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Pesquisa : D12.776.260.643 [Categoria DeCS]
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  1 / 2353 MEDLINE  
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[PMID]:28844671
[Au] Autor:Choi YJ; Song I; Jin Y; Jin HS; Ji HM; Jeong SY; Won YY; Chung YS
[Ad] Endereço:Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, South Korea.
[Ti] Título:Transcriptional profiling of human femoral mesenchymal stem cells in osteoporosis and its association with adipogenesis.
[So] Source:Gene;632:7-15, 2017 Oct 20.
[Is] ISSN:1879-0038
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Genetic alterations are major contributing factors in the development of osteoporosis. Osteoblasts and adipocytes share a common origin, mesenchymal stem cells (MSCs), and their genetic determinants might be important in the relationship between osteoporosis and obesity. In the present study, we aimed to isolate differentially expressed genes (DEGs) in osteoporosis and normal controls using human MSCs, and elucidate the common pathways and genes related to osteoporosis and adipogenesis. Human MSCs were obtained from the bone marrow of femurs from postmenopausal women during orthopedic surgeries. RNA sequencing (RNA-seq) was carried out using next-generation sequencing (NGS) technology. DEGs were identified using RNA-seq data. Ingenuity pathway analysis (IPA) was used to elucidate the common pathway related to osteoporosis and adipogenesis. Candidate genes for the common pathway were validated with other independent osteoporosis and obese subjects using RT-PCR (reverse transcription-polymerase chain reaction) analysis. Fifty-three DEGs were identified between postmenopausal osteoporosis patients and normal bone mineral density (BMD) controls. Most of the genetic changes were related to the differentiation of cells. The nuclear receptor subfamily 4 group A (NR4A) family was identified as possible common genes related to osteogenesis and adipogenesis. The expression level of the mRNA of NR4A1 was significantly higher in osteoporosis patients than in controls (p=0.018). The expression level of the mRNA of NR4A2 was significantly higher in obese patients than in controls (p=0.041). Some genetic changes in MSCs are involved in the pathophysiology of osteoporosis. The NR4A family might comprise common genes related to osteoporosis and obesity.
[Mh] Termos MeSH primário: Adipogenia
Células Mesenquimais Estromais/metabolismo
Osteoporose Pós-Menopausa/genética
Transcriptoma
[Mh] Termos MeSH secundário: Idoso
Animais
Estudos de Casos e Controles
Células Cultivadas
Feminino
Fêmur/citologia
Seres Humanos
Células Mesenquimais Estromais/citologia
Camundongos
Meia-Idade
Receptores Nucleares Órfãos/genética
Receptores Nucleares Órfãos/metabolismo
Osteoblastos/citologia
Osteoblastos/metabolismo
Osteogênese
Osteoporose Pós-Menopausa/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Orphan Nuclear Receptors)
[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:170829
[St] Status:MEDLINE


  2 / 2353 MEDLINE  
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[PMID]:28808448
[Au] Autor:Malhotra SS; Gupta SK
[Ad] Endereço:Reproductive Cell Biology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, -110 067 India.
[Ti] Título:Relevance of the NR4A sub-family of nuclear orphan receptors in trophoblastic BeWo cell differentiation.
[So] Source:Cell Mol Biol Lett;22:15, 2017.
[Is] ISSN:1689-1392
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Nur-77, a member of the NR4A sub-family of nuclear orphan receptors, is downregulated in the placentae of pre-eclamptic women. Here, we investigate the relevance of Nor-1, Nurr-1 and Nur-77 in trophoblastic cell differentiation. Their transcript levels were found to be significantly upregulated in BeWo cells treated with forskolin. The maximum increase was observed after 2 h, with a second peak in the expression levels after 48 h. The expression of NR4A sub-family members was also found to be upregulated in BeWo cells after treatment with hCG and GnRH. A similar significant increase was observed at the respective protein levels after 2 and 48 h of treatment with forskolin, hCG or GnRH. Silencing Nor-1, Nurr-1 or Nur-77 individually did not show any effect on forskolin-, hCG- and/or GnRH-mediated BeWo cell fusion and/or hCG secretion. After silencing any one member of the NR4A sub-family, an increase in the transcript levels of the other sub-family members was observed, indicating a compensatory effect due to their functional redundancy. Simultaneously silencing all three NR4A sub-family members significantly downregulated forskolin- and hCG-mediated BeWo cell fusion and/or hCG secretion. However, a considerable amount of cell death occurred after forskolin or hCG treatment as compared to the control siRNA-transfected cells. These results suggest that the NR4A sub-family of nuclear orphan receptors has a role in trophoblastic cell differentiation.
[Mh] Termos MeSH primário: Diferenciação Celular
Receptores Nucleares Órfãos/fisiologia
Trofoblastos/metabolismo
[Mh] Termos MeSH secundário: Gonadotropina Coriônica Humana Subunidade beta/farmacologia
Colforsina/farmacologia
Regulação da Expressão Gênica no Desenvolvimento
Hormônio Liberador de Gonadotropina/farmacologia
Seres Humanos
Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética
Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/fisiologia
Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética
Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/fisiologia
Membro 3 do Grupo A da Subfamília 4 de Receptores Nucleares/genética
Membro 3 do Grupo A da Subfamília 4 de Receptores Nucleares/fisiologia
Receptores Nucleares Órfãos/genética
Trofoblastos/efeitos dos fármacos
Trofoblastos/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Chorionic Gonadotropin, beta Subunit, Human); 0 (Nuclear Receptor Subfamily 4, Group A, Member 1); 0 (Nuclear Receptor Subfamily 4, Group A, Member 2); 0 (Nuclear Receptor Subfamily 4, Group A, Member 3); 0 (Orphan Nuclear Receptors); 1F7A44V6OU (Colforsin); 33515-09-2 (Gonadotropin-Releasing Hormone)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170816
[St] Status:MEDLINE
[do] DOI:10.1186/s11658-017-0046-0


  3 / 2353 MEDLINE  
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[PMID]:28300834
[Au] Autor:Fulton J; Mazumder B; Whitchurch JB; Monteiro CJ; Collins HM; Chan CM; Clemente MP; Hernandez-Quiles M; Stewart EA; Amoaku WM; Moran PM; Mongan NP; Persson JL; Ali S; Heery DM
[Ad] Endereço:School of Pharmacy, University of Nottingham, Nottingham, UK.
[Ti] Título:Heterodimers of photoreceptor-specific nuclear receptor (PNR/NR2E3) and peroxisome proliferator-activated receptor-γ (PPARγ) are disrupted by retinal disease-associated mutations.
[So] Source:Cell Death Dis;8(3):e2677, 2017 Mar 16.
[Is] ISSN:2041-4889
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Photoreceptor-specific nuclear receptor (PNR/NR2E3) and Tailless homolog (TLX/NR2E1) are human orthologs of the NR2E group, a subgroup of phylogenetically related members of the nuclear receptor (NR) superfamily of transcription factors. We assessed the ability of these NRs to form heterodimers with other members of the human NRs representing all major subgroups. The TLX ligand-binding domain (LBD) did not appear to form homodimers or interact directly with any other NR tested. The PNR LBD was able to form homodimers, but also exhibited robust interactions with the LBDs of peroxisome proliferator-activated receptor-γ (PPARγ)/NR1C3 and thyroid hormone receptor b (TRb) TRß/NR1A2. The binding of PNR to PPARγ was specific for this paralog, as no interaction was observed with the LBDs of PPARα/NR1C1 or PPARδ/NR1C2. In support of these findings, PPARγ and PNR were found to be co-expressed in human retinal tissue extracts and could be co-immunoprecipitated as a native complex. Selected sequence variants in the PNR LBD associated with human retinopathies, or a mutation in the dimerization region of PPARγ LBD associated with familial partial lipodystrophy type 3, were found to disrupt PNR/PPARγ complex formation. Wild-type PNR, but not a PNR309G mutant, was able to repress PPARγ-mediated transcription in reporter assays. In summary, our results reveal novel heterodimer interactions in the NR superfamily, suggesting previously unknown functional interactions of PNR with PPARγ and TRß that have potential importance in retinal development and disease.
[Mh] Termos MeSH primário: Mutação/genética
Receptores Nucleares Órfãos/genética
PPAR gama/genética
Retina/patologia
Doenças Retinianas/genética
Doenças Retinianas/patologia
[Mh] Termos MeSH secundário: Linhagem Celular
Linhagem Celular Tumoral
Dimerização
Células HEK293
Seres Humanos
Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética
Conformação Proteica
Receptores beta dos Hormônios Tireóideos/genética
Fatores de Transcrição/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NR2E3 protein, human); 0 (Nuclear Receptor Subfamily 1, Group D, Member 1); 0 (Orphan Nuclear Receptors); 0 (PPAR gamma); 0 (Thyroid Hormone Receptors beta); 0 (Transcription Factors)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170317
[St] Status:MEDLINE
[do] DOI:10.1038/cddis.2017.98


  4 / 2353 MEDLINE  
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[PMID]:28242276
[Au] Autor:Nefzi A; Marconi GD; Ortiz MA; Davis JC; Piedrafita FJ
[Ad] Endereço:Torrey Pines Institute for Molecular Studies, Port Saint Lucie, FL, United States. Electronic address: adeln@tpims.org.
[Ti] Título:Synthesis of dihydroimidazole tethered imidazolinethiones and their activity as novel antagonists of the nuclear retinoic acid receptor-related orphan receptors (RORs).
[So] Source:Bioorg Med Chem Lett;27(7):1608-1610, 2017 04 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Targeting the transcriptional activity of nuclear hormone receptors has proven an effective strategy to treat certain human diseases, and they have become a major focus point to develop novel therapies for the treatment of cancer, inflammation, autoimmune diseases, metabolic disorders, and others. One family of nuclear receptors that has attracted most interest in recent years is the retinoic acid receptor-related orphan receptors (RORs), in particular RORγ. RORγ is a critical regulator of the immune system and RORγ antagonists have shown activity in animal models of inflammatory autoimmune diseases. Here we present the synthesis and biological evaluation of dihydroimidazole tethered imidazolinethiones. We have identified several dual RORγ/α and pan-ROR antagonists with significant activity in cellular assays that could serve as starting points for future optimization efforts to generate potent and selective RORγ modulators.
[Mh] Termos MeSH primário: Imidazolinas/farmacologia
Receptores Nucleares Órfãos/antagonistas & inibidores
Tionas/farmacologia
[Mh] Termos MeSH secundário: Animais
Células CHO
Cricetulus
Imidazolinas/síntese química
Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores
Membro 2 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores
Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores
Tionas/síntese química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Imidazolines); 0 (Nuclear Receptor Subfamily 1, Group F, Member 1); 0 (Nuclear Receptor Subfamily 1, Group F, Member 2); 0 (Nuclear Receptor Subfamily 1, Group F, Member 3); 0 (Orphan Nuclear Receptors); 0 (Thiones)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171124
[Lr] Data última revisão:
171124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170301
[St] Status:MEDLINE


  5 / 2353 MEDLINE  
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[PMID]:28148939
[Au] Autor:Kingwell K
[Ti] Título:Receptor pharmacology: Picking the pocketome for orphan receptor ligands.
[So] Source:Nat Rev Drug Discov;16(2):86, 2017 Feb 02.
[Is] ISSN:1474-1784
[Cp] País de publicação:England
[La] Idioma:eng
[Mh] Termos MeSH primário: Receptores Nucleares Órfãos/metabolismo
[Mh] Termos MeSH secundário: Seres Humanos
Ligantes
Ligação Proteica/efeitos dos fármacos
Receptores Acoplados a Proteínas-G/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ligands); 0 (Orphan Nuclear Receptors); 0 (Receptors, G-Protein-Coupled)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170203
[St] Status:MEDLINE
[do] DOI:10.1038/nrd.2017.6


  6 / 2353 MEDLINE  
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[PMID]:28096232
[Au] Autor:Liu H; Wan C; Ding Y; Han R; He Y; Xiao J; Hao J
[Ad] Endereço:Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China.
[Ti] Título:PR-957, a selective inhibitor of immunoproteasome subunit low-MW polypeptide 7, attenuates experimental autoimmune neuritis by suppressing T 17-cell differentiation and regulating cytokine production.
[So] Source:FASEB J;31(4):1756-1766, 2017 Apr.
[Is] ISSN:1530-6860
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Experimental autoimmune neuritis (EAN) is a CD4 T-cell-mediated autoimmune inflammatory demyelinating disease of the peripheral nervous system. It has been replicated in an animal model of human inflammatory demyelinating polyradiculoneuropathy, Guillain-Barré syndrome. In this study, we evaluated the therapeutic efficacy of a selective inhibitor of the immunoproteasome subunit, low-MW polypeptide 7 (PR-957) in rats with EAN. Our results showed that PR-957 significantly delayed onset day, reduced severity and shortened duration of EAN, and alleviated demyelination and inflammatory infiltration in sciatic nerves. In addition to significantly regulating expression of the cytokine profile, PR-957 treatment down-regulated the proportion of proinflammatory T-helper (T )17 cells in sciatic nerves and spleens of rats with EAN. Data presented show the role of PR-957 in the signal transducer and activator of transcription 3 (STAT3) pathway. PR-957 not only decreased expression of IL-6 and IL-23 but also led to down-regulation of STAT3 phosphorylation in CD4 T cells. Regulation of the STAT3 pathway led to a reduction in retinoid-related orphan nuclear receptor γ t and IL-17 production. Furthermore, reduction of STAT3 phosphorylation may have directly suppressed T 17-cell differentiation. Therefore, our study demonstrates that PR-957 could potently alleviate inflammation in rats with EAN and that it may be a likely candidate for treating Guillain-Barré syndrome.-Liu, H., Wan, C., Ding, Y., Han, R., He, Y., Xiao, J., Hao, J. PR-957, a selective inhibitor of immunoproteasome subunit low-MW polypeptide 7, attenuates experimental autoimmune neuritis by suppressing T 17-cell differentiation and regulating cytokine production.
[Mh] Termos MeSH primário: Diferenciação Celular
Interleucinas/metabolismo
Neurite Autoimune Experimental/tratamento farmacológico
Oligopeptídeos/uso terapêutico
Inibidores de Proteassoma/uso terapêutico
Células Th17/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Interleucinas/genética
Masculino
Oligopeptídeos/farmacologia
Receptores Nucleares Órfãos/genética
Receptores Nucleares Órfãos/metabolismo
Complexo de Endopeptidases do Proteassoma/metabolismo
Inibidores de Proteassoma/farmacologia
Ratos
Ratos Endogâmicos Lew
Fator de Transcrição STAT3/metabolismo
Células Th17/citologia
Células Th17/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Interleukins); 0 (Oligopeptides); 0 (Orphan Nuclear Receptors); 0 (PR-957); 0 (Proteasome Inhibitors); 0 (STAT3 Transcription Factor); 0 (Stat3 protein, rat); EC 3.4.25.1 (LMP7 protein); EC 3.4.25.1 (Proteasome Endopeptidase Complex)
[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:170119
[St] Status:MEDLINE
[do] DOI:10.1096/fj.201601147R


  7 / 2353 MEDLINE  
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[PMID]:28082403
[Au] Autor:Irshad S; Flores-Borja F; Lawler K; Monypenny J; Evans R; Male V; Gordon P; Cheung A; Gazinska P; Noor F; Wong F; Grigoriadis A; Fruhwirth GO; Barber PR; Woodman N; Patel D; Rodriguez-Justo M; Owen J; Martin SG; Pinder SE; Gillett CE; Poland SP; Ameer-Beg S; McCaughan F; Carlin LM; Hasan U; Withers DR; Lane P; Vojnovic B; Quezada SA; Ellis P; Tutt AN; Ng T
[Ad] Endereço:Breast Cancer Now (BCN) Research Unit, King's College London, London, United Kingdom.
[Ti] Título:RORγt Innate Lymphoid Cells Promote Lymph Node Metastasis of Breast Cancers.
[So] Source:Cancer Res;77(5):1083-1096, 2017 Mar 01.
[Is] ISSN:1538-7445
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cancer cells tend to metastasize first to tumor-draining lymph nodes, but the mechanisms mediating cancer cell invasion into the lymphatic vasculature remain little understood. Here, we show that in the human breast tumor microenvironment (TME), the presence of increased numbers of RORγt group 3 innate lymphoid cells (ILC3) correlates with an increased likelihood of lymph node metastasis. In a preclinical mouse model of breast cancer, CCL21-mediated recruitment of ILC3 to tumors stimulated the production of the CXCL13 by TME stromal cells, which in turn promoted ILC3-stromal interactions and production of the cancer cell motile factor RANKL. Depleting ILC3 or neutralizing CCL21, CXCL13, or RANKL was sufficient to decrease lymph node metastasis. Our findings establish a role for RORγt ILC3 in promoting lymphatic metastasis by modulating the local chemokine milieu of cancer cells in the TME. .
[Mh] Termos MeSH primário: Neoplasias da Mama/imunologia
Neoplasias da Mama/patologia
Linfócitos/imunologia
Linfócitos/patologia
Receptores Nucleares Órfãos/imunologia
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Quimiocina CCL21/imunologia
Quimiocina CXCL13/imunologia
Feminino
Seres Humanos
Imunidade Inata
Metástase Linfática
Neoplasias Mamárias Experimentais/imunologia
Neoplasias Mamárias Experimentais/patologia
Camundongos
Camundongos Endogâmicos BALB C
Camundongos Transgênicos
Metástase Neoplásica
Neoplasias de Mama Triplo Negativas/imunologia
Neoplasias de Mama Triplo Negativas/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Chemokine CCL21); 0 (Chemokine CXCL13); 0 (Orphan Nuclear Receptors)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170114
[St] Status:MEDLINE
[do] DOI:10.1158/0008-5472.CAN-16-0598


  8 / 2353 MEDLINE  
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[PMID]:27992436
[Au] Autor:Corley SM; Tsai SY; Wilkins MR; Shannon Weickert C
[Ad] Endereço:Systems Biology Initiative, School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia.
[Ti] Título:Transcriptomic Analysis Shows Decreased Cortical Expression of NR4A1, NR4A2 and RXRB in Schizophrenia and Provides Evidence for Nuclear Receptor Dysregulation.
[So] Source:PLoS One;11(12):e0166944, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Many genes are differentially expressed in the cortex of people with schizophrenia, implicating factors that control transcription more generally. Hormone nuclear receptors dimerize to coordinate context-dependent changes in gene expression. We hypothesized that members of two families of nuclear receptors (NR4As), and retinoid receptors (RARs and RXRs), are altered in the dorsal lateral prefrontal cortex (DLPFC) of people with schizophrenia. We used next generation sequencing and then qPCR analysis to test for changes in mRNA levels for transcripts encoding nuclear receptors: orphan nuclear receptors (3 in the NR4A, 3 in the RAR, 3 in the RXR families and KLF4) in total RNA extracted from the DLPFC from people with schizophrenia compared to controls (n = 74). We also correlated mRNA levels with demographic factors and with estimates of antipsychotic drug exposure (schizophrenia group only). We tested for correlations between levels of transcription factor family members and levels of genes putatively regulated by these transcription factors. We found significantly down regulated expression of NR4A1 (Nurr 77) and KLF4 mRNAs in people with schizophrenia compared to controls, by both NGS and qPCR (p = or <0.01). We also detected decreases in NR4A2 (Nurr1) and RXRB mRNAs by using qPCR in the larger cohort (p<0.05 and p<0.01, respectively). We detected decreased expression of RARG and NR4A2 mRNAs in females with schizophrenia (p<0.05). The mRNA levels of NR4A1, NR4A2 and NR4A3 were all negative correlated with lifetime estimates of antipsychotic exposure. These novel findings, which may be influenced by antipsychotic drug exposure, implicate the orphan and retinoid nuclear receptors in the cortical pathology found in schizophrenia. Genes down stream of these receptors can be dysregulated as well, but the direction of change is not immediately predictable based on the putative transcription factor changes.
[Mh] Termos MeSH primário: Regulação para Baixo
Perfilação da Expressão Gênica/métodos
Receptores Nucleares Órfãos/genética
Receptor X Retinoide beta/genética
Esquizofrenia/genética
[Mh] Termos MeSH secundário: Adulto
Idoso
Autopsia
Contraindicações
Proteínas de Ligação a DNA/genética
Feminino
Predisposição Genética para Doença
Sequenciamento de Nucleotídeos em Larga Escala/métodos
Seres Humanos
Masculino
Meia-Idade
Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética
Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética
Córtex Pré-Frontal/metabolismo
Receptores do Ácido Retinoico/genética
Receptores de Esteroides/genética
Receptores dos Hormônios Tireóideos/genética
Análise de Sequência de RNA/métodos
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA-Binding Proteins); 0 (NR4A1 protein, human); 0 (NR4A2 protein, human); 0 (NR4A3 protein, human); 0 (Nuclear Receptor Subfamily 4, Group A, Member 1); 0 (Nuclear Receptor Subfamily 4, Group A, Member 2); 0 (Orphan Nuclear Receptors); 0 (Receptors, Retinoic Acid); 0 (Receptors, Steroid); 0 (Receptors, Thyroid Hormone); 0 (Retinoid X Receptor beta); 0 (retinoic acid receptor gamma)
[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:161220
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0166944


  9 / 2353 MEDLINE  
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[PMID]:27893103
[Au] Autor:Nakamura PA; Tang S; Shimchuk AA; Ding S; Reh TA
[Ad] Endereço:Department of Biological Structure, University of Washington, School of Medicine, Seattle, Washington, United States.
[Ti] Título:Potential of Small Molecule-Mediated Reprogramming of Rod Photoreceptors to Treat Retinitis Pigmentosa.
[So] Source:Invest Ophthalmol Vis Sci;57(14):6407-6415, 2016 Nov 01.
[Is] ISSN:1552-5783
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Purpose: Mutations in rod photoreceptor genes can cause retinitis pigmentosa (RP). Rod gene expression is regulated by the nuclear hormone receptor, Nr2e3. Genetic deletion of Nr2e3 reprograms rods into cells that resemble cone photoreceptors, and might therefore prevent their death from some forms of RP. There are no identified ligands for Nr2e3; however, reverse agonists might mimic the genetic rescue effect and may be therapeutically useful for the treatment of RP. Methods: We screened for small molecule modulators of Nr2e3 using primary retinal cell cultures and characterized the most potent, which we have named photoregulin1 (PR1), in vitro and in vivo. We also tested the ability of PR1 to slow the progression of photoreceptor degeneration in two common mouse models of autosomal dominant RP, the RhoP23H and the Pde6brd1 mutations. Results: In developing retina, PR1 causes a decrease in rod gene expression and an increase in S opsin+ cones. Photoregulin1 continues to inhibit rod gene expression in adult mice. When applied to two mouse models of RP, PR1 slows the degeneration of photoreceptors. Conclusions: Chemical compounds identified as modulators of Nr2e3 activity may be useful for the treatment of RP through their effects on expression of disease-causing mutant genes.
[Mh] Termos MeSH primário: DNA/genética
Regulação da Expressão Gênica no Desenvolvimento
Receptores Nucleares Órfãos/genética
Retina/metabolismo
Células Fotorreceptoras Retinianas Cones/metabolismo
Células Fotorreceptoras Retinianas Bastonetes/metabolismo
Retinite Pigmentosa/genética
[Mh] Termos MeSH secundário: Animais
Animais Recém-Nascidos
Western Blotting
Células Cultivadas
Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/genética
Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/metabolismo
Análise Mutacional de DNA
Modelos Animais de Doenças
Marcação In Situ das Extremidades Cortadas
Camundongos
Camundongos Endogâmicos C57BL
Mutação
Receptores Nucleares Órfãos/biossíntese
Reação em Cadeia da Polimerase em Tempo Real
Retina/patologia
Células Fotorreceptoras Retinianas Cones/patologia
Células Fotorreceptoras Retinianas Bastonetes/patologia
Retinite Pigmentosa/diagnóstico
Retinite Pigmentosa/metabolismo
Técnicas de Cultura de Tecidos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nr2e3 protein, mouse); 0 (Orphan Nuclear Receptors); 9007-49-2 (DNA); EC 3.1.4.35 (Cyclic Nucleotide Phosphodiesterases, Type 6); EC 3.1.4.35 (Pde6b protein, mouse)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170623
[Lr] Data última revisão:
170623
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161129
[St] Status:MEDLINE
[do] DOI:10.1167/iovs.16-20177


  10 / 2353 MEDLINE  
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Fotocópia
Alonso, Vivian
[PMID]:27782803
[Au] Autor:Corso-Díaz X; de Leeuw CN; Alonso V; Melchers D; Wong BK; Houtman R; Simpson EM
[Ad] Endereço:Centre for Molecular Medicine and Therapeutics at the Child and Family Research Institute, University of British Columbia, Vancouver, BC, V5Z 4H4, Canada.
[Ti] Título:Co-activator candidate interactions for orphan nuclear receptor NR2E1.
[So] Source:BMC Genomics;17(1):832, 2016 10 26.
[Is] ISSN:1471-2164
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: NR2E1 (Tlx) is an orphan nuclear receptor that regulates the maintenance and self-renewal of neural stem cells, and promotes tumourigenesis. Nr2e1-null mice exhibit reduced cortical and limbic structures and pronounced retinal dystrophy. NR2E1 functions mainly as a repressor of gene transcription in association with the co-repressors atrophin-1, LSD1, HDAC and BCL11A. Recent evidence suggests that NR2E1 also acts as an activator of gene transcription. However, co-activator complexes that interact with NR2E1 have not yet been identified. In order to find potential novel co-regulators for NR2E1, we used a microarray assay for real-time analysis of co-regulator-nuclear receptor interaction (MARCoNI) that contains peptides representing interaction motifs from potential co-regulatory proteins, including known co-activator nuclear receptor box sequences (LxxLL motif). RESULTS: We found that NR2E1 binds strongly to an atrophin-1 peptide (Atro box) used as positive control and to 19 other peptides that constitute candidate NR2E1 partners. Two of these proteins, p300 and androgen receptor (AR), were further validated by reciprocal pull-down assays. The specificity of NR2E1 binding to peptides in the array was evaluated using two single amino acid variants, R274G and R276Q, which disrupted the majority of the binding interactions observed with wild-type NR2E1. The decreased binding affinity of these variants to co-regulators was further validated by pull-down assays using atrophin1 as bait. Despite the high conservation of arginine 274 in vertebrates, its reduced interactions with co-regulators were not significant in vivo as determined by retinal phenotype analysis in single-copy Nr2e1-null mice carrying the variant R274G. CONCLUSIONS: We showed that MARCoNI is a specific assay to test interactions of NR2E1 with candidate co-regulators. In this way, we unveiled 19 potential co-regulator partners for NR2E1, including eight co-activators. All the candidates here identified need to be further validated using in vitro and in vivo models. This assay was sensitive to point mutations in NR2E1 ligand binding domain making it useful to identify mutations and/or small molecules that alter binding of NR2E1 to protein partners.
[Mh] Termos MeSH primário: Ligantes
Receptores Nucleares Órfãos/agonistas
Receptores Citoplasmáticos e Nucleares/agonistas
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Proteínas de Transporte
Descoberta de Drogas
Variação Genética
Seres Humanos
Camundongos
Camundongos Knockout
Receptores Nucleares Órfãos/química
Receptores Nucleares Órfãos/metabolismo
Fenótipo
Ligação Proteica
Domínios e Motivos de Interação entre Proteínas
Mapeamento de Interação de Proteínas
Receptores Citoplasmáticos e Nucleares/química
Receptores Citoplasmáticos e Nucleares/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (Ligands); 0 (Nr2e1 protein, mouse); 0 (Orphan Nuclear Receptors); 0 (Receptors, Cytoplasmic and Nuclear)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171119
[Lr] Data última revisão:
171119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161027
[St] Status:MEDLINE



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