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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]:28724759
[Au] Autor:Ke W; Fang L; Jing H; Tao R; Wang T; Li Y; Long S; Wang D; Xiao S
[Ad] Endereço:State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.
[Ti] Título:Cholesterol 25-Hydroxylase Inhibits Porcine Reproductive and Respiratory Syndrome Virus Replication through Enzyme Activity-Dependent and -Independent Mechanisms.
[So] Source:J Virol;91(19), 2017 Oct 01.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cholesterol 25-hydroxylase (CH25H) has recently been identified as a host restriction factor that exerts antiviral effects by catalyzing the production of 25-hydroxycholesterol (25HC). CH25H can be rapidly induced upon infection with some viruses. Porcine reproductive and respiratory syndrome virus (PRRSV), an arterivirus, has ranked among the most important swine pathogens since it was discovered in the late 1980s. In this study, we found that PRRSV infection significantly downregulated the expression of CH25H in cells by a so-far unknown mechanism, suggesting that CH25H exerts antiviral activity against PRRSV. Indeed, overexpression of CH25H inhibited PRRSV replication, whereas knockdown of CH25H by short interfering RNA (siRNA) promoted PRRSV infection. The anti-PRRSV effect of 25HC operates via inhibition of viral penetration. Interestingly, a CH25H mutant (CH25H-M) lacking hydroxylase activity still inhibited PRRSV infection. Screening using a yeast two-hybrid system followed by coimmunoprecipitation and immunofluorescence colocalization analyses confirmed that both CH25H and CH25H-M interact with the nonstructural protein 1 alpha (nsp1α) of PRRSV. Unexpectedly, the expression of nsp1α decreased following coexpression with CH25H or CH25H-M. Detailed analyses demonstrated that CH25H/CH25H-M could degrade nsp1α through the ubiquitin-proteasome pathway and that site K169 in the nsp1α protein is the key site of ubiquitination. Taken together, our findings demonstrate that CH25H restricts PRRSV replication by targeting viral penetration as well as degrading nsp1α, revealing a novel antiviral mechanism used by CH25H. PRRSV has been a continuous threat to the global swine industry, and current vaccines are insufficient to provide sustainable control. CH25H has been found to exert a broad antiviral effect; thus, it is an attractive target for the development of anti-PRRSV drugs. Here, we demonstrate that CH25H is an interferon-stimulated gene that is highly expressed in porcine alveolar macrophages. CH25H exerts its anti-PRRSV effect not only via the production of 25HC to inhibit viral penetration but also by degrading viral protein through the ubiquitin-proteasome pathway, suggesting that CH25H is a candidate for the development of antiviral therapeutics. However, PRRSV infection appears to actively decrease CH25H expression to promote viral replication, highlighting the complex game between PRRSV and its host.
[Mh] Termos MeSH primário: Antivirais/metabolismo
Vírus da Síndrome Respiratória e Reprodutiva Suína/crescimento & desenvolvimento
Esteroide Hidroxilases/metabolismo
Replicação Viral/fisiologia
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Cercopithecus aethiops
Células HEK293
Seres Humanos
Interferência de RNA
RNA Interferente Pequeno/genética
Esteroide Hidroxilases/genética
Suínos
Ubiquitinação
Proteínas não Estruturais Virais/metabolismo
Internalização do Vírus
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antiviral Agents); 0 (RNA, Small Interfering); 0 (Viral Nonstructural Proteins); EC 1.14.- (Steroid Hydroxylases); EC 1.14.99.38 (cholesterol 25-hydroxylase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170721
[St] Status:MEDLINE


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[PMID]:28631596
[Au] Autor:Wang J; Zeng L; Zhang L; Guo ZZ; Lu SF; Ming SL; Li GL; Wan B; Tian KG; Yang GY; Chu BB
[Ad] Endereço:1​College of Animal Sciences and Veterinary Medicine, Henan Agricultural University, Zhengzhou 450002, Henan Province, PR China.
[Ti] Título:Cholesterol 25-hydroxylase acts as a host restriction factor on pseudorabies virus replication.
[So] Source:J Gen Virol;98(6):1467-1476, 2017 Jun.
[Is] ISSN:1465-2099
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Cholesterol 25-hydroxylase (CH25H) catalyses the production of 25-hydroxycholesterol (25HC) from cholesterol by adding a second hydroxyl group at position 25. The aim of this study was to examine the antiviral effect of CH25H on pseudorabies virus (PRV), a swine pathogen that can cause devastating disease and economic losses worldwide. The results showed that porcine ch25h was induced by either interferon or PRV infection. PRV infection of porcine alveolar macrophages (3D4/21 cells) was attenuated by CH25H overexpression and enhanced by silencing of CH25H. Furthermore, treatment of 3D4/21 cells with 25HC inhibited the growth of PRV in vitro, suggesting that CH25H may restrict PRV replication by 25HC production. We further identified that the anti-PRV role of CH25H and 25HC was subject to their inhibitory effect on PRV attachment and entry. Collectively, these findings demonstrate that CH25H is an intrinsic host restriction factor in PRV infection of porcine alveolar macrophages.
[Mh] Termos MeSH primário: Antivirais/metabolismo
Herpesvirus Suídeo 1/crescimento & desenvolvimento
Herpesvirus Suídeo 1/imunologia
Interações Hospedeiro-Patógeno
Hidroxicolesteróis/metabolismo
Esteroide Hidroxilases/metabolismo
Replicação Viral
[Mh] Termos MeSH secundário: Animais
Células Cultivadas
Imunidade Inata
Macrófagos Alveolares/imunologia
Macrófagos Alveolares/virologia
Suínos
Ligação Viral/efeitos dos fármacos
Internalização do Vírus/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antiviral Agents); 0 (Hydroxycholesterols); 767JTD2N31 (25-hydroxycholesterol); EC 1.14.- (Steroid Hydroxylases); EC 1.14.99.38 (cholesterol 25-hydroxylase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170717
[Lr] Data última revisão:
170717
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170621
[St] Status:MEDLINE
[do] DOI:10.1099/jgv.0.000797


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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]:28479230
[Au] Autor:Thussagunpanit J; Jutamanee K; Homvisasevongsa S; Suksamrarn A; Yamagami A; Nakano T; Asami T
[Ad] Endereço:Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan; Department of Botany, Faculty of Science, 50 Kasetsart University, Ladyao, Chatuchak, Bangkok 10900, Thailand. Electronic address: ju
[Ti] Título:Characterization of synthetic ecdysteroid analogues as functional mimics of brassinosteroids in plant growth.
[So] Source:J Steroid Biochem Mol Biol;172:1-8, 2017 Sep.
[Is] ISSN:1879-1220
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Brassinosteroids (BRs) are plant steroidal hormones that play important roles in many stages of plant growth. Several plant species produce ecdysteroids, which are known as insect molting steroid hormones. In this study, we evaluated the biological activities of three hydroxysteroidal compounds, 20-hydroxyecdysone (ECD), 7,8-dihydro-8α-20-hydroxyecdysone (DHECD), and 7,8-dihydro-5α,8α-20-hydroxyecdysone (α-DHECD), and compared their activities with that of brassinolide (BL), the most potent BR. In rice, DHECD and α-DHECD enhanced the degree of lamina inclination, as do BRs. In Arabidopsis thaliana, DHECD and α-DHECD increased hypocotyl length in the wild-type, and also partially overcame the hypocotyl shortening in the wild-type caused by 0.3µM brassinazole, a specific BR biosynthesis inhibitor. DHECD and α-DHECD partially reduced dwarfism in the BR-biosynthesis-deficient mutant det2. Treatment with DHECD or α-DHECD downregulated the expression of the BR biosynthesis genes DWF4 and CPD, which are generally, suppressed by BR, and upregulated the expression of TCH4 and SAUR-AC1, which are generally promoted by BR. However, their regulated activities were less effective than BL. Moreover, the 10 M DHECD and α-DHECD induced the accumulation of dephosphorylated BIL1/BZR1 that enhanced BR signaling as a master transcription factor. In contrast, ECD did not affect rice lamina bending, Arabidopsis hypocotyl elongation, the expression levels of BR-related genes and BIL1/BZR1 phosphorylation status. Based on these results, we hypothesize that both DHECD and α-DHECD have functional activities similar to those of BR.
[Mh] Termos MeSH primário: Arabidopsis/efeitos dos fármacos
Materiais Biomiméticos/farmacologia
Brassinosteroides/farmacologia
Ecdisterona/farmacologia
Oryza/efeitos dos fármacos
Reguladores de Crescimento de Planta/farmacologia
Esteroides Heterocíclicos/farmacologia
[Mh] Termos MeSH secundário: Arabidopsis/genética
Arabidopsis/crescimento & desenvolvimento
Arabidopsis/metabolismo
Proteínas de Arabidopsis/genética
Proteínas de Arabidopsis/metabolismo
Materiais Biomiméticos/síntese química
Sistema Enzimático do Citocromo P-450/genética
Sistema Enzimático do Citocromo P-450/metabolismo
Ecdisterona/análogos & derivados
Ecdisterona/metabolismo
Regulação da Expressão Gênica no Desenvolvimento
Regulação da Expressão Gênica de Plantas
Glicosiltransferases/genética
Glicosiltransferases/metabolismo
Hipocótilo/efeitos dos fármacos
Hipocótilo/genética
Hipocótilo/crescimento & desenvolvimento
Hipocótilo/metabolismo
Proteínas Nucleares/genética
Proteínas Nucleares/metabolismo
Oryza/genética
Oryza/crescimento & desenvolvimento
Oryza/metabolismo
Fosforilação/efeitos dos fármacos
Reação em Cadeia da Polimerase em Tempo Real
Sementes/efeitos dos fármacos
Sementes/genética
Sementes/crescimento & desenvolvimento
Sementes/metabolismo
Transdução de Sinais
Esteroide Hidroxilases/genética
Esteroide Hidroxilases/metabolismo
Triazóis/antagonistas & inibidores
Triazóis/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Arabidopsis Proteins); 0 (BZR1 protein, Arabidopsis); 0 (Brassinosteroids); 0 (DET2 protein, Arabidopsis); 0 (DWF4 protein, Arabidopsis); 0 (Nuclear Proteins); 0 (Plant Growth Regulators); 0 (SAUR-AC1 protein, Arabidopsis); 0 (Steroids, Heterocyclic); 0 (Triazoles); 5289-74-7 (Ecdysterone); 9035-51-2 (Cytochrome P-450 Enzyme System); EC 1.14.- (CPD protein, Arabidopsis); EC 1.14.- (Steroid Hydroxylases); EC 2.4.- (Glycosyltransferases); EC 2.4.1.- (TCH4 protein, Arabidopsis); N9XRW3TF90 (brassinazole); Y9IQ1L53OX (brassinolide)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170509
[St] Status:MEDLINE


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[PMID]:28428022
[Au] Autor:Wang R; Sui P; Hou X; Cao T; Jia L; Lu F; Singh S; Wang Z; Liu X
[Ad] Endereço:College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China.
[Ti] Título:Cloning and identification of a novel steroid 11α-hydroxylase gene from Absidia coerulea.
[So] Source:J Steroid Biochem Mol Biol;171:254-261, 2017 Jul.
[Is] ISSN:1879-1220
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Steroid 11-hydroxylation by filamentous fungi is a major route for industrial scale production of key intermediates in the synthesis of steroid drugs. Although it is well established that enzymes involved in fungal hydroxylation of steroids are cytochrome P450s (CYP), few fungal steroid hydroxylase genes have been identified. In this study, we identified a novel 11α-hydroxylase gene CYP5311B1 from Absidia coerulea AS3.65 by a combination of transcriptome sequencing, real-time qRT-PCR and heterologous expression in Pichia pastoris. The full-length open reading frame (ORF) of CYP5311B1 is predicted to encode a CYP protein of 527 amino acids whose expression in Pichia cells was confirmed by western blot. In addition, the major hydroxylation product was characterized by HPLC and 2D NMR. CYP5311B1 was highly induced by steroid substrate at the transcriptional level. The cloning and identification of an 11α-hydroxylase gene from A. coerulea should aid in a better understanding of the structural basis underlying regio- and stereoselectivity, and substrate specificity of fungal steroid 11α-hydroxylases, thus facilitating the engineering of more efficient steroid hydroxylases for industrial applications.
[Mh] Termos MeSH primário: Absidia/enzimologia
Proteínas Fúngicas/metabolismo
Esteroide Hidroxilases/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Células Clonais
Eletroporação
Indução Enzimática
Compostos de Epóxi/química
Compostos de Epóxi/metabolismo
Escherichia coli
Proteínas Fúngicas/genética
Hidroxilação
Estrutura Molecular
Fases de Leitura Aberta
Filogenia
Pichia
Progesterona/análogos & derivados
Progesterona/química
Progesterona/metabolismo
Proteínas Recombinantes/metabolismo
Alinhamento de Sequência
Análise de Sequência de RNA
Homologia de Sequência de Aminoácidos
Estereoisomerismo
Esteroide Hidroxilases/genética
Terminologia como Assunto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Epoxy Compounds); 0 (Fungal Proteins); 0 (Recombinant Proteins); 1097-51-4 (16 alpha,17-epoxyprogesterone); 4G7DS2Q64Y (Progesterone); EC 1.14.- (Steroid Hydroxylases); EC 1.14.99.- (steroid 11-alpha-hydroxylase)
[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:170422
[St] Status:MEDLINE


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[PMID]:28350814
[Au] Autor:Kumar R; Mota LC; Litoff EJ; Rooney JP; Boswell WT; Courter E; Henderson CM; Hernandez JP; Corton JC; Moore DD; Baldwin WS
[Ad] Endereço:Biological Sciences, Clemson University, Clemson, SC, United States of America.
[Ti] Título:Compensatory changes in CYP expression in three different toxicology mouse models: CAR-null, Cyp3a-null, and Cyp2b9/10/13-null mice.
[So] Source:PLoS One;12(3):e0174355, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Targeted mutant models are common in mechanistic toxicology experiments investigating the absorption, metabolism, distribution, or elimination (ADME) of chemicals from individuals. Key models include those for xenosensing transcription factors and cytochrome P450s (CYP). Here we investigated changes in transcript levels, protein expression, and steroid hydroxylation of several xenobiotic detoxifying CYPs in constitutive androstane receptor (CAR)-null and two CYP-null mouse models that have subfamily members regulated by CAR; the Cyp3a-null and a newly described Cyp2b9/10/13-null mouse model. Compensatory changes in CYP expression that occur in these models may also occur in polymorphic humans, or may complicate interpretation of ADME studies performed using these models. The loss of CAR causes significant changes in several CYPs probably due to loss of CAR-mediated constitutive regulation of these CYPs. Expression and activity changes include significant repression of Cyp2a and Cyp2b members with corresponding drops in 6α- and 16ß-testosterone hydroxylase activity. Further, the ratio of 6α-/15α-hydroxylase activity, a biomarker of sexual dimorphism in the liver, indicates masculinization of female CAR-null mice, suggesting a role for CAR in the regulation of sexually dimorphic liver CYP profiles. The loss of Cyp3a causes fewer changes than CAR. Nevertheless, there are compensatory changes including gender-specific increases in Cyp2a and Cyp2b. Cyp2a and Cyp2b were down-regulated in CAR-null mice, suggesting activation of CAR and potentially PXR following loss of the Cyp3a members. However, the loss of Cyp2b causes few changes in hepatic CYP transcript levels and almost no significant compensatory changes in protein expression or activity with the possible exception of 6α-hydroxylase activity. This lack of a compensatory response in the Cyp2b9/10/13-null mice is probably due to low CYP2B hepatic expression, especially in male mice. Overall, compensatory and regulatory CYP changes followed the order CAR-null > Cyp3a-null > Cyp2b-null mice.
[Mh] Termos MeSH primário: Hidrocarboneto de Aril Hidroxilases/genética
Sistema Enzimático do Citocromo P-450/genética
Família 2 do Citocromo P450/genética
Receptores Citoplasmáticos e Nucleares/genética
Esteroide Hidroxilases/genética
[Mh] Termos MeSH secundário: Animais
Hidrocarboneto de Aril Hidroxilases/metabolismo
Sistemas CRISPR-Cas
Sistema Enzimático do Citocromo P-450/metabolismo
Família 2 do Citocromo P450/metabolismo
Feminino
Deleção de Genes
Expressão Gênica
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Fenômenos Farmacológicos e Toxicológicos
Receptores Citoplasmáticos e Nucleares/metabolismo
Esteroide Hidroxilases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Cytoplasmic and Nuclear); 0 (constitutive androstane receptor); 9035-51-2 (Cytochrome P-450 Enzyme System); EC 1.- (cytochrome P-450 2B13, mouse); EC 1.14.- (Steroid Hydroxylases); EC 1.14.14.1 (Aryl Hydrocarbon Hydroxylases); EC 1.14.14.1 (CYP3A protein, mouse); EC 1.14.14.1 (Cyp2b10 protein, mouse); EC 1.14.14.1 (Cyp2b9 protein, mouse); EC 1.14.14.1 (Cytochrome P450 Family 2)
[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:170329
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0174355


  8 / 5233 MEDLINE  
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[PMID]:28299341
[Au] Autor:Noebauer B; Jais A; Todoric J; Gossens K; Sutterlüty-Fall H; Einwallner E
[Ad] Endereço:Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
[Ti] Título:Hepatic Cholesterol-25-Hydroxylase Overexpression Improves Systemic Insulin Sensitivity in Mice.
[So] Source:J Diabetes Res;2017:4108768, 2017.
[Is] ISSN:2314-6753
[Cp] País de publicação:Egypt
[La] Idioma:eng
[Ab] Resumo:Obesity is a major risk factor for several diseases including diabetes, heart disease, and some forms of cancer and due to its rapidly increasing prevalence it has become one of the biggest problems medicine is facing today. All the more surprising, a substantial percentage of obese patients are metabolically healthy when classified based on insulin resistance and systemic inflammation. Oxysterols are naturally occurring molecules that play important role in various metabolic and inflammatory processes and their levels are elevated in patients suffering from obesity and diabetes. 25-Hydroxycholesterol (25-OHC) is produced in cells from cholesterol by the enzyme cholesterol 25-hydroxylase (Ch25h) and is involved in lipid metabolism, inflammatory processes, and cell proliferation. Here, we investigated the role of hepatic Ch25h in the transition from metabolically healthy obesity to insulin resistance and diabetes. Using several different experimental approaches, we demonstrated the significance of Ch25h on the border of "healthy" and "diseased" states of obesity. Adenovirus-mediated Ch25h overexpression in mice improved glucose tolerance and insulin sensitivity and lowered HOMA-IR. Our data suggest that low hepatic Ch25h levels could be considered a risk marker for unhealthy obesity.
[Mh] Termos MeSH primário: Diabetes Mellitus Tipo 2/genética
Resistência à Insulina/genética
Fígado/metabolismo
Obesidade/genética
Esteroide Hidroxilases/genética
[Mh] Termos MeSH secundário: Animais
Glicemia/metabolismo
Diabetes Mellitus Tipo 2/metabolismo
Progressão da Doença
Masculino
Camundongos
Camundongos Transgênicos
Obesidade/metabolismo
Esteroide Hidroxilases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Blood Glucose); EC 1.14.- (Steroid Hydroxylases); EC 1.14.99.38 (cholesterol 25-hydroxylase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170615
[Lr] Data última revisão:
170615
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170317
[St] Status:MEDLINE
[do] DOI:10.1155/2017/4108768


  9 / 5233 MEDLINE  
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[PMID]:28281299
[Au] Autor:Khatri Y; Schifrin A; Bernhardt R
[Ad] Endereço:Institute of Biochemistry, Saarland University, Saarbrücken, Germany.
[Ti] Título:Investigating the effect of available redox protein ratios for the conversion of a steroid by a myxobacterial CYP260A1.
[So] Source:FEBS Lett;591(8):1126-1140, 2017 Apr.
[Is] ISSN:1873-3468
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Since cytochromes P450 are external monooxygenases, available surrogate redox partners have been used to reconstitute the P450 activity. However, the effect of various ratios of P450s and the redox proteins have not been extensively studied so far, although different combinations of the redox partners have shown variations in substrate conversion. To address this issue, CYP260A1 was reconstituted with various ratios of adrenodoxin and adrenodoxin reductase to convert 11-deoxycorticosterone, and the products were characterized by NMR. We show the effect of the available redox protein ratios not only on the P450 catalytic activity but also on the product pattern.
[Mh] Termos MeSH primário: Adrenodoxina/metabolismo
Proteínas de Bactérias/metabolismo
Desoxicorticosterona/metabolismo
Ferredoxina-NADP Redutase/metabolismo
Modelos Moleculares
Myxococcales/enzimologia
Ácido Retinoico 4 Hidroxilase/metabolismo
Esteroide Hidroxilases/metabolismo
[Mh] Termos MeSH secundário: Adrenodoxina/genética
Animais
Ácido Ascórbico/metabolismo
Proteínas de Bactérias/genética
Biocatálise
Catalase/metabolismo
Desoxicorticosterona/análogos & derivados
Desoxicorticosterona/química
Ferredoxina-NADP Redutase/genética
Depuradores de Radicais Livres/metabolismo
Peróxido de Hidrogênio/química
Espectroscopia de Ressonância Magnética
Estrutura Molecular
NADP/metabolismo
Oxirredução
Proteínas Recombinantes/metabolismo
Estereoisomerismo
Esteroide Hidroxilases/genética
Superóxido Dismutase/metabolismo
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (11-deoxycorticosterone-1-ene); 0 (Bacterial Proteins); 0 (Free Radical Scavengers); 0 (Recombinant Proteins); 12687-22-8 (Adrenodoxin); 40GP35YQ49 (Desoxycorticosterone); 53-59-8 (NADP); BBX060AN9V (Hydrogen Peroxide); EC 1.11.1.6 (Catalase); EC 1.14.- (Steroid Hydroxylases); EC 1.14.14.1 (Retinoic Acid 4-Hydroxylase); EC 1.15.1.1 (Superoxide Dismutase); EC 1.18.1.2 (Ferredoxin-NADP Reductase); PQ6CK8PD0R (Ascorbic Acid)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170808
[Lr] Data última revisão:
170808
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170311
[St] Status:MEDLINE
[do] DOI:10.1002/1873-3468.12619


  10 / 5233 MEDLINE  
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[PMID]:28163026
[Au] Autor:Nikolaus J; Nguyen KT; Virus C; Riehm JL; Hutter M; Bernhardt R
[Ad] Endereço:Department of Biochemistry, Saarland University, Campus B2.2, 66123 Saarbrücken, Germany.
[Ti] Título:Engineering of CYP106A2 for steroid 9α- and 6ß-hydroxylation.
[So] Source:Steroids;120:41-48, 2017 Apr.
[Is] ISSN:1878-5867
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:CYP 106A2 from Bacillus megaterium ATCC 13368 has been described as a 15ß-hydroxylase showing also minor 11α-, 9α- and 6ß-hydroxylase activity for progesterone conversion. Previously, mutant proteins with a changed selectivity towards 11α-OH-progesterone have already been produced. The challenge of this work was to create mutant proteins with a higher regioselectivity towards hydroxylation at positions 9 and 6 of the steroid molecule. 9α-hydroxyprogesterone exhibits pharmaceutical importance, because it is a useful intermediate in the production of physiologically active substances which possess progestational activity. Sixteen mutant proteins were selected from a library containing mutated proteins created by a combination of site-directed and saturation mutagenesis of active site residues. Four mutant proteins out of these catalyzed the conversion of progesterone to 9α-OH-progesterone as a main product. For further optimization site-directed mutagenesis was performed. The introduction of seven mutations (D217V, A243V, A106T, F165L, T89N, T247V or T247W) into these four mutant proteins led to 28 new variants, which were also used for an in vivo conversion of progesterone. The best mutant protein, F165L/A395E/G397V, showed a ten-fold increase in the selectivity towards progesterone 9α-hydroxylation compared with the wild type CYP106A2. Also 6ß-OH-progesterone is a pharmaceutically important compound, especially as intermediate for the production of drugs against breast cancer. For the rational design of mutant proteins with 6ß-selectivity, docking of the 3D-structure of CYP106A2 with progesterone was performed. The introduction of three mutations (T247A, A243S, F173A) led to seven new mutant proteins. Clone A243S showed the greatest improvement in 6ß-selectivity being more than ten-fold. Finally, an in vivo conversion of 11-deoxycorticosterone (DOC), testosterone and cortisol with the best five mutant proteins displaying 9α- or 6ß-hydroxylation, respectively, of progesterone was performed to investigate whether the introduced mutations also effected the conversion of other substrates.
[Mh] Termos MeSH primário: Proteínas de Bactérias/metabolismo
Sistema Enzimático do Citocromo P-450/metabolismo
[Mh] Termos MeSH secundário: Adrenodoxina/química
Adrenodoxina/metabolismo
Desoxicorticosterona/química
Desoxicorticosterona/metabolismo
Hidroxilação
Mutação
Progesterona/química
Progesterona/metabolismo
Estereoisomerismo
Esteroide Hidroxilases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); 12687-22-8 (Adrenodoxin); 40GP35YQ49 (Desoxycorticosterone); 4G7DS2Q64Y (Progesterone); 9035-51-2 (Cytochrome P-450 Enzyme System); EC 1.14.- (15beta-hydroxylase CYP106A2, Bacillus megaterium); EC 1.14.- (Steroid Hydroxylases); EC 1.14.99.- (steroid 9-alpha-hydroxylase)
[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:170207
[St] Status:MEDLINE



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