lipopolysaccharides); 0 (Neuroprotective Agents); 0 (Receptors, Erythropoietin); 11096-26-7 (Erythropoietin); 31C4KY9ESH (Nitric Oxide); EC 1.14.13.39 (Nitric Oxide Synthase Type II)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170305
[St] Status:MEDLINE


  9 / 1966 MEDLINE  
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[PMID]:28256220
[Au] Autor:Corbett MSP; Mark AE; Poger D
[Ad] Endereço:School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland, Australia.
[Ti] Título:Do All X-ray Structures of Protein-Ligand Complexes Represent Functional States? EPOR, a Case Study.
[So] Source:Biophys J;112(4):595-604, 2017 Feb 28.
[Is] ISSN:1542-0086
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Based on differences between the x-ray crystal structures of ligand-bound and unbound forms, the activation of the erythropoietin receptor (EPOR) was initially proposed to involve a cross-action scissorlike motion. However, the validity of the motions involved in the scissorlike model has been recently challenged. Here, atomistic molecular dynamics simulations are used to examine the structure of the extracellular domain of the EPOR dimer in the presence and absence of erythropoietin and a series of agonistic or antagonistic mimetic peptides free in solution. The simulations suggest that in the absence of crystal packing effects, the EPOR chains in the different dimers adopt very similar conformations with no clear distinction between the agonist and antagonist-bound complexes. This questions whether the available x-ray crystal structures of EPOR truly represent active or inactive conformations. The study demonstrates the difficulty in using such structures to infer a mechanism of action, especially in the case of membrane receptors where just part of the structure has been considered in addition to potential confounding effects that arise from the comparison of structures in a crystal as opposed to a membrane environment. The work highlights the danger of assigning functional significance to small differences between structures of proteins bound to different ligands in a crystal environment without consideration of the effects of the crystal lattice and thermal motion.
[Mh] Termos MeSH primário: Receptores da Eritropoetina/química
Receptores da Eritropoetina/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Apoproteínas/química
Apoproteínas/metabolismo
Cristalografia por Raios X
Ligantes
Modelos Moleculares
Ligação Proteica
Multimerização Proteica
Estrutura Quaternária de Proteína
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Apoproteins); 0 (Ligands); 0 (Receptors, Erythropoietin)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170304
[St] Status:MEDLINE


  10 / 1966 MEDLINE  
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[PMID]:28142212
[Au] Autor:Miljus N; Massih B; Weis MA; Rison JV; Bonnas CB; Sillaber I; Ehrenreich H; Geurten BR; Heinrich R
[Ad] Endereço:Department of Cellular Neurobiology, Institute for Zoology, University of Goettingen, Goettingen, Germany.
[Ti] Título:Neuroprotection and endocytosis: erythropoietin receptors in insect nervous systems.
[So] Source:J Neurochem;141(1):63-74, 2017 Apr.
[Is] ISSN:1471-4159
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Erythropoietin (Epo) plays a dual role as an erythropoiesis-stimulating hormone and a locally produced cytoprotectant in various vertebrate tissues. Splice variants and engineered derivatives of Epo that mediate neuroprotection but do not stimulate erythropoiesis suggest that alternative receptors, different from the 'classical' homodimeric receptor involved in haematopoiesis, mediate neuroprotective Epo functions. Previous studies on grasshoppers demonstrated neuroprotective and neuroregenerative effects of Epo that involved similar transduction pathways as in mammals. To advance the characterization of yet unidentified neuroprotective Epo receptors, we studied the neuroprotective potency of the human non-erythropoietic Epo splice variant EV-3 in primary cultured locust brain neurons. We demonstrate that EV-3, like Epo, protects locust neurons from hypoxia-induced apoptotic death through activation of the Janus kinase/signal transducer and activator of transcription transduction pathway. Using the fluorescent dye FM1-43 to quantify endocytotic activity we show that both Epo and EV-3 increase the number of fluorescently labelled endocytotic vesicles. This reveals that binding of Epo to its neuroprotective receptor induces endocytosis, as it has been described for the mammalian homodimeric Epo-receptor expressed by erythroid progenitors. Reduction in Epo-stimulated endocytotic activity following pre-exposure to EV-3 indicated that both Epo and its splice variant bind to the same receptor on locust neurons. The shared neuroprotective potency of Epo and EV-3 in insect and mammalian neurons, in the absence of erythropoietic effects of EV-3 in mammals, suggests a greater similarity of the unidentified nervous Epo receptors (or receptor complexes) across phyla than between mammalian haematopoietic and neuroprotective receptors. Insects may serve as suitable models to evaluate the specific protective mechanisms mediated by Epo and its variants in non-erythropoietic mammalian tissues.
[Mh] Termos MeSH primário: Encéfalo/metabolismo
Endocitose/fisiologia
Neuroproteção/fisiologia
Receptores da Eritropoetina/metabolismo
[Mh] Termos MeSH secundário: Animais
Encéfalo/efeitos dos fármacos
Células CHO
Células Cultivadas
Cricetinae
Cricetulus
Endocitose/efeitos dos fármacos
Eritropoetina/metabolismo
Eritropoetina/farmacologia
Feminino
Seres Humanos
Insetos
Locusta migratoria
Masculino
Neuroproteção/efeitos dos fármacos
Receptores da Eritropoetina/agonistas
Proteínas Recombinantes/metabolismo
Proteínas Recombinantes/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (EPO protein, human); 0 (Receptors, Erythropoietin); 0 (Recombinant Proteins); 11096-26-7 (Erythropoietin)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170201
[St] Status:MEDLINE
[do] DOI:10.1111/jnc.13967



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