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[PMID]:29357290
[Au] Autor:Fujimoto N; Kitamura S; Uramaru N; Miyagawa S; Iguchi T
[Ad] Endereço:Institute for Radiation Biology and Medicine (RIRBM), Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan. Electronic address: nfjm@hiroshima-u.ac.jp.
[Ti] Título:Identification of hepatic thyroid hormone-responsive genes in neonatal rats: Potential targets for thyroid hormone-disrupting chemicals.
[So] Source:Toxicol Lett;286:48-53, 2018 Apr.
[Is] ISSN:1879-3169
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:There have been many concerns about the possible adverse effects of thyroid hormone-disrupting chemicals in the environment. Because thyroid hormones are essential for regulating the growth and differentiation of many tissues, disruption of thyroid hormones during the neonatal period of an organism might lead to permanent effects on that organism. We postulated that there are target genes that are sensitive to thyroid hormones particularly during the neonatal period and that would thus be susceptible to thyroid hormone-disrupting chemicals. Global gene expression analysis was used to identify these genes in the liver of rat neonates. The changes in hepatic gene expression were examined 24 h after administering 1.0, 10, and 100 ng/g body weight (bw) triiodothyronine (T3) to male rats on postnatal day 3. Thirteen upregulated and four downregulated genes were identified in the neonatal liver. Among these, Pdp2 and Slc25a25 were found to be upregulated and more sensitive to T3 than the others, whereas Cyp7b1 and Hdc were found to be downregulated even at the lowest dose of 1.0 ng/g bw T3. Interestingly, when the responses of gene expression to T3 were examined in adult rats (8-week old), one-third of them did not respond to T3. The environmental chemicals with thyroid hormone-like activity, hydroxylated polybrominated diphenyl ethers, were then administered to neonatal rats to examine the effects on expression of the identified genes. The results showed that these chemicals were indeed capable of changing the expression of Slc25a25 and Hdc. Our results demonstrated a series of hepatic T3-responsive genes that are more sensitive to hormones during the neonatal period than during adulthood. These genes might be the potential targets of thyroid hormone-disrupting chemicals in newborns.
[Mh] Termos MeSH primário: Disruptores Endócrinos/toxicidade
Regulação da Expressão Gênica/efeitos dos fármacos
Fígado/efeitos dos fármacos
Tri-Iodotironina/farmacologia
[Mh] Termos MeSH secundário: Animais
Animais Recém-Nascidos
Família 7 do Citocromo P450/genética
Família 7 do Citocromo P450/metabolismo
Relação Dose-Resposta a Droga
Perfilação da Expressão Gênica/métodos
Histidina Descarboxilase/genética
Histidina Descarboxilase/metabolismo
Fígado/metabolismo
Masculino
Proteínas de Transporte da Membrana Mitocondrial/genética
Proteínas de Transporte da Membrana Mitocondrial/metabolismo
Análise de Sequência com Séries de Oligonucleotídeos
Piruvato Desidrogenase (Lipoamida)-Fosfatase/genética
Piruvato Desidrogenase (Lipoamida)-Fosfatase/metabolismo
Ratos Endogâmicos F344
Medição de Risco
Esteroide Hidroxilases/genética
Esteroide Hidroxilases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Endocrine Disruptors); 0 (Mitochondrial Membrane Transport Proteins); 0 (Slc25a25 protein, rat); 06LU7C9H1V (Triiodothyronine); EC 1.14.- (Steroid Hydroxylases); EC 1.14.13.100 (Cyp7b1 protein, rat); EC 1.14.14.23 (Cytochrome P450 Family 7); EC 3.1.3.43 (Pyruvate Dehydrogenase (Lipoamide)-Phosphatase); EC 4.1.1.22 (Histidine Decarboxylase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180123
[St] Status:MEDLINE


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[PMID]:28604703
[Au] Autor:Worthmann A; John C; Rühlemann MC; Baguhl M; Heinsen FA; Schaltenberg N; Heine M; Schlein C; Evangelakos I; Mineo C; Fischer M; Dandri M; Kremoser C; Scheja L; Franke A; Shaul PW; Heeren J
[Ad] Endereço:Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
[Ti] Título:Cold-induced conversion of cholesterol to bile acids in mice shapes the gut microbiome and promotes adaptive thermogenesis.
[So] Source:Nat Med;23(7):839-849, 2017 Jul.
[Is] ISSN:1546-170X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Adaptive thermogenesis is an energy-demanding process that is mediated by cold-activated beige and brown adipocytes, and it entails increased uptake of carbohydrates, as well as lipoprotein-derived triglycerides and cholesterol, into these thermogenic cells. Here we report that cold exposure in mice triggers a metabolic program that orchestrates lipoprotein processing in brown adipose tissue (BAT) and hepatic conversion of cholesterol to bile acids via the alternative synthesis pathway. This process is dependent on hepatic induction of cytochrome P450, family 7, subfamily b, polypeptide 1 (CYP7B1) and results in increased plasma levels, as well as fecal excretion, of bile acids that is accompanied by distinct changes in gut microbiota and increased heat production. Genetic and pharmacological interventions that targeted the synthesis and biliary excretion of bile acids prevented the rise in fecal bile acid excretion, changed the bacterial composition of the gut and modulated thermogenic responses. These results identify bile acids as important metabolic effectors under conditions of sustained BAT activation and highlight the relevance of cholesterol metabolism by the host for diet-induced changes of the gut microbiota and energy metabolism.
[Mh] Termos MeSH primário: Ácidos e Sais Biliares/metabolismo
Colesterol/metabolismo
Temperatura Baixa
Microbioma Gastrointestinal
Termogênese
[Mh] Termos MeSH secundário: Subfamília B de Transportador de Cassetes de Ligação de ATP/genética
Tecido Adiposo Marrom/metabolismo
Alanina Transaminase/metabolismo
Animais
Aspartato Aminotransferases/metabolismo
Western Blotting
Calorimetria Indireta
Estudos de Casos e Controles
Família 7 do Citocromo P450/genética
Família 7 do Citocromo P450/metabolismo
Microbioma Gastrointestinal/genética
Perfilação da Expressão Gênica
Seres Humanos
Fígado/metabolismo
Camundongos
Camundongos Knockout
Obesidade
RNA Ribossômico 16S/genética
Receptores de LDL/genética
Reação em Cadeia da Polimerase Via Transcriptase Reversa
Esteroide Hidroxilases/genética
Esteroide Hidroxilases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ATP Binding Cassette Transporter, Sub-Family B); 0 (Bile Acids and Salts); 0 (P-glycoprotein 2); 0 (RNA, Ribosomal, 16S); 0 (Receptors, LDL); 97C5T2UQ7J (Cholesterol); EC 1.14.- (Steroid Hydroxylases); EC 1.14.13.100 (Cyp7b1 protein, mouse); EC 1.14.14.23 (Cytochrome P450 Family 7); EC 2.6.1.1 (Aspartate Aminotransferases); EC 2.6.1.2 (Alanine Transaminase)
[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:170613
[St] Status:MEDLINE
[do] DOI:10.1038/nm.4357


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[PMID]:26851362
[Au] Autor:Heverin M; Ali Z; Olin M; Tillander V; Joibari MM; Makoveichuk E; Leitersdorf E; Warner M; Olivercrona G; Gustafsson JÅ; Björkhem I
[Ad] Endereço:Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden.
[Ti] Título:On the regulatory importance of 27-hydroxycholesterol in mouse liver.
[So] Source:J Steroid Biochem Mol Biol;169:10-21, 2017 May.
[Is] ISSN:1879-1220
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:27-Hydroxycholesterol (27OH) is a strong suppressor of cholesterol synthesis and a weak activator of LXR in vitro. The regulatory importance of 27OH in vivo is controversial. Here we utilized male mice with increased levels of 27OH either due to increased production (CYP27A1 transgenic mice) or reduced metabolism (Cyp7b1-/- mice). We also used mice lacking 27OH due to a knockout of Cyp27a1. The latter mice were treated with cholic acid to compensate for reduced bile acid synthesis. The effects of the different levels of 27OH on Srebp- and other LXR-regulated genes in the liver were investigated. In the liver of CYP27tg mice we found a modest increase of the mRNA levels corresponding to the LXR target genes Cyp7b1 and Abca1. A number of other LXR-regulated genes were not affected. The effect on Abca1 mRNA was not seen in the liver of Cyp7b1-/- mice. There were little or no effects on cholesterol synthesis. In the liver of the Cyp27-/- mice treated with 0.025% cholic acid there was no significant effect of the knockout on the LXR target genes. In a previous work triple-knockout mice deficient in the biosynthesis of 24S-hydroxycholesterol, 25-hydroxycholesterol and 27OH were shown to have impaired response to dietary cholesterol, suggesting side-chain oxidized oxysterols to be mediators in cholesterol-induced effects on LXR target genes at a transcriptional level (Chen W. et al., Cell Metab. 5 (2007) 73-79). The hydroxylated oxysterol responsible for the effect was not defined. We show here that treatment of wildtype mice with dietary cholesterol under the same conditions as in the above study induced the LXR target genes Lpl, Abcg8 and Srebp1c in wild type mice but failed to activate the same genes in mice lacking 27-hydroxycholesterol due to a knockout of Cyp27. We failed to demonstrate the above effects at the protein level (Abcg8) or at the activity level (Lpl). The results suggest that 27OH is not an important regulator of Srebp- or LXR regulated genes under basal conditions in mouse liver. On the other hand 27OH appears to mediate cholesterol-induced effects on some LXR target genes at a transcriptional level under some in vivo conditions.
[Mh] Termos MeSH primário: Hidroxicolesteróis/metabolismo
Fígado/metabolismo
[Mh] Termos MeSH secundário: Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo
Animais
Colestanotriol 26-Mono-Oxigenase/genética
Família 7 do Citocromo P450/genética
Perfilação da Expressão Gênica
Lipase Lipoproteica/metabolismo
Lipoproteínas/metabolismo
Receptores X do Fígado/metabolismo
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Receptores Citoplasmáticos e Nucleares/metabolismo
Esteroide Hidroxilases/genética
Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
Transcrição Genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ABCG8 protein, mouse); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 8); 0 (Hydroxycholesterols); 0 (Lipoproteins); 0 (Liver X Receptors); 0 (Receptors, Cytoplasmic and Nuclear); 0 (Srebf1 protein, mouse); 0 (Sterol Regulatory Element Binding Protein 1); 6T2NA6P5SQ (27-hydroxycholesterol); EC 1.14.- (Steroid Hydroxylases); EC 1.14.13.100 (Cyp7b1 protein, mouse); EC 1.14.14.23 (Cytochrome P450 Family 7); EC 1.14.15.15 (Cholestanetriol 26-Monooxygenase); EC 1.14.15.15 (Cyp27a1 protein, mouse); EC 3.1.1.34 (Lipoprotein Lipase)
[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:160207
[St] Status:MEDLINE


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[PMID]:27278684
[Au] Autor:Xi XP; Zhuang J; Teng MJ; Xia LJ; Yang MY; Liu QG; Chen JB
[Ad] Endereço:Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China.
[Ti] Título:MicroRNA-17 induces epithelial-mesenchymal transition consistent with the cancer stem cell phenotype by regulating CYP7B1 expression in colon cancer.
[So] Source:Int J Mol Med;38(2):499-506, 2016 Aug.
[Is] ISSN:1791-244X
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:MicroRNA-17 (miRNA-17/miR­17) expression has been confirmed to be significantly higher in colorectal cancer tissues than in normal tissues. However, its exact role in colorectal cancer has not yet been fully elucidated. In this study, we found that miR-17 not only promoted epithelial-mesenchymal transition (EMT), but also promoted the formation of a stem cell-like population in colon cancer DLD1 cells. We also wished to determine the role of cytochrome P450, family 7, subfamily B, polypeptide 1 (CYP7B1) in CRC. miR-17 was overexpressed using a recombinant plasmid and CYP7B1 was silenced by transfection with shRNA. Western blot analysis was used to determine protein expression in the DLD1 cells and in tumor tissues obtained from patients with colon cancer. Our results revealed that miR­17 overexpression led to the degradation of CYP7B1 mRNA expression in DLD1 cells. In addition, we found that the silencing of CYB7B1 promoted EMT and the formation of a stem cell-like population in the cells. Thus, our findings demonstrate that miR­17 induces EMT consistent with the cancer stem cell phenotype by regulating CYP7B1 expression in colon cancer.
[Mh] Termos MeSH primário: Neoplasias do Colo/genética
Neoplasias do Colo/patologia
Família 7 do Citocromo P450/genética
Transição Epitelial-Mesenquimal/genética
Regulação Neoplásica da Expressão Gênica
MicroRNAs/metabolismo
Células-Tronco Neoplásicas/metabolismo
Células-Tronco Neoplásicas/patologia
Esteroide Hidroxilases/genética
[Mh] Termos MeSH secundário: Sequência de Bases
Linhagem Celular Tumoral
Família 7 do Citocromo P450/metabolismo
Inativação Gênica
Seres Humanos
MicroRNAs/genética
Fenótipo
Proteólise
Esteroide Hidroxilases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (MIRN17 microRNA, human); 0 (MicroRNAs); EC 1.14.- (Steroid Hydroxylases); EC 1.14.13.100 (CYP7B1 protein, human); EC 1.14.14.23 (Cytochrome P450 Family 7)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170306
[Lr] Data última revisão:
170306
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160610
[St] Status:MEDLINE
[do] DOI:10.3892/ijmm.2016.2624


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[PMID]:26898310
[Au] Autor:Rutkowska A; Dev KK; Sailer AW
[Ad] Endereço:School of Medicine, Department of Physiology, Trinity College Dublin, Dublin 152 - 160 Pearse Street, Ireland.
[Ti] Título:The Role of the Oxysterol/EBI2 Pathway in the Immune and Central Nervous Systems.
[So] Source:Curr Drug Targets;17(16):1851-1860, 2016.
[Is] ISSN:1873-5592
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Oxysterols are pleiotropic messengers interacting with multiple receptor systems. One of the cognate receptors for oxysterols is EBI2, a G protein-coupled receptor highly expressed in the cells of the immune system. Here we discuss the receptor's role in the adapted immunity and inflammation as well as the receptor's expression and function in the CNS with the focus on astrocytes. We also discuss expression and signalling of oxysterol-producing enzymes such as CH25H and CYP7B1 in the CNS and the immune system. These steps will help to elucidate a possible role for this pathway in the physiology of the central and peripheral nervous system and its possible link to human disease.
[Mh] Termos MeSH primário: Sistema Nervoso Central/metabolismo
Sistema Imunitário/metabolismo
Oxisteróis/metabolismo
Receptores Acoplados a Proteínas-G/metabolismo
[Mh] Termos MeSH secundário: Imunidade Adaptativa
Animais
Astrócitos/metabolismo
Família 7 do Citocromo P450/metabolismo
Seres Humanos
Inflamação/metabolismo
Doenças Neurodegenerativas/metabolismo
Receptores Acoplados a Proteínas-G/genética
Transdução de Sinais
Esteroide Hidroxilases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (GPR183 protein, human); 0 (Oxysterols); 0 (Receptors, G-Protein-Coupled); EC 1.14.- (Steroid Hydroxylases); EC 1.14.13.100 (CYP7B1 protein, human); EC 1.14.14.23 (Cytochrome P450 Family 7)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170830
[Lr] Data última revisão:
170830
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160223
[St] Status:MEDLINE


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[PMID]:26714052
[Au] Autor:Schubert SF; Hoffjan S; Dekomien G
[Ad] Endereço:Department of Human Genetics, Ruhr-University Bochum, 44801 Bochum, Germany; University Witten/Herdecke, Faculty of Health, 58448 Witten, Germany; Center for Rare Diseases Ruhr (CeSER), 44791 Bochum, Germany.
[Ti] Título:Mutational analysis of the CYP7B1, PNPLA6 and C19orf12 genes in autosomal recessive hereditary spastic paraplegia.
[So] Source:Mol Cell Probes;30(1):53-5, 2016 Feb.
[Is] ISSN:1096-1194
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The hereditary spastic paraplegias (HSPs) comprise a group of genetically heterogeneous neurodegenerative diseases. Here, we evaluated the spectrum and frequency of mutations in the CYP7B1, PNPLA6 and C19orf12 genes (causative for the subtypes SPG5A, SPG39 and SPG43, respectively) in a cohort of 63 unrelated HSP patients with suspected autosomal recessive inheritance. Two novel homozygous mutations (one frameshift and one missense mutation) were detected in CYP7B1 (SPG5A), while no disease-causing mutation was identified for SPG39 or SPG43.
[Mh] Termos MeSH primário: Proteínas Mitocondriais/genética
Mutação
Fosfolipases/genética
Paraplegia Espástica Hereditária/genética
Esteroide Hidroxilases/genética
[Mh] Termos MeSH secundário: Adolescente
Adulto
Sequência de Bases
Estudos de Coortes
Família 7 do Citocromo P450
Análise Mutacional de DNA/métodos
Saúde da Família
Feminino
Mutação da Fase de Leitura
Homozigoto
Seres Humanos
Masculino
Mutação de Sentido Incorreto
Linhagem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (C19orf12 protein, human); 0 (Mitochondrial Proteins); EC 1.14.- (Steroid Hydroxylases); EC 1.14.13.100 (CYP7B1 protein, human); EC 1.14.14.23 (Cytochrome P450 Family 7); EC 3.1.- (PNPLA6 protein, human); EC 3.1.- (Phospholipases)
[Em] Mês de entrada:1611
[Cu] Atualização por classe:170103
[Lr] Data última revisão:
170103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151230
[St] Status:MEDLINE


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[PMID]:26374131
[Au] Autor:Lynch DS; Koutsis G; Tucci A; Panas M; Baklou M; Breza M; Karadima G; Houlden H
[Ad] Endereço:Department of Molecular Neuroscience, The National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, London, UK.
[Ti] Título:Hereditary spastic paraplegia in Greece: characterisation of a previously unexplored population using next-generation sequencing.
[So] Source:Eur J Hum Genet;24(6):857-63, 2016 Jun.
[Is] ISSN:1476-5438
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Hereditary Spastic Paraplegia (HSP) is a syndrome characterised by lower limb spasticity, occurring alone or in association with other neurological manifestations, such as cognitive impairment, seizures, ataxia or neuropathy. HSP occurs worldwide, with different populations having different frequencies of causative genes. The Greek population has not yet been characterised. The purpose of this study was to describe the clinical presentation and molecular epidemiology of the largest cohort of HSP in Greece, comprising 54 patients from 40 families. We used a targeted next-generation sequencing (NGS) approach to genetically assess a proband from each family. We made a genetic diagnosis in >50% of cases and identified 11 novel variants. Variants in SPAST and KIF5A were the most common causes of autosomal dominant HSP, whereas SPG11 and CYP7B1 were the most common cause of autosomal recessive HSP. We identified a novel variant in SPG11, which led to disease with later onset and may be unique to the Greek population and report the first nonsense mutation in KIF5A. Interestingly, the frequency of HSP mutations in the Greek population, which is relatively isolated, was very similar to other European populations. We confirm that NGS approaches are an efficient diagnostic tool and should be employed early in the assessment of HSP patients.
[Mh] Termos MeSH primário: Taxa de Mutação
Paraplegia Espástica Hereditária/genética
[Mh] Termos MeSH secundário: Adenosina Trifosfatases/genética
Adolescente
Adulto
Criança
Família 7 do Citocromo P450/genética
Feminino
Testes Genéticos
Grécia
Heterozigoto
Sequenciamento de Nucleotídeos em Larga Escala
Seres Humanos
Cinesina/genética
Masculino
Meia-Idade
Linhagem
Proteínas/genética
Análise de Sequência de DNA
Paraplegia Espástica Hereditária/diagnóstico
Espastina
Esteroide Hidroxilases/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (KIF5A protein, human); 0 (Proteins); 0 (SPG11 protein, human); EC 1.14.- (Steroid Hydroxylases); EC 1.14.13.100 (CYP7B1 protein, human); EC 1.14.14.23 (Cytochrome P450 Family 7); EC 3.6.1.- (Adenosine Triphosphatases); EC 3.6.4.3 (SPAST protein, human); EC 3.6.4.3 (Spastin); EC 3.6.4.4 (Kinesin)
[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:150917
[St] Status:MEDLINE
[do] DOI:10.1038/ejhg.2015.200


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[PMID]:26370385
[Au] Autor:Criscuolo C; Carbone R; Lieto M; Peluso S; Guacci A; Filla A; Quarantelli M; Lanzillo R; Morra VB; De Michele G
[Ad] Endereço:Department of Neurosciences, Reproductive Sciences and Odontostomatology, 'Federico II' University of Naples, Naples, Italy.
[Ti] Título:SPG5 and multiple sclerosis: clinical and genetic overlap?
[So] Source:Acta Neurol Scand;133(6):410-4, 2016 Jun.
[Is] ISSN:1600-0404
[Cp] País de publicação:Denmark
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Autosomal recessive (AR) spastic paraplegia type 5 (SPG5) is due to mutations in the CYP7B1 gene, encoding for the cytochrome P450-7B1, responsible for oxysterols 7α-hydroxylation. Oxysterol/cholestenoic acids pool plays a role in motor neuron survival and immune response. SPG5 is characterized by white matter abnormalities at brain resonance imaging (MRI). In view of clinical presentation and MRI findings, multiple sclerosis (MS) is a possible differential diagnosis of SPG5. This study aimed to evaluate the frequency of CYP7B1 mutations in patients with MS. METHODS: One hundred and seventeen MS patients with clinical spastic paraplegia or possible AR transmission were selected for the mutational screening. RESULTS: Forty-three patients had primary progressive, 26 relapsing remitting, 26 secondary progressive, and 22 relapsing progressive MS clinical course. No CYP7B1 homozygous mutations were identified. Two novel variants and one pathogenic mutation were found at heterozygous state. CONCLUSIONS: The two novel variants cosegregated with pyramidal signs and autoimmune diseases suggesting that they might be susceptibility factors. Reduced cytochrome P450-7B1 enzymatic activity could alter the balance among neurotoxic and neuroprotective oxysterols promoting motor neuron degeneration and/or immune response.
[Mh] Termos MeSH primário: Família 7 do Citocromo P450/genética
Esclerose Múltipla/genética
Paraplegia Espástica Hereditária/genética
Esteroide Hidroxilases/genética
[Mh] Termos MeSH secundário: Adolescente
Adulto
Encéfalo/patologia
Criança
Feminino
Heterozigoto
Seres Humanos
Masculino
Meia-Idade
Esclerose Múltipla/complicações
Esclerose Múltipla/diagnóstico
Mutação
Paraplegia Espástica Hereditária/complicações
Paraplegia Espástica Hereditária/diagnóstico
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
EC 1.14.- (Steroid Hydroxylases); EC 1.14.13.100 (CYP7B1 protein, human); EC 1.14.14.23 (Cytochrome P450 Family 7)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150916
[St] Status:MEDLINE
[do] DOI:10.1111/ane.12476


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[PMID]:26399852
[Au] Autor:Sironi M; Biasin M; Pontremoli C; Cagliani R; Saulle I; Trabattoni D; Vichi F; Lo Caputo S; Mazzotta F; Aguilar-Jimenez W; Rugeles MT; Cedeno S; Sanchez J; Brander C; Clerici M
[Ad] Endereço:Scientific Institute IRCCS E. MEDEA, Bioinformatics, 23842, Bosisio Parini, Italy. msironi@bp.lnf.it.
[Ti] Título:Variants in the CYP7B1 gene region do not affect natural resistance to HIV-1 infection.
[So] Source:Retrovirology;12:80, 2015 Sep 24.
[Is] ISSN:1742-4690
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The genetic bases of natural resistance to HIV-1 infection remain largely unknown. Recently, two genome-wide association studies suggested a role for variants within or in the vicinity of the CYP7B1 gene in modulating HIV susceptibility. CYP7B1 is an appealing candidate for this due to its contribution to antiviral immune responses. We analyzed the frequency of two previously described CYP7B1 variants (rs6996198 and rs10808739) in three independent cohorts of HIV-1 infected subjects and HIV-1 exposed seronegative individuals (HESN). FINDINGS: rs6996198 and rs10808739 were genotyped in three case/control cohorts of sexually-exposed HESN and HIV-1-infected individuals from Italy, Peru and Colombia. Comparison of the allele and genotype frequencies of the two SNPs under different models showed that the only significant difference was seen for rs6996198 in the Peruvian sample (nominal p = 0.048, dominant model). For this variant, a random-effect meta-analysis yielded non-significant results (dominant model, p = 0.78) and revealed substantial heterogeneity among cohorts. No significant effect of the rs10808739 allelic status on HIV-1 infection susceptibility (additive model, p = 0.30) emerged from the meta-analysis. CONCLUSIONS: Although our study had limited power to detect association due to the small sample size, comparisons among the three cohorts revealed very similar allelic and genotypic frequencies in HESN and HIV-1 positive subjects. Overall, these data indicate that the two GWAS-defined variants in the CYP7B1 region do not strongly influence HIV-1 infection susceptibility.
[Mh] Termos MeSH primário: Predisposição Genética para Doença
Infecções por HIV/genética
Infecções por HIV/imunologia
Imunidade Inata/genética
Esteroide Hidroxilases/genética
[Mh] Termos MeSH secundário: Adulto
Alelos
Família 7 do Citocromo P450
Feminino
Estudo de Associação Genômica Ampla
Genótipo
Infecções por HIV/virologia
HIV-1/fisiologia
Seres Humanos
Masculino
Polimorfismo de Nucleotídeo Único
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
EC 1.14.- (Steroid Hydroxylases); EC 1.14.13.100 (CYP7B1 protein, human); EC 1.14.14.23 (Cytochrome P450 Family 7)
[Em] Mês de entrada:1607
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150925
[St] Status:MEDLINE
[do] DOI:10.1186/s12977-015-0206-0


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[PMID]:26169917
[Au] Autor:Jung JI; Price AR; Ladd TB; Ran Y; Park HJ; Ceballos-Diaz C; Smithson LA; Hochhaus G; Tang Y; Akula R; Ba S; Koo EH; Shapiro G; Felsenstein KM; Golde TE
[Ad] Endereço:Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, 32610, USA. jjung@ufl.edu.
[Ti] Título:Cholestenoic acid, an endogenous cholesterol metabolite, is a potent γ-secretase modulator.
[So] Source:Mol Neurodegener;10:29, 2015 Jul 14.
[Is] ISSN:1750-1326
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Amyloid-ß (Aß) 42 has been implicated as the initiating molecule in the pathogenesis of Alzheimer's disease (AD); thus, therapeutic strategies that target Aß42 are of great interest. γ-Secretase modulators (GSMs) are small molecules that selectively decrease Aß42. We have previously reported that many acidic steroids are GSMs with potencies ranging in the low to mid micromolar concentration with 5ß-cholanic acid being the most potent steroid identified GSM with half maximal effective concentration (EC50) of 5.7 µM. RESULTS: We find that the endogenous cholesterol metabolite, 3ß-hydroxy-5-cholestenoic acid (CA), is a steroid GSM with enhanced potency (EC50 of 250 nM) relative to 5ß-cholanic acid. CA i) is found in human plasma at ~100-300 nM concentrations ii) has the typical acidic GSM signature of decreasing Aß42 and increasing Aß38 levels iii) is active in in vitro γ-secretase assay iv) is made in the brain. To test if CA acts as an endogenous GSM, we used Cyp27a1 knockout (Cyp27a1-/-) and Cyp7b1 knockout (Cyp7b1-/-) mice to investigate if manipulation of cholesterol metabolism pathways relevant to CA formation would affect brain Aß42 levels. Our data show that Cyp27a1-/- had increased brain Aß42, whereas Cyp7b1-/- mice had decreased brain Aß42 levels; however, peripheral dosing of up to 100 mg/kg CA did not affect brain Aß levels. Structure-activity relationship (SAR) studies with multiple known and novel CA analogs studies failed to reveal CA analogs with increased potency. CONCLUSION: These data suggest that CA may act as an endogenous GSM within the brain. Although it is conceptually attractive to try and increase the levels of CA in the brain for prevention of AD, our data suggest that this will not be easily accomplished.
[Mh] Termos MeSH primário: Secretases da Proteína Precursora do Amiloide/metabolismo
Peptídeos beta-Amiloides/metabolismo
Encéfalo/metabolismo
Colesterol/análogos & derivados
Fragmentos de Peptídeos/metabolismo
[Mh] Termos MeSH secundário: Animais
Barreira Hematoencefálica
Células CHO
Células Cultivadas
Colestanotriol 26-Mono-Oxigenase/deficiência
Colestanotriol 26-Mono-Oxigenase/genética
Colesterol/química
Colesterol/metabolismo
Colesterol/farmacologia
Ácidos Cólicos/farmacologia
Técnicas de Cocultura
Cricetinae
Cricetulus
Família 7 do Citocromo P450
Relação Dose-Resposta a Droga
Avaliação Pré-Clínica de Medicamentos
Seres Humanos
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Estrutura Molecular
Neuroglia/metabolismo
Neurônios/metabolismo
Esteroide Hidroxilases/deficiência
Esteroide Hidroxilases/genética
Relação Estrutura-Atividade
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Amyloid beta-Peptides); 0 (Cholic Acids); 0 (Peptide Fragments); 0 (amyloid beta-protein (1-38)); 0 (amyloid beta-protein (1-42)); 6561-58-6 (3-hydroxy-5-cholestenoic acid); 97C5T2UQ7J (Cholesterol); EC 1.14.- (Steroid Hydroxylases); EC 1.14.13.100 (Cyp7b1 protein, mouse); EC 1.14.14.23 (Cytochrome P450 Family 7); EC 1.14.15.15 (Cholestanetriol 26-Monooxygenase); EC 1.14.15.15 (Cyp27a1 protein, mouse); EC 3.4.- (Amyloid Precursor Protein Secretases); NS0L7RS7DA (cholanic acid)
[Em] Mês de entrada:1603
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150715
[St] Status:MEDLINE
[do] DOI:10.1186/s13024-015-0021-z



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