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Pesquisa : D12.776.826.701.500.500 [Categoria DeCS]
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[PMID]:28740126
[Au] Autor:Korpal M; Puyang X; Jeremy Wu Z; Seiler R; Furman C; Oo HZ; Seiler M; Irwin S; Subramanian V; Julie Joshi J; Wang CK; Rimkunas V; Tortora D; Yang H; Kumar N; Kuznetsov G; Matijevic M; Chow J; Kumar P; Zou J; Feala J; Corson L; Henry R; Selvaraj A; Davis A; Bloudoff K; Douglas J; Kiss B; Roberts M; Fazli L; Black PC; Fekkes P; Smith PG; Warmuth M; Yu L; Hao MH; Larsen N; Daugaard M; Zhu P
[Ad] Endereço:H3 Biomedicine Inc., 300 Technology Square, Cambridge, MA, 02139, USA. Manav.korpal@outlook.com.
[Ti] Título:Evasion of immunosurveillance by genomic alterations of PPARγ/RXRα in bladder cancer.
[So] Source:Nat Commun;8(1):103, 2017 07 24.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Muscle-invasive bladder cancer (MIBC) is an aggressive disease with limited therapeutic options. Although immunotherapies are approved for MIBC, the majority of patients fail to respond, suggesting existence of complementary immune evasion mechanisms. Here, we report that the PPARγ/RXRα pathway constitutes a tumor-intrinsic mechanism underlying immune evasion in MIBC. Recurrent mutations in RXRα at serine 427 (S427F/Y), through conformational activation of the PPARγ/RXRα heterodimer, and focal amplification/overexpression of PPARγ converge to modulate PPARγ/RXRα-dependent transcription programs. Immune cell-infiltration is controlled by activated PPARγ/RXRα that inhibits expression/secretion of inflammatory cytokines. Clinical data sets and an in vivo tumor model indicate that PPARγ /RXRα impairs CD8 T-cell infiltration and confers partial resistance to immunotherapies. Knockdown of PPARγ or RXRα and pharmacological inhibition of PPARγ significantly increase cytokine expression suggesting therapeutic approaches to reviving immunosurveillance and sensitivity to immunotherapies. Our study reveals a class of tumor cell-intrinsic "immuno-oncogenes" that modulate the immune microenvironment of cancer.Muscle-invasive bladder cancer (MIBC) is a potentially lethal disease. Here the authors characterize diverse genetic alterations in MIBC that convergently lead to constitutive activation of PPARgamma/RXRalpha and result in immunosurveillance escape by inhibiting CD8+ T-cell recruitment.
[Mh] Termos MeSH primário: Evasão da Resposta Imune/imunologia
Monitorização Imunológica
PPAR gama/imunologia
Receptor X Retinoide alfa/imunologia
Neoplasias da Bexiga Urinária/imunologia
[Mh] Termos MeSH secundário: Animais
Linfócitos T CD8-Positivos/imunologia
Linfócitos T CD8-Positivos/metabolismo
Linhagem Celular Tumoral
Citocinas/genética
Citocinas/imunologia
Citocinas/metabolismo
Perfilação da Expressão Gênica/métodos
Células HCT116
Seres Humanos
Immunoblotting
Imunoterapia/métodos
Mediadores da Inflamação/imunologia
Mediadores da Inflamação/metabolismo
Camundongos
Microscopia de Fluorescência
Mutação/imunologia
Invasividade Neoplásica
PPAR gama/química
PPAR gama/genética
Multimerização Proteica/imunologia
Receptor X Retinoide alfa/química
Receptor X Retinoide alfa/genética
Neoplasias da Bexiga Urinária/genética
Neoplasias da Bexiga Urinária/terapia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cytokines); 0 (Inflammation Mediators); 0 (PPAR gamma); 0 (Retinoid X Receptor alpha)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171128
[Lr] Data última revisão:
171128
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-00147-w


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[PMID]:28617824
[Au] Autor:Sakane Y; Kanamoto N; Yamauchi I; Tagami T; Morita Y; Miura M; Sone M; Yasoda A; Kimura T; Nakao K; Inagaki N
[Ad] Endereço:Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan.
[Ti] Título:Regulation of type 1 iodothyronine deiodinase by LXRα.
[So] Source:PLoS One;12(6):e0179213, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The iodothyronine deiodinases are selenoenzymes that regulate the activity of thyroid hormone via specific inner- or outer-ring deiodination. In humans, type 1 deiodinase (D1) is highly expressed in the liver, but the mechanism by which its gene expression is regulated remains to be elucidated. Liver X receptor α (LXRα), a transcription factor of the nuclear receptor superfamily, is highly expressed in the liver, where it functions as a sensor for excess intracellular oxysterols. LXRα interacts with other nuclear receptors on promoters of genes that contain a binding core sequence for nuclear receptors. In addition, it is reported that the promoter of the gene encoding human D1 (hDIO1) contains the core sequence for one of nuclear receptors, thyroid hormone receptor (TR). We investigated the involvement of LXRα in the regulation of hDIO1, in the liver. We performed hDIO1 promoter-reporter assays using a synthetic LXR agonist, T0901317, and compared promoter activity between a human liver carcinoma cell line, HepG2, and a clone of human embryonic kidney cells, TSA201. We defined the region between nucleotides -131 and -114, especially nucleotides -126 and -125, of the hDIO1 promoter as critical for basal and LXRα-mediated specific transcriptional activation in HepG2 cells. An increase in hDIO1 expression was observed in LXRα-stimulated cells, but absent in cycloheximide-treated cells, indicating that new protein synthesis is required for LXRα-mediated regulation of hDIO1. On the other hand, electrophoretic mobility shift assays revealed that LXRα and RXRα bound to the hDIO1 promoter. We also demonstrated that LXRα and TRß compete with each other on this specific region of the promoter. In conclusion, our results indicated that LXRα plays a specific and important role in activation of TH by regulating D1, and that LXRα binds to and regulates the hDIO1 promoter, competing with TRß on specific sequences within the promoter.
[Mh] Termos MeSH primário: Regulação Enzimológica da Expressão Gênica/fisiologia
Iodeto Peroxidase/biossíntese
Receptores X do Fígado/metabolismo
Fígado/metabolismo
Elementos de Resposta/fisiologia
Ativação Transcricional/fisiologia
[Mh] Termos MeSH secundário: Cicloeximida/farmacologia
Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos
Células HEK293
Células Hep G2
Seres Humanos
Hidrocarbonetos Fluorados/farmacologia
Iodeto Peroxidase/genética
Receptores X do Fígado/genética
Receptores dos Hormônios Tireóideos/genética
Receptores dos Hormônios Tireóideos/metabolismo
Receptor X Retinoide alfa/genética
Receptor X Retinoide alfa/metabolismo
Sulfonamidas/farmacologia
Ativação Transcricional/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Hydrocarbons, Fluorinated); 0 (Liver X Receptors); 0 (NR1H3 protein, human); 0 (Receptors, Thyroid Hormone); 0 (Retinoid X Receptor alpha); 0 (Sulfonamides); 0 (TO-901317); 98600C0908 (Cycloheximide); EC 1.11.1.- (iodothyronine deiodinase type I); EC 1.11.1.8 (Iodide Peroxidase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170913
[Lr] Data última revisão:
170913
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170616
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0179213


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[PMID]:28346830
[Au] Autor:Fu Y; Zhen J; Lu Z
[Ad] Endereço:1 Department of Neurology, Renmin Hospital of Wuhan University, Wuhan University , Wuhan, China .
[Ti] Título:Synergetic Neuroprotective Effect of Docosahexaenoic Acid and Aspirin in SH-Y5Y by Inhibiting miR-21 and Activating RXRα and PPARα.
[So] Source:DNA Cell Biol;36(6):482-489, 2017 Jun.
[Is] ISSN:1557-7430
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Parkinson's disease (PD) is a serious neurodegenerative disorder that lacks effective therapeutic methods. In this research, expressions of PPARα, RXRα, and miR-21 were evaluated in PD patients and normal controls. To investigate the effects of miR-21, docosahexaenoic acid (DHA) and aspirin (ASA) on PD, as well as the relationships between them, SH-Y5Y cells were treated with DHA, ASA, or both for 24 h. The assay showed that levels of miR-21 were increased and levels of PPARα were decreased in PD patients compared with normal controls. miR-21 was negatively correlated with PPARα in PD patients. DHA and ASA could activate RXRα and PPARα, respectively. Additionally, DHA upregulated PPARα expression by inhibiting miR-21 in SH-Y5Y cells. A combination of DHA and ASA efficiently enhanced heterodimer formations of PPARα and RXRα and increased the expression of neurotrophic factors PSD-95, brain-derived neurotrophic factor (BDNF), and glial cell-derived neurotrophic factor (GDNF), while inhibiting NFκB and COX2. These findings suggest that a combination of DHA and ASA could significantly improve the expression of PSD-95, BDNF, and GDNF by promoting heterodimerization of PPARα and RXRα, thus supplying a new therapeutic method for PD.
[Mh] Termos MeSH primário: Aspirina/farmacologia
Ácidos Docosa-Hexaenoicos/farmacologia
MicroRNAs/antagonistas & inibidores
Fármacos Neuroprotetores/farmacologia
PPAR alfa/metabolismo
Receptor X Retinoide alfa/metabolismo
[Mh] Termos MeSH secundário: Sequência de Bases
Linhagem Celular Tumoral
Sinergismo Farmacológico
Seres Humanos
PPAR alfa/agonistas
PPAR alfa/genética
Receptor X Retinoide alfa/agonistas
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (MIRN21 microRNA, human); 0 (MicroRNAs); 0 (Neuroprotective Agents); 0 (PPAR alpha); 0 (Retinoid X Receptor alpha); 25167-62-8 (Docosahexaenoic Acids); R16CO5Y76E (Aspirin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170908
[Lr] Data última revisão:
170908
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170328
[St] Status:MEDLINE
[do] DOI:10.1089/dna.2017.3643


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[PMID]:28267642
[Au] Autor:Cheng B; Al-Shammari FH; Ghader IA; Sequeira F; Thakkar J; Mathew TC
[Ad] Endereço:Department of Biochemistry, Faculty of Medicine, Kuwait University Health Science Center, P. O. Box 24923, Safat 13110, Kuwait. Electronic address: behling@hsc.edu.kw.
[Ti] Título:Fundamental studies of adrenal retinoid-X-receptor: Protein isoform, tissue expression, subcellular distribution, and ligand availability.
[So] Source:J Steroid Biochem Mol Biol;171:110-120, 2017 Jul.
[Is] ISSN:1879-1220
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Adrenal gland reportedly expresses many nuclear receptors that are known to heterodimerize with retinoid-X-receptor (RXR) for functions, but the information regarding the glandular RXR is not adequate. Studies of rat adrenal homogenate by Western blotting revealed three RXR proteins: RXRα (55kDa), RXRß (47kDa) and RXR (56kDa). RXRγ was not detectable. After fractionation, RXRα was almost exclusively localized in the nuclear fraction. In comparison, substantial portions of RXRß and RXR were found in both nuclear and post-nuclear particle fractions, suggesting genomic and non-genomic functions. Cells immunostained for RXRα were primarily localized in zona fasciculata (ZF) and medulla, although some stained cells were found in zona glomerulosa (ZG) and zona reticularis (ZR). In contrast, cells immunostained for RXRß were concentrated principally in ZG, although some stained cells were seen in ZR, ZF, and medulla (in descending order, qualitatively). Analysis of adrenal lipid extracts by LC/MS did not detect 9-cis-retinoic acid (a potent RXR-ligand) but identified all-trans retinoic acid. Since C20 and C22 polyunsaturated fatty acids (PUFAs) can also activate RXR, subcellular availabilities of unesterified fatty acids were investigated by GC/MS. As results, arachidonic acid (C20:4), adrenic acid (C22:4), docosapentaenoic acid (C22:5), and cervonic acid (C22:6) were detected in the lipids extracted from each subcellular fraction. Thus, the RXR-agonizing PUFAs are available in all the main subcellular compartments considerably. The present findings not only shed light on the adrenal network of RXRs but also provide baseline information for further investigations of RXR heterodimers in the regulation of adrenal steroidogenesis.
[Mh] Termos MeSH primário: Glândulas Suprarrenais/metabolismo
Ácidos Graxos Insaturados/metabolismo
Receptor X Retinoide alfa/metabolismo
Receptor X Retinoide beta/metabolismo
Tretinoína/metabolismo
[Mh] Termos MeSH secundário: Córtex Suprarrenal/citologia
Córtex Suprarrenal/metabolismo
Glândulas Suprarrenais/citologia
Medula Suprarrenal/citologia
Medula Suprarrenal/metabolismo
Animais
Biomarcadores/metabolismo
Núcleo Celular/metabolismo
Seres Humanos
Ligantes
Fígado/citologia
Fígado/metabolismo
Masculino
Peso Molecular
Especificidade de Órgãos
Domínios e Motivos de Interação entre Proteínas
Isoformas de Proteínas/agonistas
Isoformas de Proteínas/química
Isoformas de Proteínas/genética
Isoformas de Proteínas/metabolismo
Transporte Proteico
Ratos Wistar
Receptor X Retinoide alfa/agonistas
Receptor X Retinoide alfa/química
Receptor X Retinoide alfa/genética
Receptor X Retinoide beta/agonistas
Receptor X Retinoide beta/química
Receptor X Retinoide beta/genética
Zona Fasciculada/citologia
Zona Fasciculada/metabolismo
Zona Reticular/citologia
Zona Reticular/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Fatty Acids, Unsaturated); 0 (Ligands); 0 (Protein Isoforms); 0 (Retinoid X Receptor alpha); 0 (Retinoid X Receptor beta); 5688UTC01R (Tretinoin)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170718
[Lr] Data última revisão:
170718
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170308
[St] Status:MEDLINE


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[PMID]:28241052
[Au] Autor:Sierra B; Triska P; Soares P; Garcia G; Perez AB; Aguirre E; Oliveira M; Cavadas B; Regnault B; Alvarez M; Ruiz D; Samuels DC; Sakuntabhai A; Pereira L; Guzman MG
[Ad] Endereço:Virology Department, PAHO/WHO Collaborating Center for the Study of Dengue and its Vector, Pedro Kourí Institute of Tropical Medicine (IPK),Havana, Cuba.
[Ti] Título:OSBPL10, RXRA and lipid metabolism confer African-ancestry protection against dengue haemorrhagic fever in admixed Cubans.
[So] Source:PLoS Pathog;13(2):e1006220, 2017 Feb.
[Is] ISSN:1553-7374
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ethnic groups can display differential genetic susceptibility to infectious diseases. The arthropod-born viral dengue disease is one such disease, with empirical and limited genetic evidence showing that African ancestry may be protective against the haemorrhagic phenotype. Global ancestry analysis based on high-throughput genotyping in admixed populations can be used to test this hypothesis, while admixture mapping can map candidate protective genes. A Cuban dengue fever cohort was genotyped using a 2.5 million SNP chip. Global ancestry was ascertained through ADMIXTURE and used in a fine-matched corrected association study, while local ancestry was inferred by the RFMix algorithm. The expression of candidate genes was evaluated by RT-PCR in a Cuban dengue patient cohort and gene set enrichment analysis was performed in a Thai dengue transcriptome. OSBPL10 and RXRA candidate genes were identified, with most significant SNPs placed in inferred weak enhancers, promoters and lncRNAs. OSBPL10 had significantly lower expression in Africans than Europeans, while for RXRA several SNPs may differentially regulate its transcription between Africans and Europeans. Their expression was confirmed to change through dengue disease progression in Cuban patients and to vary with disease severity in a Thai transcriptome dataset. These genes interact in the LXR/RXR activation pathway that integrates lipid metabolism and immune functions, being a key player in dengue virus entrance into cells, its replication therein and in cytokine production. Knockdown of OSBPL10 expression in THP-1 cells by two shRNAs followed by DENV2 infection tests led to a significant reduction in DENV replication, being a direct functional proof that the lower OSBPL10 expression profile in Africans protects this ancestry against dengue disease.
[Mh] Termos MeSH primário: Metabolismo dos Lipídeos/genética
Receptores de Esteroides/genética
Receptor X Retinoide alfa/genética
Dengue Grave/genética
[Mh] Termos MeSH secundário: Grupo com Ancestrais do Continente Africano/genética
Cuba/etnologia
Predisposição Genética para Doença
Estudo de Associação Genômica Ampla
Genótipo
Seres Humanos
Análise de Sequência com Séries de Oligonucleotídeos
Reação em Cadeia da Polimerase
Polimorfismo de Nucleotídeo Único
Dengue Grave/etnologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Steroid); 0 (Retinoid X Receptor alpha); 0 (oxysterol binding protein)
[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:170228
[St] Status:MEDLINE
[do] DOI:10.1371/journal.ppat.1006220


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[PMID]:28191262
[Au] Autor:Pauwels S; Ghosh M; Duca RC; Bekaert B; Freson K; Huybrechts I; Langie SAS; Koppen G; Devlieger R; Godderis L
[Ad] Endereço:Department of Public Health and Primary Care, Environment and Health, KU Leuven - University of Leuven, Kapucijnenvoer 35 blok D box 7001, 3000 Leuven, Belgium.
[Ti] Título:Maternal intake of methyl-group donors affects DNA methylation of metabolic genes in infants.
[So] Source:Clin Epigenetics;9:16, 2017.
[Is] ISSN:1868-7083
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Maternal nutrition during pregnancy and infant nutrition in the early postnatal period (lactation) are critically involved in the development and health of the newborn infant. The Maternal Nutrition and Offspring's Epigenome (MANOE) study was set up to assess the effect of maternal methyl-group donor intake (choline, betaine, folate, methionine) on infant DNA methylation. Maternal intake of dietary methyl-group donors was assessed using a food-frequency questionnaire (FFQ). Before and during pregnancy, we evaluated maternal methyl-group donor intake through diet and supplementation (folic acid) in relation to gene-specific ( DMR, , , ) buccal epithelial cell DNA methylation in 6 months old infants ( = 114) via pyrosequencing. In the early postnatal period, we determined the effect of maternal choline intake during lactation (in mothers who breast-fed for at least 3 months) on gene-specific buccal DNA methylation ( = 65). RESULTS: Maternal dietary and supplemental intake of methyl-group donors (folate, betaine, folic acid), only in the periconception period, was associated with buccal cell DNA methylation in genes related to growth ( DMR), metabolism ( ), and appetite control ( ). A negative association was found between maternal folate and folic acid intake before pregnancy and infant (slope = -1.233, 95% CI -2.342; -0.125, = 0.0298) and DMR methylation (slope = -0.706, 95% CI -1.242; -0.107, = 0.0101), respectively. Positive associations were observed for maternal betaine (slope = 0.875, 95% CI 0.118; 1.633, = 0.0241) and folate (slope = 0.685, 95% CI 0.245; 1.125, = 0.0027) intake before pregnancy and methylation. Buccal methylation in the infant was negatively associated with maternal methyl-group donor intake in the first and second trimester of pregnancy and negatively in the third trimester. We found no clear association between maternal choline intake during lactation and buccal infant DNA methylation. CONCLUSIONS: This study suggests that maternal dietary and supplemental intake of methyl-group donors, especially in the periconception period, can influence infant's buccal DNA methylation in genes related to metabolism, growth, appetite regulation, and maintenance of DNA methylation reactions.
[Mh] Termos MeSH primário: Betaína/administração & dosagem
Colina/administração & dosagem
Metilação de DNA/efeitos dos fármacos
Ácido Fólico/administração & dosagem
Fenômenos Fisiológicos da Nutrição Materna
[Mh] Termos MeSH secundário: DNA (Citosina-5-)-Metiltransferase 1
DNA (Citosina-5-)-Metiltransferases/genética
Suplementos Nutricionais
Feminino
Sequenciamento de Nucleotídeos em Larga Escala/métodos
Seres Humanos
Lactente
Fator de Crescimento Insulin-Like II/genética
Leptina/genética
Inquéritos Nutricionais
Gravidez
Receptor X Retinoide alfa/genética
Análise de Sequência de DNA/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (IGF2 protein, human); 0 (Leptin); 0 (Retinoid X Receptor alpha); 3SCV180C9W (Betaine); 67763-97-7 (Insulin-Like Growth Factor II); 935E97BOY8 (Folic Acid); EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferase 1); EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferases); EC 2.1.1.37 (DNMT1 protein, human); N91BDP6H0X (Choline)
[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:170214
[St] Status:MEDLINE
[do] DOI:10.1186/s13148-017-0321-y


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[PMID]:28129653
[Au] Autor:Xu L; Zeng Z; Zhang W; Ren G; Ling X; Huang F; Xie P; Su Y; Zhang XK; Zhou H
[Ad] Endereço:School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, Fujian, China.
[Ti] Título:RXRα ligand Z-10 induces PML-RARα cleavage and APL cell apoptosis through disrupting PML-RARα/RXRα complex in a cAMP-independent manner.
[So] Source:Oncotarget;8(7):12311-12322, 2017 Feb 14.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The major oncogenic driver of acute promyelocytic leukemia (APL) is the fusion protein PML-RARα originated from the chromosomal translocation t(15;17). All-trans retinoic acid (ATRA) and arsenic trioxide cure most patients by directly targeting PML-RARα. However, major issues including the resistance of ATRA and arsenic therapy still remain in APL clinical management. Here we showed that compound Z-10, a nitro-ligand of retinoid X receptor α (RXRα), strongly promoted the cAMP-independent apoptosis of both ATRA- sensitive and resistant NB4 cells via the induction of caspase-mediated PML-RARα degradation. RXRα was vital for the stability of both PML-RARα and RARα likely through the interactions. The binding of Z-10 to RXRα dramatically inhibited the interaction of RXRα with PML-RARα but not with RARα, leading to Z-10's selective induction of PML-RARα but not RARα degradation. Z-36 and Z-38, two derivatives of Z-10, had improved potency of inducing PML-RARα reduction and NB4 cell apoptosis. Hence, RXRα ligand Z-10 and its derivatives could target both ATRA- sensitive and resistant APL cells through their distinct acting mechanism, and are potential drug leads for APL treatment.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Naftalenos/farmacologia
Nitrocompostos/farmacologia
Proteínas de Fusão Oncogênicas/metabolismo
Receptor X Retinoide alfa/metabolismo
Estirenos/farmacologia
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/metabolismo
Antineoplásicos/farmacologia
Arsenicais/farmacologia
Western Blotting
Células COS
Caspases/metabolismo
Linhagem Celular Tumoral
Cercopithecus aethiops
AMP Cíclico/metabolismo
Citometria de Fluxo
Células HEK293
Seres Humanos
Leucemia Promielocítica Aguda/genética
Leucemia Promielocítica Aguda/metabolismo
Leucemia Promielocítica Aguda/patologia
Ligantes
Naftalenos/metabolismo
Nitrocompostos/metabolismo
Óxidos/farmacologia
Ligação Proteica
Proteólise/efeitos dos fármacos
Estirenos/metabolismo
Tretinoína/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Arsenicals); 0 (Ligands); 0 (Naphthalenes); 0 (Nitro Compounds); 0 (Oncogene Proteins, Fusion); 0 (Oxides); 0 (Retinoid X Receptor alpha); 0 (Styrenes); 0 (Z-10 nitro compound); 0 (promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein); 5287E3OUAV (beta-nitrostyrene); 5688UTC01R (Tretinoin); E0399OZS9N (Cyclic AMP); EC 3.4.22.- (Caspases); S7V92P67HO (arsenic trioxide)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170811
[Lr] Data última revisão:
170811
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170128
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.14812


  8 / 590 MEDLINE  
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[PMID]:28111285
[Au] Autor:Saeed A; Hoekstra M; Hoeke MO; Heegsma J; Faber KN
[Ad] Endereço:Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Institute of Molecular biology & Bio-technology, Bahauddin Zakariya University, Multan, Pakistan. Electronic address: a.saeed@umcg.nl.
[Ti] Título:The interrelationship between bile acid and vitamin A homeostasis.
[So] Source:Biochim Biophys Acta;1862(5):496-512, 2017 05.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Vitamin A is a fat-soluble vitamin important for vision, reproduction, embryonic development, cell differentiation, epithelial barrier function and adequate immune responses. Efficient absorption of dietary vitamin A depends on the fat-solubilizing properties of bile acids. Bile acids are synthesized in the liver and maintained in an enterohepatic circulation. The liver is also the main storage site for vitamin A in the mammalian body, where an intimate collaboration between hepatocytes and hepatic stellate cells leads to the accumulation of retinyl esters in large cytoplasmic lipid droplet hepatic stellate cells. Chronic liver diseases are often characterized by disturbed bile acid and vitamin A homeostasis, where bile production is impaired and hepatic stellate cells lose their vitamin A in a transdifferentiation process to myofibroblasts, cells that produce excessive extracellular matrix proteins leading to fibrosis. Chronic liver diseases thus may lead to vitamin A deficiency. Recent data reveal an intricate crosstalk between vitamin A metabolites and bile acids, in part via the Retinoic Acid Receptor (RAR), Retinoid X Receptor (RXR) and the Farnesoid X Receptor (FXR), in maintaining vitamin A and bile acid homeostasis. Here, we provide an overview of the various levels of "communication" between vitamin A metabolites and bile acids and its relevance for the treatment of chronic liver diseases.
[Mh] Termos MeSH primário: Ácidos e Sais Biliares/metabolismo
Hepatopatias/metabolismo
Fígado/metabolismo
Vitamina A/metabolismo
[Mh] Termos MeSH secundário: Ácidos e Sais Biliares/biossíntese
Homeostase
Seres Humanos
Fígado/patologia
Hepatopatias/complicações
Hepatopatias/patologia
Receptores Citoplasmáticos e Nucleares/metabolismo
Receptores do Ácido Retinoico/metabolismo
Receptor X Retinoide alfa/metabolismo
Deficiência de Vitamina A/complicações
Deficiência de Vitamina A/metabolismo
Deficiência de Vitamina A/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (Bile Acids and Salts); 0 (Receptors, Cytoplasmic and Nuclear); 0 (Receptors, Retinoic Acid); 0 (Retinoid X Receptor alpha); 0 (farnesoid X-activated receptor); 11103-57-4 (Vitamin A)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170713
[Lr] Data última revisão:
170713
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170124
[St] Status:MEDLINE


  9 / 590 MEDLINE  
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[PMID]:28089347
[Au] Autor:Xu D; Cai L; Guo S; Xie L; Yin M; Chen Z; Zhou H; Su Y; Zeng Z; Zhang X
[Ad] Endereço:School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361005, China.
[Ti] Título:Virtual screening and experimental validation identify novel modulators of nuclear receptor RXRα from Drugbank database.
[So] Source:Bioorg Med Chem Lett;27(4):1055-1061, 2017 02 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Retinoid X receptor alpha (RXRα), an important ligand-dependent transcription factor, plays a critical role in the development of various cancers and metabolic and neurodegenerative diseases. Therefore, RXRα represents one of the most important targets in modern drug discovery. In this study, Drugbank 2.0 with 1280 old drugs were virtually screened by Glide according to the crystal structure of ligand-binding domain (LBP) of RXRα. 15 compounds selected were tested for their binding and transcriptional activity toward RXRα by Biacore and reporter gene assay, respectively. The identified new scafford ligand of RXRα, Pitavastatin (1), was chemically optimized. Our results demonstrated that statin compounds Pitavastatin (1) and Fluvastatin (4) could bind to the LBP of RXRα (K =13.30µM and 11.04µM, respectively) and serve as transcriptional antagonists of RXRα. On the contrary, compound (12) (domperidone) and (13) (rosiglitazone maleate) could bind to the LBP of RXRα (K =8.80µM and 15.01µM, respectively) but serve as transcriptional agonists of RXRα.
[Mh] Termos MeSH primário: Bases de Dados Factuais
Receptor X Retinoide alfa/antagonistas & inibidores
[Mh] Termos MeSH secundário: Cristalografia por Raios X
Avaliação Pré-Clínica de Medicamentos
Ácidos Graxos Monoinsaturados/química
Ácidos Graxos Monoinsaturados/farmacologia
Indóis/química
Indóis/farmacologia
Ligantes
Quinolinas/química
Quinolinas/farmacologia
Receptor X Retinoide alfa/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; VALIDATION STUDIES; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Fatty Acids, Monounsaturated); 0 (Indoles); 0 (Ligands); 0 (Quinolines); 0 (Retinoid X Receptor alpha); 4L066368AS (fluvastatin); M5681Q5F9P (pitavastatin)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171124
[Lr] Data última revisão:
171124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170117
[St] Status:MEDLINE


  10 / 590 MEDLINE  
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[PMID]:27852823
[Au] Autor:Jusu S; Presley JF; Kremer R
[Ad] Endereço:From the Department of Medicine, Calcium Research Laboratory, Royal Victoria Hospital, McGill University, Montreal, Quebec H4A 3J1.
[Ti] Título:Phosphorylation of Human Retinoid X Receptor α at Serine 260 Impairs Its Subcellular Localization, Receptor Interaction, Nuclear Mobility, and 1α,25-Dihydroxyvitamin D3-dependent DNA Binding in Ras-transformed Keratinocytes.
[So] Source:J Biol Chem;292(4):1490-1509, 2017 Jan 27.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Human retinoid X receptor α (hRXRα) plays a critical role in DNA binding and transcriptional activity through heterodimeric association with several members of the nuclear receptor superfamily, including the human vitamin D receptor (hVDR). We previously showed that hRXRα phosphorylation at serine 260 through the Ras-Raf-MAPK ERK1/2 activation is responsible for resistance to the growth inhibitory effects of 1α,25-dihydroxyvitamin D (1α,25(OH) D ), the biologically active metabolite of vitamin D To further investigate the mechanism of this resistance, we studied intranuclear dynamics of hVDR and hRXRα-tagged constructs in living cells together with endogenous and tagged protein in fixed cells. We find that hVDR-, hRXRα-, and hVDR-hRXRα complex accumulate in the nucleus in 1α,25(OH) D -treated HPK1A cells but to a lesser extent in HPK1ARas-treated cells. Also, by using fluorescence resonance energy transfer (FRET), we demonstrate increased interaction of the hVDR-hRXRα complex in 1α,25(OH) D -treated HPK1A but not HPK1ARas cells. In HPK1ARas cells, 1α,25(OH) D -induced nuclear localization and interaction of hRXRα are restored when cells are treated with the MEK1/2 inhibitor UO126 or following transfection of the non-phosphorylatable hRXRα Ala-260 mutant. Finally, we demonstrate using fluorescence loss in photobleaching and quantitative co-localization with chromatin that RXR immobilization and co-localization with chromatin are significantly increased in 1α,25(OH) D -treated HPK1ARas cells transfected with the non-phosphorylatable hRXRα Ala-260 mutant. This suggests that hRXRα phosphorylation significantly disrupts its nuclear localization, interaction with VDR, intra-nuclear trafficking, and binding to chromatin of the hVDR-hRXR complex.
[Mh] Termos MeSH primário: Calcitriol/farmacologia
Núcleo Celular/metabolismo
Queratinócitos/metabolismo
Receptor X Retinoide alfa/metabolismo
[Mh] Termos MeSH secundário: Transporte Ativo do Núcleo Celular/efeitos dos fármacos
Substituição de Aminoácidos
Linhagem Celular Transformada
Núcleo Celular/genética
MAP Quinases Reguladas por Sinal Extracelular/genética
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Seres Humanos
Mutação de Sentido Incorreto
Fosforilação/efeitos dos fármacos
Fosforilação/genética
Receptor X Retinoide alfa/genética
Serina
Proteínas ras/genética
Proteínas ras/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Retinoid X Receptor alpha); 452VLY9402 (Serine); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases); EC 3.6.5.2 (ras Proteins); FXC9231JVH (Calcitriol)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170605
[Lr] Data última revisão:
170605
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161118
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.758185



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