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[PMID]:29184919
[Au] Autor:Luo Z; Friscic T; Khaliullin RZ
[Ad] Endereço:Department of Chemistry, McGill University, 801 Sherbrooke St. West, Montreal, QC H3A 0B8, Canada. rustam@khaliullin.com.
[Ti] Título:Why pregnenolone and progesterone, two structurally similar steroids, exhibit remarkably different cocrystallization with aromatic molecules.
[So] Source:Phys Chem Chem Phys;20(2):898-904, 2018 Jan 03.
[Is] ISSN:1463-9084
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Selective binding of steroid molecules is of paramount importance for designing drugs that can target the biological pathways of only individual steroids. From this perspective, it is remarkable that progesterone (PRO) and pregnenolone (PRE), two structurally similar steroids, demonstrate a dramatically different propensity to interact with aromatic molecules. It has been recently reported that, in solid-state cocrystallization, PRO forms cocrystals with a wide variety of aromatic systems whereas PRE cocrystallizes only with a few. In this work, a simple yet effective computational procedure was developed to explain the fundamental origins of this surprising phenomenon. This procedure enables a direct comparison of the strength of intermolecular binding in the structurally similar cocrystals of PRO and PRE by generating experimentally inaccessible meta-stable cocrystals of PRE that closely resemble those observed for PRO. Direct comparative analysis shows that interactions between the α-face of the steroid and the π-electrons of aromatic molecules, the focus of previous studies, are not sufficiently different to explain the cocrystallization behavior of PRO and PRE. Instead, the observed difference is attributed to the different stabilities of the cocrystals relative to their pure components: organic and steroid crystals. It is calculated that the cocrystallization process is thermodynamically favorable in the case of PRO and unfavorable in the case of PRE. Furthermore, strong hydrogen bonds in the pure PRE crystal appear to be the major factor that makes the cocrystallization of PRE energetically unfavorable for a wide range of aromatic molecules. The fundamental analysis performed in this work has important practical implications for designing new steroid-containing crystals, selective biomolecular steroid receptors, and steroid-specific drugs. It suggests that a strategy for the selective binding of steroids should focus primarily on tuning the strength of hydrogen bonding.
[Mh] Termos MeSH primário: Ligações de Hidrogênio
Pregnenolona/química
Progesterona/química
[Mh] Termos MeSH secundário: Cristalização
Cristalografia
Desenho de Drogas
Elétrons
Termodinâmica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
4G7DS2Q64Y (Progesterone); 73R90F7MQ8 (Pregnenolone)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180209
[Lr] Data última revisão:
180209
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171130
[St] Status:MEDLINE
[do] DOI:10.1039/c7cp06828j


  2 / 3904 MEDLINE  
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[PMID]:28870733
[Au] Autor:Stenger B; Gerber A; Bernhardt R; Hannemann F
[Ad] Endereço:Institute of Biochemistry, Saarland University, Saarbrücken, Germany.
[Ti] Título:Functionalized poly(3-hydroxybutyric acid) bodies as new in vitro biocatalysts.
[So] Source:Biochim Biophys Acta;1866(1):52-59, 2018 01.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Cytochromes P450 play a key role in the drug and steroid metabolism in the human body. This leads to a high interest in this class of proteins. Mammalian cytochromes P450 are rather delicate. Due to their localization in the mitochondrial or microsomal membrane, they tend to aggregate during expression and purification and to convert to an inactive form so that they have to be purified and stored in complex buffers. The complex buffers and low storage temperatures, however, limit the feasibility of fast, automated screening of the corresponding cytochrome P450-effector interactions, which are necessary to study substrate-protein and inhibitor-protein interactions. Here, we present the production and isolation of functionalized poly(3-hydroxybutyrate) granules (PHB bodies) from Bacillus megaterium MS941 strain. In contrast to the expression in Escherichia coli, where mammalian cytochromes P450 are associated to the cell membrane, when CYP11A1 is heterologously expressed in Bacillus megaterium, it is located on the PHB bodies. The surface of these particles provides a matrix for immobilization and stabilization of the CYP11A1 during the storage of the protein and substrate conversion. It was demonstrated that the PHB polymer basis is inert concerning the performed conversion. Immobilization of the CYP11A1 onto the PHB bodies allows freeze-drying of the complex without significant decrease of the CYP11A1 activity. This is the first lyophilization of a mammalian cytochrome P450, which allows storage over more than 18days at 4°C instead of storage at -80°C. In addition, we were able to immobilize the cytochrome P450 on the PHB bodies in vitro. In this case the expression of the protein is separated from the production of the immobilization matrix, which widens the application of this method. This article is part of a Special Issue entitled: Cytochrome P450 biodiversity and biotechnology, edited by Erika Plettner, Gianfranco Gilardi, Luet Wong, Vlada Urlacher, Jared Goldstone.
[Mh] Termos MeSH primário: Ácido 3-Hidroxibutírico/química
Bacillus megaterium/genética
Biotecnologia/métodos
Enzima de Clivagem da Cadeia Lateral do Colesterol/química
Proteínas Imobilizadas/biossíntese
Proteínas Mitocondriais/biossíntese
[Mh] Termos MeSH secundário: Ácido 3-Hidroxibutírico/biossíntese
Animais
Bacillus megaterium/enzimologia
Biocatálise
Bovinos
Colesterol/química
Colesterol/metabolismo
Enzima de Clivagem da Cadeia Lateral do Colesterol/genética
Enzima de Clivagem da Cadeia Lateral do Colesterol/metabolismo
Grânulos Citoplasmáticos/química
Liofilização
Expressão Gênica
Proteínas Imobilizadas/química
Proteínas Imobilizadas/genética
Proteínas Mitocondriais/química
Proteínas Mitocondriais/genética
Pregnenolona/biossíntese
Pregnenolona/química
Refrigeração
Transgenes
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Immobilized Proteins); 0 (Mitochondrial Proteins); 73R90F7MQ8 (Pregnenolone); 97C5T2UQ7J (Cholesterol); EC 1.14.15.6 (Cholesterol Side-Chain Cleavage Enzyme); TZP1275679 (3-Hydroxybutyric Acid)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180208
[Lr] Data última revisão:
180208
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170906
[St] Status:MEDLINE


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[PMID]:28458115
[Au] Autor:Daftary S; Yon JM; Choi EK; Kim YB; Bice C; Kulikova A; Park J; Sherwood Brown E
[Ad] Endereço:Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
[Ti] Título:Microtubule associated protein 2 in bipolar depression: Impact of pregnenolone.
[So] Source:J Affect Disord;218:49-52, 2017 Aug 15.
[Is] ISSN:1573-2517
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Pregnenolone, and related neurosteroids, may have antidepressant properties. Preclinical research proposes that microtubule associated protein 2 (MAP2) binding may be a mechanism for antidepressant properties of pregnenolone. Thus, MAP2 might be a novel target for antidepressant therapy. This clinical study is the first to examine serum MAP2 levels in people with bipolar depression and controls, and whether pregnenolone treatment is associated with a change in MAP2 levels. METHODS: Blood samples from a previously published clinical trial of pregnenolone for adult bipolar depression were analyzed at baseline and week 6 of treatment with pregnenolone or placebo for serum MAP2 levels using Western Blot. MAP2 levels from healthy controls were also obtained. RESULTS: MAP2 levels in the bipolar depressed patients (n=11) tended to be higher than in controls (n=4) (p=0.062). MAP2 levels decreased non-significantly from baseline to week 6 in placebo (n=5) and pregnenolone-treated patients (n=6). MAP2 level changes correlated positively with change in self-reported depressive symptom scores in the pregnenolone group (r=0.771, p=0.072) but not in the placebo group (r=0.000, p=1.000). LIMITATIONS: This study, exploring relationships between MAP-2 in humans with mood disorders, is limited by the small sample size. Thus, the findings must be viewed with great caution. CONCLUSION: These findings suggest possible differences in serum MAP-2 levels between bipolar depressed persons and controls and a relationship between changes in depressive symptoms and MAP-2 levels during pregnenolone therapy. Findings suggest additional research is needed on MAP-2 in mood disorders.
[Mh] Termos MeSH primário: Antidepressivos/uso terapêutico
Transtorno Bipolar/sangue
Transtorno Bipolar/tratamento farmacológico
Proteínas Associadas aos Microtúbulos/sangue
Pregnenolona/uso terapêutico
[Mh] Termos MeSH secundário: Adulto
Western Blotting
Feminino
Seres Humanos
Masculino
Transtornos do Humor/tratamento farmacológico
[Pt] Tipo de publicação:JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Antidepressive Agents); 0 (MAP2 protein, human); 0 (Microtubule-Associated Proteins); 73R90F7MQ8 (Pregnenolone)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180115
[Lr] Data última revisão:
180115
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE


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[PMID]:28471529
[Au] Autor:Trivisano M; Lucchi C; Rustichelli C; Terracciano A; Cusmai R; Ubertini GM; Giannone G; Bertini ES; Vigevano F; Gecz J; Biagini G; Specchio N
[Ad] Endereço:Neurology Unit, Department of Neuroscience, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
[Ti] Título:Reduced steroidogenesis in patients with PCDH19-female limited epilepsy.
[So] Source:Epilepsia;58(6):e91-e95, 2017 06.
[Is] ISSN:1528-1167
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Patients affected by protocadherin 19 (PCDH19)-female limited epilepsy (PCDH19-FE) present a remarkable reduction in allopregnanolone blood levels. However, no information is available on other neuroactive steroids and the steroidogenic response to hormonal stimulation. For this reason, we evaluated allopregnanolone, pregnanolone, and pregnenolone sulfate by liquid chromatographic procedures coupled with electrospray tandem mass spectrometry in 12 unrelated patients and 15 age-matched controls. We also tested cortisol, estradiol, progesterone, and 17OH-progesterone using standard immunoassays. Apart from estradiol and progesterone, all the considered hormones were evaluated in basal condition and after stimulation with adrenocorticotropic hormone (ACTH). A generalized decrease in blood levels of almost all measured neuroactive steroids was found. When considering sexual development, cortisol and pregnenolone sulfate basal levels were significantly reduced in postpubertal girls affected by PCDH19-FE. Of interest, ACTH administration did not recover pregnenolone sulfate serum levels but restored cortisol to control levels. In prepubertal girls with PCDH19-FE, by challenging adrenal function with ACTH we disclosed defects in the production of cortisol, pregnenolone sulfate, and 17OH-progesterone, which were not apparent in basal condition. These findings point to multiple defects in peripheral steroidogenesis associated with and potentially relevant to PCDH19-FE. Some of these defects could be addressed by stimulating adrenocortical activity.
[Mh] Termos MeSH primário: Caderinas/genética
Epilepsia/sangue
Epilepsia/genética
Doenças Genéticas Ligadas ao Cromossomo X/sangue
Doenças Genéticas Ligadas ao Cromossomo X/genética
Hormônios Esteroides Gonadais/sangue
Deficiência Intelectual/sangue
Deficiência Intelectual/genética
Pregnanolona/sangue
Pregnanolona/deficiência
Pregnenolona/sangue
[Mh] Termos MeSH secundário: 17-alfa-Hidroxiprogesterona/sangue
Adolescente
Hormônio Adrenocorticotrópico/farmacologia
Síndrome Adrenogenital/sangue
Estudos de Casos e Controles
Criança
Pré-Escolar
Análise Mutacional de DNA
Estradiol/sangue
Feminino
Seres Humanos
Hidrocortisona/sangue
Progesterona/sangue
Estudos Prospectivos
Puberdade Precoce/sangue
Puberdade Precoce/genética
Valores de Referência
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cadherins); 0 (Gonadal Steroid Hormones); 0 (PCDH19 protein, human); 04Y4D91RG0 (pregnenolone sulfate); 4G7DS2Q64Y (Progesterone); 4TI98Z838E (Estradiol); 68-96-2 (17-alpha-Hydroxyprogesterone); 73R90F7MQ8 (Pregnenolone); 9002-60-2 (Adrenocorticotropic Hormone); BXO86P3XXW (Pregnanolone); WI4X0X7BPJ (Hydrocortisone)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:180107
[Lr] Data última revisão:
180107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1111/epi.13772


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[PMID]:28919340
[Au] Autor:Song JL; Zhang J; Liu CL; Liu C; Zhu KK; Yang FF; Liu XG; Figueiró Longo JP; Alexandre Muehlmann L; Azevedo RB; Zhang YY; Guo YW; Jiang CS; Zhang H
[Ad] Endereço:School of Biological Science and Technology, University of Jinan, Jinan 250022, China.
[Ti] Título:Design and synthesis of pregnenolone/2-cyanoacryloyl conjugates with dual NF-κB inhibitory and anti-proliferative activities.
[So] Source:Bioorg Med Chem Lett;27(20):4682-4686, 2017 10 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Twenty-five novel pregnenolone/2-cyanoacryloyl conjugates (6-30) were designed and prepared, with the aim of developing novel anticancer drugs with dual NF-κB inhibitory and anti-proliferative activities. Compounds 22 and 27-30 showed inhibition against TNF-α-induced NF-κB activation in luciferase assay, which was confirmed by Western blotting. Among them, compound 30 showed potent NF-κB inhibitory activity (IC =2.5µM) and anti-proliferative against MCF-7, A549, H157, and HL-60 cell lines (IC =6.5-36.2µM). The present study indicated that pregnenolone/2-cyanoacryloyl conjugate I can server asa novel scaffold for developing NF-κB inhibitors and anti-proliferative agents in cancer chemotherapy.
[Mh] Termos MeSH primário: Antineoplásicos/síntese química
Cianoacrilatos/química
Desenho de Drogas
NF-kappa B/metabolismo
Pregnenolona/química
[Mh] Termos MeSH secundário: Células A549
Antineoplásicos/farmacologia
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Ensaios de Seleção de Medicamentos Antitumorais
Células HL-60
Seres Humanos
Células MCF-7
NF-kappa B/antagonistas & inibidores
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Cyanoacrylates); 0 (NF-kappa B); 73R90F7MQ8 (Pregnenolone)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170919
[St] Status:MEDLINE


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[PMID]:28720298
[Au] Autor:Dembek KA; Timko KJ; Johnson LM; Hart KA; Barr BS; David B; Burns TA; Toribio RE
[Ad] Endereço:College of Veterinary Medicine, The Ohio State University, 601 Vernon Tharp St., Columbus, OH 43210, USA.
[Ti] Título:Steroids, steroid precursors, and neuroactive steroids in critically ill equine neonates.
[So] Source:Vet J;225:42-49, 2017 Jul.
[Is] ISSN:1532-2971
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Hypothalamic-pituitary-adrenal axis (HPAA) dysfunction has been associated with sepsis and mortality in foals. Most studies have focused on cortisol, while other steroids have not been investigated. The objectives of this study were to characterise the adrenal steroid and steroid precursor response to disease and to determine their association with the HPAA response to illness, disease severity, and mortality in hospitalised foals. All foals (n=326) were classified by two scoring systems into three categories: based on the sepsis score (septic, sick non-septic [SNS] and healthy) and the foal survival score (Group 1: 3-18%; Group 2: 38-62%; Group 3: 82-97% likelihood of survival). Blood concentrations of adrenocorticotropic hormone (ACTH) and steroids were determined by immunoassays. ACTH-cortisol imbalance (ACI) was defined as a high ACTH/cortisol ratio. Septic foals had higher ACTH, cortisol, progesterone, 17α-OH-progesterone, pregnenolone, and androstenedione concentrations as well as higher ACTH/cortisol, ACTH/progesterone, ACTH/aldosterone, and ACTH/DHEAS ratios than SNS and healthy foals (P<0.01). Foals with DHEAS of 0.4-5.4ng/mL were more likely to have ACI (OR=2.5). Foals in Group 1 had higher ACTH, aldosterone, progesterone, and cortisol concentrations as well as ACTH/cortisol, ACTH/progesterone, and ACTH/DHEAS ratios than foals in Groups 2 and 3 (P<0.01). High progesterone concentrations were associated with non-survival and the cutoff value below which survival could be predicted was 23.5ng/mL, with 75% sensitivity and 72% specificity. In addition to cortisol, the response to the stress of illness in foals is characterised by the release of multiple adrenal steroids. DHEAS and progesterone were good predictors of HPAA dysfunction and outcome in hospitalised foals.
[Mh] Termos MeSH primário: Animais Recém-Nascidos/sangue
Doenças dos Cavalos/sangue
Doenças Hipotalâmicas/veterinária
Sistema Hipotálamo-Hipofisário/fisiopatologia
Sistema Hipófise-Suprarrenal/fisiopatologia
Esteroides/sangue
[Mh] Termos MeSH secundário: Hormônio Adrenocorticotrópico/sangue
Androstenodiona/sangue
Animais
Estado Terminal
Doenças dos Cavalos/mortalidade
Cavalos
Hidrocortisona/sangue
Doenças Hipotalâmicas/sangue
Pregnenolona/sangue
Progesterona/sangue
Prognóstico
Sepse/veterinária
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Steroids); 409J2J96VR (Androstenedione); 4G7DS2Q64Y (Progesterone); 73R90F7MQ8 (Pregnenolone); 9002-60-2 (Adrenocorticotropic Hormone); WI4X0X7BPJ (Hydrocortisone)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171026
[Lr] Data última revisão:
171026
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170720
[St] Status:MEDLINE


  7 / 3904 MEDLINE  
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[PMID]:28684414
[Au] Autor:Gonzalez E; Guengerich FP
[Ad] Endereço:From the Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146.
[Ti] Título:Kinetic processivity of the two-step oxidations of progesterone and pregnenolone to androgens by human cytochrome P450 17A1.
[So] Source:J Biol Chem;292(32):13168-13185, 2017 Aug 11.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cytochrome P450 (P450, CYP) 17A1 plays a critical role in steroid metabolism, catalyzing both the 17α-hydroxylation of pregnenolone and progesterone and the subsequent 17α,20-lyase reactions to form dehydroepiandrosterone (DHEA) and androstenedione (Andro), respectively, critical for generating glucocorticoids and androgens. Human P450 17A1 reaction rates examined are enhanced by the accessory protein cytochrome ( ), but the exact role of in P450 17A1-catalyzed reactions is unclear as are several details of these reactions. Here, we examined in detail the processivity of the 17α-hydroxylation and lyase steps. did not enhance reaction rates by decreasing the rates of any of the steroids. Steroid binding to P450 17A1 was more complex than a simple two-state system. Pre-steady-state experiments indicated lag phases for Andro production from progesterone and for DHEA from pregnenolone, indicating a distributive character of the enzyme. However, we observed processivity in pregnenolone/DHEA pulse-chase experiments. ( )-Orteronel was three times more inhibitory toward the conversion of 17α-hydroxypregnenolone to DHEA than toward the 17α-hydroxylation of pregnenolone. IC values for ( )-orteronel were identical for blocking DHEA formation from pregnenolone and for 17α-hydroxylation, suggestive of processivity. Global kinetic modeling helped assign sets of rate constants for individual or groups of reactions, indicating that human P450 17A1 is an inherently distributive enzyme but that some processivity is present, some of the 17α-OH pregnenolone formed from pregnenolone did not dissociate from P450 17A1 before conversion to DHEA. Our results also suggest multiple conformations of P450 17A1, as previously proposed on the basis of NMR spectroscopy and X-ray crystallography.
[Mh] Termos MeSH primário: 17-alfa-Hidroxipregnenolona/metabolismo
Citocromos b5/metabolismo
Desidroepiandrosterona/metabolismo
Modelos Moleculares
NADPH-Ferri-Hemoproteína Redutase/metabolismo
Pregnenolona/metabolismo
Esteroide 17-alfa-Hidroxilase/metabolismo
[Mh] Termos MeSH secundário: 17-alfa-Hidroxipregnenolona/química
Androstenodiona/química
Androstenodiona/metabolismo
Animais
Sítios de Ligação
Biocatálise/efeitos dos fármacos
Inibidores das Enzimas do Citocromo P-450/química
Inibidores das Enzimas do Citocromo P-450/metabolismo
Inibidores das Enzimas do Citocromo P-450/farmacologia
Citocromos b5/genética
Desidroepiandrosterona/química
Seres Humanos
Imidazóis/química
Imidazóis/metabolismo
Imidazóis/farmacologia
Cinética
Ligantes
NADPH-Ferri-Hemoproteína Redutase/genética
Naftalenos/química
Naftalenos/metabolismo
Naftalenos/farmacologia
Oxirredução
Pregnenolona/química
Progesterona/química
Progesterona/metabolismo
Conformação Proteica
Ratos
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Estereoisomerismo
Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores
Esteroide 17-alfa-Hidroxilase/química
Esteroide 17-alfa-Hidroxilase/genética
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CYB5A protein, human); 0 (Cytochrome P-450 Enzyme Inhibitors); 0 (Imidazoles); 0 (Ligands); 0 (Naphthalenes); 0 (Recombinant Proteins); 387-79-1 (17-alpha-Hydroxypregnenolone); 409J2J96VR (Androstenedione); 459AG36T1B (Dehydroepiandrosterone); 4G7DS2Q64Y (Progesterone); 73R90F7MQ8 (Pregnenolone); 9035-39-6 (Cytochromes b5); EC 1.14.14.19 (CYP17A1 protein, human); EC 1.14.14.19 (Steroid 17-alpha-Hydroxylase); EC 1.6.2.4 (NADPH-Ferrihemoprotein Reductase); UE5K2FNS92 (orteronel)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171119
[Lr] Data última revisão:
171119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170708
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.794917


  8 / 3904 MEDLINE  
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[PMID]:28665486
[Au] Autor:Qaiser MZ; Dolman DEM; Begley DJ; Abbott NJ; Cazacu-Davidescu M; Corol DI; Fry JP
[Ad] Endereço:Blood-Brain Barrier Research Group, Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, London, UK.
[Ti] Título:Uptake and metabolism of sulphated steroids by the blood-brain barrier in the adult male rat.
[So] Source:J Neurochem;142(5):672-685, 2017 Sep.
[Is] ISSN:1471-4159
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Little is known about the origin of the neuroactive steroids dehydroepiandrosterone sulphate (DHEAS) and pregnenolone sulphate (PregS) in the brain or of their subsequent metabolism. Using rat brain perfusion in situ, we have found H-PregS to enter more rapidly than H-DHEAS and both to undergo extensive (> 50%) desulphation within 0.5 min of uptake. Enzyme activity for the steroid sulphatase catalysing this deconjugation was enriched in the capillary fraction of the blood-brain barrier and its mRNA expressed in cultures of rat brain endothelial cells and astrocytes. Although permeability measurements suggested a net efflux, addition of the efflux inhibitors GF120918 and/or MK571 to the perfusate reduced rather than enhanced the uptake of H-DHEAS and H-PregS; a further reduction was seen upon the addition of unlabelled steroid sulphate, suggesting a saturable uptake transporter. Analysis of brain fractions after 0.5 min perfusion with the H-steroid sulphates showed no further metabolism of PregS beyond the liberation of free steroid pregnenolone. By contrast, DHEAS underwent 17-hydroxylation to form androstenediol in both the steroid sulphate and the free steroid fractions, with some additional formation of androstenedione in the latter. Our results indicate a gain of free steroid from circulating steroid sulphates as hormone precursors at the blood-brain barrier, with implications for ageing, neurogenesis, neuronal survival, learning and memory.
[Mh] Termos MeSH primário: Barreira Hematoencefálica/metabolismo
Encéfalo/metabolismo
Permeabilidade Capilar/fisiologia
Sulfato de Desidroepiandrosterona/metabolismo
Pregnenolona/metabolismo
[Mh] Termos MeSH secundário: Animais
Transporte Biológico/efeitos dos fármacos
Transporte Biológico/fisiologia
Barreira Hematoencefálica/efeitos dos fármacos
Encéfalo/irrigação sanguínea
Encéfalo/efeitos dos fármacos
Permeabilidade Capilar/efeitos dos fármacos
Masculino
Propionatos/farmacologia
Quinolinas/farmacologia
Ratos
Ratos Wistar
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Propionates); 0 (Quinolines); 04Y4D91RG0 (pregnenolone sulfate); 57B09Q7FJR (Dehydroepiandrosterone Sulfate); 5Q9O54P0H7 (verlukast); 73R90F7MQ8 (Pregnenolone)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171005
[Lr] Data última revisão:
171005
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170701
[St] Status:MEDLINE
[do] DOI:10.1111/jnc.14117


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[PMID]:28648378
[Au] Autor:Alyamani M; Li Z; Berk M; Li J; Tang J; Upadhyay S; Auchus RJ; Sharifi N
[Ad] Endereço:Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Chemistry, Cleveland State University, Cleveland, OH 44115, USA.
[Ti] Título:Steroidogenic Metabolism of Galeterone Reveals a Diversity of Biochemical Activities.
[So] Source:Cell Chem Biol;24(7):825-832.e6, 2017 Jul 20.
[Is] ISSN:2451-9456
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Galeterone is a steroidal CYP17A1 inhibitor, androgen receptor (AR) antagonist, and AR degrader, under evaluation in a phase III clinical trial for castration-resistant prostate cancer (CRPC). The A/B steroid ring (Δ ,3ß-hydroxyl) structure of galeterone is identical to that of cholesterol, which makes endogenous steroids with the same structure (e.g., dehydroepiandrosterone and pregnenolone) substrates for the enzyme 3ß-hydroxysteroid dehydrogenase (3ßHSD). We found that galeterone is metabolized by 3ßHSD to Δ -galeterone (D4G), which is further converted by steroid-5α-reductase (SRD5A) to 3-keto-5α-galeterone (5αG), 3α-OH-5α-galeterone, and 3ß-OH-5α-galeterone; in vivo it is also converted to the three corresponding 5ß-reduced metabolites. D4G inhibits steroidogenesis and suppresses AR protein stability, AR target gene expression, and xenograft growth comparably with galeterone, and further conversion by SRD5A leads to loss of several activities that inhibit the androgen axis that may compromise clinical efficacy. Together, these findings define a critical metabolic class effect of steroidal drugs with a Δ ,3ß-hydroxyl structure.
[Mh] Termos MeSH primário: Androstadienos/metabolismo
Benzimidazóis/metabolismo
[Mh] Termos MeSH secundário: 17-Hidroxiesteroide Desidrogenases/genética
17-Hidroxiesteroide Desidrogenases/metabolismo
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/metabolismo
Androstadienos/análise
Androstadienos/uso terapêutico
Animais
Benzimidazóis/análise
Benzimidazóis/uso terapêutico
Linhagem Celular Tumoral
Cromatografia Líquida de Alta Pressão
Células HEK293
Seres Humanos
Hidroxiesteroide Desidrogenases/genética
Hidroxiesteroide Desidrogenases/metabolismo
Estimativa de Kaplan-Meier
Masculino
Camundongos
Pregnenolona/farmacologia
Neoplasias da Próstata/tratamento farmacológico
Neoplasias da Próstata/mortalidade
Neoplasias da Próstata/patologia
Receptores Androgênicos/genética
Receptores Androgênicos/metabolismo
Transdução de Sinais/efeitos dos fármacos
Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores
Esteroide 17-alfa-Hidroxilase/metabolismo
Espectrometria de Massas em Tandem
Transplante Heterólogo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Androstadienes); 0 (Benzimidazoles); 0 (Receptors, Androgen); 73R90F7MQ8 (Pregnenolone); EC 1.1.- (17-Hydroxysteroid Dehydrogenases); EC 1.1.- (Hydroxysteroid Dehydrogenases); EC 1.1.1.357 (AKR1C2 protein, human); EC 1.1.1.51 (3 (or 17)-beta-hydroxysteroid dehydrogenase); EC 1.14.14.19 (CYP17A1 protein, human); EC 1.14.14.19 (Steroid 17-alpha-Hydroxylase); EC 1.3.99.5 (3-Oxo-5-alpha-Steroid 4-Dehydrogenase); WA33E149SW (3-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene)
[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:170627
[St] Status:MEDLINE


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[PMID]:28472487
[Au] Autor:Turcu AF; Mallappa A; Elman MS; Avila NA; Marko J; Rao H; Tsodikov A; Auchus RJ; Merke DP
[Ad] Endereço:Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan 48109.
[Ti] Título:11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency.
[So] Source:J Clin Endocrinol Metab;102(8):2701-2710, 2017 Aug 01.
[Is] ISSN:1945-7197
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Context: Patients with 21-hydroxylase deficiency (21OHD) have long-term complications, resulting from poor disease control and/or glucocorticoid overtreatment. Lack of optimal biomarkers has made it challenging to tailor therapy and predict long-term outcomes. Objective: To identify biomarkers of disease control and long-term complications in 21OHD. Setting and Participants: Cross-sectional study of 114 patients (70 males), ages 2 to 67 years (median, 15 years), seen in a tertiary referral center. Methods: We correlated a mass-spectrometry panel of 23 steroids, obtained before first morning medication, with bone age advancement (children), adrenal volume (adults), testicular adrenal rest tumors (TART), hirsutism, menstrual disorders, and pituitary hormones. Results: Total adrenal volume correlated positively with 18 steroids, most prominently 21-deoxycortisol and four 11-oxygenated-C19 (11oxC19) steroids: 11ß-hydroxyandrostenedione (11OHA4), 11-ketoandrostenedione (11ketoA4), 11ß-hydroxytestosterone (11OHT), and 11-ketotestosterone (11ketoT) (r ≈ 0.7, P < 0.0001). Nine steroids were significantly higher (P ≤ 0.01) in males with TART compared with those without TART, including 11OHA4 (6.8-fold), 11OHT (4.9-fold), 11ketoT (3.6-fold), 11ketoA4 (3.3-fold), and pregnenolone sulfate (PregS; 4.8-fold). PregS (28.5-fold) and 17-hydroxypregnenolone sulfate (19-fold) levels were higher (P < 0.01) in postpubertal females with menstrual disorders. In males, testosterone levels correlated positively with all 11oxC19 steroids in Tanner stages 1 and 2 (r ≈ 0.7; P < 0.001) but negatively in Tanner stage 5 (r = -0.3 and P < 0.05 for 11ketoA4 and 11ketoT). In females, testosterone level correlated positively with all four 11oxC19 steroids across all Tanner stages (r ≈ 0.8; P < 0.0001). Conclusion: 11oxC19 steroids and PregS might serve as clinically useful biomarkers of disease control and long-term complications in 21OHD.
[Mh] Termos MeSH primário: Hiperplasia Suprarrenal Congênita/metabolismo
Tumor de Resto Suprarrenal/metabolismo
Androgênios/metabolismo
Hirsutismo/metabolismo
Distúrbios Menstruais/metabolismo
Neoplasias Testiculares/metabolismo
[Mh] Termos MeSH secundário: 17-alfa-Hidroxipregnenolona/análogos & derivados
17-alfa-Hidroxipregnenolona/metabolismo
Adolescente
Glândulas Suprarrenais/patologia
Adulto
Determinação da Idade pelo Esqueleto
Idoso
Androstenodiona/análogos & derivados
Androstenodiona/metabolismo
Androstenos/metabolismo
Criança
Pré-Escolar
Cortodoxona/metabolismo
Estudos Transversais
Feminino
Seres Humanos
Hidroxitestosteronas/metabolismo
Masculino
Meia-Idade
Tamanho do Órgão
Pregnenolona/metabolismo
Testosterona/análogos & derivados
Testosterona/metabolismo
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Androgens); 0 (Androstenes); 0 (Hydroxytestosterones); 04Y4D91RG0 (pregnenolone sulfate); 1816-85-9 (11-hydroxytestosterone); 28901-70-4 (17-hydroxypregnenolone sulfate); 387-79-1 (17-alpha-Hydroxypregnenolone); 3XMK78S47O (Testosterone); 409J2J96VR (Androstenedione); 564-32-9 (11-hydroxyandrostenedione); 641-77-0 (21-deoxycortisol); 73R90F7MQ8 (Pregnenolone); AE4E9102GY (adrenosterone); KF38W1A85U (11-ketotestosterone); WDT5SLP0HQ (Cortodoxone)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170920
[Lr] Data última revisão:
170920
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1210/jc.2016-3989



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