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[PMID]: 28461575 [Au] Autor: Phuc NM; Wu Z; O Y; Lee JH; Oh S; Song GY; Liu KH [Ad] Endereço: BK21 Plus KNU Multi-Omics-Based Creative Drug Research Team, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Korea (N.M.P., Z.W., K.-H.L.); College of Pharmacy, Chungnam National University, Daejeon, Korea (Y.O., J.-H.L., G.-Y.S.); and Dep [Ti] Título: LKY-047: First Selective Inhibitor of Cytochrome P450 2J2. [So] Source: Drug Metab Dispos;45(7):765-769, 2017 Jul. [Is] ISSN: 1521-009X [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Highly selective cytochrome P450 CYP2J2 (CYP2J2) inhibitors suitable for reaction phenotyping are currently not available. (7 )-(+)-(4-Nitro-phenyl)-acrylic acid, 8,8-dimethyl-2-oxo-6,7-dihydro- -pyrano[3,2-g]chromen-7-yl-ester (LKY-047), a decursin derivative, was synthesized, and its inhibitor potencies toward CYP2J2 as well as other cytochrome P450 (P450) enzymes in human liver microsomes (HLM) were evaluated. LKY-047 was demonstrated to be a strong competitive inhibitor of CYP2J2-mediated astemizole -demethylase and terfenadine hydroxylase activity, with values of 0.96 and 2.61 M, respectively. It also acted as an uncompetitive inhibitor of CYP2J2-mediated ebastine hydroxylation with a value of 3.61 M. Preincubation of LKY-047 with HLMs and NADPH did not alter inhibition potency, indicating that it is not a mechanism-based inhibitor. LKY-047 was found to be a selective CYP2J2 inhibitor with no inhibitory effect on other human P450s, such as CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A (IC > 50 M). These in vitro data support the use of LKY-047 as a selective CYP2J2 inhibitor with potential application in the identification of P450 isoforms responsible for drug metabolism in reaction phenotyping assays. [Mh] Termos MeSH primário: Inibidores das Enzimas do Citocromo P-450/farmacologia Sistema Enzimático do Citocromo P-450/metabolismo [Mh] Termos MeSH secundário: Seres Humanos Hidroxilação/efeitos dos fármacos Inativação Metabólica/efeitos dos fármacos Microssomos Hepáticos/efeitos dos fármacos Microssomos Hepáticos/metabolismo NADP/metabolismo Isoformas de Proteínas/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Cytochrome P-450 Enzyme Inhibitors); 0 (Protein Isoforms); 53-59-8 (NADP); 9035-51-2 (Cytochrome P-450 Enzyme System); EC 1.14.14.1 (arachidonate epoxygenase) [Em] Mês de entrada: 1803 [Cu] Atualização por classe: 180307 [Lr] Data última revisão: 180307 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170503 [St] Status: MEDLINE [do] DOI: 10.1124/dmd.117.075036

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[PMID]: 29331654 [Au] Autor: Xu Y; Mao X; Qin B; Peng Y; Zheng J [Ad] Endereço: Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China. [Ti] Título: In vitro and in vivo metabolic activation of rhein and characterization of glutathione conjugates derived from rhein. [So] Source: Chem Biol Interact;283:1-9, 2018 Mar 01. [Is] ISSN: 1872-7786 [Cp] País de publicação: Ireland [La] Idioma: eng [Ab] Resumo: Rhein (RH), 4,5-dihydroxyanthrauinone-2-carboxylic acid, is found in rhubarb (Dahuang), a traditional herbal medicine. RH has reportedly demonstrated multiple pharmacologic properties. Previous studies have also shown that RH induced hepatotoxicity, but the mechanisms of the adverse effect remain unknown. The major objective of the present study was to study the metabolic pathways of RH in order to identify potential reactive metabolites. One mono-hydroxylation metabolite (M1) was detected in urine and bile of rats given RH. M1 was also observed in rat and human liver microsomal incubations after exposure to RH. A total of three (GSH) conjugates (M2, M3 and M5) were detected in bile of rats treated with RH. We concluded that M2-M3 were directly derived from parent compound RH through spontaneous reaction with GSH. M5 was derived from M1 by reaction with GSH, which required cytoslic GSTs. M5 was further metabolized to the corresponding NAC conjugate (mercapturic acid) and was excreted in urine. P450 2C9 was mainly involved in the oxidation of RH. [Mh] Termos MeSH primário: Antraquinonas/metabolismo Glutationa/química [Mh] Termos MeSH secundário: Acetilcisteína/química Animais Antraquinonas/química Antraquinonas/farmacologia Antraquinonas/urina Bile/química Bile/efeitos dos fármacos Bile/metabolismo Cromatografia Líquida de Alta Pressão Sistema Enzimático do Citocromo P-450/genética Sistema Enzimático do Citocromo P-450/metabolismo Seres Humanos Masculino Microssomos Hepáticos/efeitos dos fármacos Microssomos Hepáticos/metabolismo Ratos Ratos Sprague-Dawley Proteínas Recombinantes/biossíntese Proteínas Recombinantes/genética Espectrometria de Massas em Tandem [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Anthraquinones); 0 (Recombinant Proteins); 9035-51-2 (Cytochrome P-450 Enzyme System); GAN16C9B8O (Glutathione); WYQ7N0BPYC (Acetylcysteine); YM64C2P6UX (rhein) [Em] Mês de entrada: 1803 [Cu] Atualização por classe: 180305 [Lr] Data última revisão: 180305 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180115 [St] Status: MEDLINE

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[PMID]: 29247934 [Au] Autor: Tang G; Yao J; Zhang X; Lu N; Zhu KY [Ad] Endereço: College of Forestry, Northwest A&F University, Yangling, Shaanxi, 712100, China; Department of Entomology, Kansas State University, Manhattan, KS 66506, USA. [Ti] Título: Comparison of gene expression profiles in the aquatic midge (Chironomus tentans) larvae exposed to two major agricultural pesticides. [So] Source: Chemosphere;194:745-754, 2018 Mar. [Is] ISSN: 1879-1298 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: We developed a high-resolution expression microarray based on 2456 unique transcripts from a cDNA library of the aquatic midge (Chironomus tentans). By using the microarray, we detected that 146, 434 and 243 genes were differentially expressed after C. tentans larvae were exposed to chlorpyrifos (organophosphate insecticide) at 0.1 and 0.5 µg/L, and atrazine (triazine herbicide) at 1000 µg/L, respectively, for 48 h. The number of differentially expressed genes in the larvae exposed to chlorpyrifos at 0.5 µg/L was three times of that in the larvae exposed to chlorpyrifos at 0.1 µg/L. Among the differentially expressed genes in response to chlorpyrifos exposures, 76 genes showed significant Blast hits, and among them 42 were in common between the chlorpyrifos and atrazine exposures. In 19 differentially expressed xenobiotic detoxification genes, 16 were significantly up-regulated in the larvae exposed to chlorpyrifos and/or atrazine. Two cytochrome P450 genes (CtCYP6EV1 and CtCYP4DG2) were specifically up-regulated by chlorpyrifos, whereas three cytochrome P450 genes (CtCYP4DG1, CtCYP6EX3 and CtCYP6EV3) were specifically up-regulated by atrazine. Our results showed that chlorpyrifos exposures even at low concentrations can lead to significant changes in gene expression. The significant transcriptional responses are likely attributed to larval intoxication by the insecticide. These results not only support our previous studies in which candidate gene approaches were used, but also can potentially help develop specific molecular markers for monitoring pesticide exposures in non-target organisms in aquatic systems. [Mh] Termos MeSH primário: Chironomidae/genética Larva/genética Praguicidas/farmacologia Transcriptoma/efeitos dos fármacos [Mh] Termos MeSH secundário: Animais Atrazina/farmacologia Clorpirifos/farmacologia Sistema Enzimático do Citocromo P-450/efeitos dos fármacos Sistema Enzimático do Citocromo P-450/genética Herbicidas/metabolismo Inseticidas/metabolismo Larva/efeitos dos fármacos Larva/metabolismo Praguicidas/metabolismo Regulação para Cima/efeitos dos fármacos Poluentes Químicos da Água/farmacologia [Pt] Tipo de publicação: COMPARATIVE STUDY; JOURNAL ARTICLE [Nm] Nome de substância: 0 (Herbicides); 0 (Insecticides); 0 (Pesticides); 0 (Water Pollutants, Chemical); 9035-51-2 (Cytochrome P-450 Enzyme System); JCS58I644W (Chlorpyrifos); QJA9M5H4IM (Atrazine) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180228 [Lr] Data última revisão: 180228 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171217 [St] Status: MEDLINE

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[PMID]: 29360842 [Au] Autor: Liu F; Yang Y; Gao J; Ma C; Bi Y [Ad] Endereço: College of Life Science, Shandong Normal University, Jinan, China. [Ti] Título: A comparative transcriptome analysis of a wild purple potato and its red mutant provides insight into the mechanism of anthocyanin transformation. [So] Source: PLoS One;13(1):e0191406, 2018. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: In this study, a red mutant was obtained through in vitro regeneration of a wild purple potato. High-performance liquid chromatography and Mass spectrometry analysis revealed that pelargonidin-3-O-glucoside and petunidin-3-O-glucoside were main anthocyanins in the mutant and wild type tubers, respectively. In order to thoroughly understand the mechanism of anthocyanin transformation in two materials, a comparative transcriptome analysis of the mutant and wild type was carried out through high-throughput RNA sequencing, and 295 differentially expressed genes (DEGs) were obtained. Real-time qRT-PCR validation of DEGs was consistent with the transcriptome date. The DEGs mainly influenced biological and metabolic pathways, including phenylpropanoid biosynthesis and translation, and biosynthesis of flavone and flavonol. In anthocyanin biosynthetic pathway, the analysis of structural genes expressions showed that three genes, one encoding phenylalanine ammonia-lyase, one encoding 4-coumarate-CoA ligase and one encoding flavonoid 3',5'-hydroxylasem were significantly down-regulated in the mutant; one gene encoding phenylalanine ammonia-lyase was significantly up-regulated. Moreover, the transcription factors, such as bZIP family, MYB family, LOB family, MADS family, zf-HD family and C2H2 family, were significantly regulated in anthocyanin transformation. Response proteins of hormone, such as gibberellin, abscisic acid and brassinosteroid, were also significantly regulated in anthocyanin transformation. The information contributes to discovering the candidate genes in anthocyanin transformation, which can serve as a comprehensive resource for molecular mechanism research of anthocyanin transformation in potatoes. [Mh] Termos MeSH primário: Antocianinas/biossíntese Antocianinas/genética Solanum tuberosum/genética Solanum tuberosum/metabolismo [Mh] Termos MeSH secundário: Vias Biossintéticas/genética Coenzima A Ligases/genética Sistema Enzimático do Citocromo P-450/genética Perfilação da Expressão Gênica Regulação da Expressão Gênica de Plantas Genes de Plantas Glucosídeos/biossíntese Glucosídeos/genética Sequenciamento de Nucleotídeos em Larga Escala Mutação Fenilalanina Amônia-Liase/genética Pigmentação/genética Reguladores de Crescimento de Planta/genética Proteínas de Plantas/genética Tubérculos/genética Tubérculos/metabolismo RNA de Plantas/genética Fatores de Transcrição/genética [Pt] Tipo de publicação: COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Anthocyanins); 0 (Glucosides); 0 (Plant Growth Regulators); 0 (Plant Proteins); 0 (RNA, Plant); 0 (Transcription Factors); 6988-81-4 (petunidin-3-glucoside); 8H1WZY9R6P (pelargonidin-3-glucoside); 9035-51-2 (Cytochrome P-450 Enzyme System); EC 1.14.- (flavonoid 3',5'-hydroxylase); EC 4.3.1.24 (Phenylalanine Ammonia-Lyase); EC 6.2.1.- (Coenzyme A Ligases); EC 6.2.1.12 (4-coumarate-CoA ligase) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180227 [Lr] Data última revisão: 180227 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180124 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0191406

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[PMID]: 28451639 [Au] Autor: Kanda H; Kobayashi K; Yamanaka H; Okubo M; Noguchi K [Ad] Endereço: Department of Anatomy and Neuroscience, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan. [Ti] Título: Microglial TNFα Induces COX2 and PGI2 Synthase Expression in Spinal Endothelial Cells during Neuropathic Pain. [So] Source: eNeuro;4(2), 2017 Mar-Apr. [Is] ISSN: 2373-2822 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Prostaglandins (PGs) are typical lipid mediators that play a role in homeostasis and disease. They are synthesized from arachidonic acid by cyclooxygenase 1 (COX1) and COX2. Although COX2 has been reported to be upregulated in the spinal cord after nerve injury, its expression and functional roles in neuropathic pain remain unclear. In this study, we investigated the expression of Cox2, PGI2 synthase (Pgis), and prostaglandin I2 receptor (IP receptor) mRNA in the rat spinal cord after spared nerve injury (SNI). Levels of Cox2 and Pgis mRNA increased in endothelial cells from 24 to 48 h after nerve injury. IP receptor mRNA was constitutively expressed in dorsal horn neurons. A COX2 inhibitor and IP receptor antagonists attenuated pain behavior in the early phase of neuropathic pain. Furthermore, we examined the relationship between COX2 and tumor necrosis factor-α (TNFα) in the spinal cord of a rat SNI model. Levels of TNFα mRNA transiently increased in the spinal microglia 24 h after SNI. The TNF receptors Tnfr1 and Tnfr2 mRNA were colocalized with COX2. Intrathecal injection of TNFα induced Cox2 and Pgis mRNA expression in endothelial cells. These results revealed that microglia-derived TNFα induced COX2 and PGIS expression in spinal endothelial cells and that endothelial PGI2 played a critical role in neuropathic pain via neuronal IP receptor. These findings further suggest that the glia-endothelial cell interaction of the neurovascular unit via transient TNFα is involved in the generation of neuropathic pain. [Mh] Termos MeSH primário: Ciclo-Oxigenase 2/metabolismo Sistema Enzimático do Citocromo P-450/metabolismo Células Endoteliais/enzimologia Oxirredutases Intramoleculares/metabolismo Microglia/metabolismo Neuralgia/metabolismo Medula Espinal/metabolismo Fator de Necrose Tumoral alfa/metabolismo [Mh] Termos MeSH secundário: Animais Inflamação/enzimologia Masculino Traumatismos dos Nervos Periféricos/metabolismo RNA Mensageiro Ratos Sprague-Dawley [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (RNA, Messenger); 0 (Tumor Necrosis Factor-alpha); 9035-51-2 (Cytochrome P-450 Enzyme System); EC 1.14.99.1 (Cyclooxygenase 2); EC 1.14.99.1 (Ptgs2 protein, rat); EC 5.3.- (Intramolecular Oxidoreductases); EC 5.3.99.4 (prostacyclin synthetase) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180228 [Lr] Data última revisão: 180228 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170429 [St] Status: MEDLINE

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[PMID]: 29329342 [Au] Autor: Ahmad M; Suhaimi SN; Chu TL; Abdul Aziz N; Mohd Kornain NK; Samiulla DS; Lo KW; Ng CH; Khoo AS [Ad] Endereço: Molecular Pathology Unit, Cancer Research Centre, Institute for Medical Research, Kuala Lumpur, Malaysia. [Ti] Título: Ternary copper(II) complex: NCI60 screening, toxicity studies, and evaluation of efficacy in xenograft models of nasopharyngeal carcinoma. [So] Source: PLoS One;13(1):e0191295, 2018. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Copper(II) ternary complex, [Cu(phen)(C-dmg)(H2O)]NO3 was evaluated against a panel of cell lines, tested for in vivo efficacy in nasopharyngeal carcinoma xenograft models as well as for toxicity in NOD scid gamma mice. The Cu(II) complex displayed broad spectrum cytotoxicity against multiple cancer types, including lung, colon, central nervous system, melanoma, ovarian, and prostate cancer cell lines in the NCI-60 panel. The Cu(II) complex did not cause significant induction of cytochrome P450 (CYP) 3A and 1A enzymes but moderately inhibited CYP isoforms 1A2, 2C9, 2C19, 2D6, 2B6, 2C8 and 3A4. The complex significantly inhibited tumor growth in nasopharyngeal carcinoma xenograft bearing mice models at doses which were well tolerated without causing significant or permanent toxic side effects. However, higher doses which resulted in better inhibition of tumor growth also resulted in toxicity. [Mh] Termos MeSH primário: Antineoplásicos/química Antineoplásicos/farmacologia Carcinoma/tratamento farmacológico Cobre/química Neoplasias Nasofaríngeas/tratamento farmacológico Compostos Organometálicos/química Compostos Organometálicos/farmacologia Ensaios Antitumorais Modelo de Xenoenxerto [Mh] Termos MeSH secundário: Animais Antineoplásicos/toxicidade Carcinoma/patologia Linhagem Celular Tumoral Inibidores das Enzimas do Citocromo P-450/química Inibidores das Enzimas do Citocromo P-450/farmacologia Inibidores das Enzimas do Citocromo P-450/toxicidade Sistema Enzimático do Citocromo P-450/biossíntese Sistema Enzimático do Citocromo P-450/metabolismo Relação Dose-Resposta a Droga Indução Enzimática/efeitos dos fármacos Feminino Hepatócitos/efeitos dos fármacos Camundongos Neoplasias Nasofaríngeas/patologia Compostos Organometálicos/toxicidade Ratos [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Cytochrome P-450 Enzyme Inhibitors); 0 (Organometallic Compounds); 789U1901C5 (Copper); 9035-51-2 (Cytochrome P-450 Enzyme System) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180226 [Lr] Data última revisão: 180226 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180113 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0191295

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[PMID]: 28943375 [Au] Autor: Emerling CA [Ad] Endereço: Museum of Vertebrate Zoology, University of California Berkeley, Berkeley, CA, USA. Electronic address: christopher.emerling@umontpellier.fr. [Ti] Título: Independent pseudogenization of CYP2J19 in penguins, owls and kiwis implicates gene in red carotenoid synthesis. [So] Source: Mol Phylogenet Evol;118:47-53, 2018 Jan. [Is] ISSN: 1095-9513 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Carotenoids have important roles in bird behavior, including pigmentation for sexual signaling and improving color vision via retinal oil droplets. Yellow carotenoids are diet-derived, but red carotenoids (ketocarotenoids) are typically synthesized from yellow precursors via a carotenoid ketolase. Recent research on passerines has provided evidence that a cytochrome p450 enzyme, CYP2J19, is responsible for this reaction, though it is unclear if this function is phylogenetically restricted. Here I provide evidence that CYP2J19 is the carotenoid ketolase common to Aves using the genomes of 65 birds and the retinal transcriptomes of 15 avian taxa. CYP2J19 is functionally intact and robustly transcribed in all taxa except for several species adapted to foraging in dim light conditions. Two penguins, an owl and a kiwi show evidence of genetic lesions and relaxed selection in their genomic copy of CYP2J19, and six owls show evidence of marked reduction in CYP2J19 retinal transcription compared to nine diurnal avian taxa. Furthermore, one of the owls appears to transcribe a CYP2J19 pseudogene. Notably, none of these taxa are known to use red carotenoids for sexual signaling and several species of owls and penguins represent the only birds known to completely lack red retinal oil droplets. The remaining avian taxa belong to groups known to possess red oil droplets, are known or expected to deposit red carotenoids in skin and/or plumage, and/or frequently forage in bright light. The loss and reduced expression of CYP2J19 is likely an adaptation to maximize retinal sensitivity, given that oil droplets reduce the amount of light available to the retina. [Mh] Termos MeSH primário: Aves/classificação Carotenoides/biossíntese Sistema Enzimático do Citocromo P-450/genética Spheniscidae/classificação Estrigiformes/classificação [Mh] Termos MeSH secundário: Animais Sequência de Bases Aves/genética Sistema Enzimático do Citocromo P-450/classificação Bases de Dados Genéticas Evolução Molecular Filogenia Retina/metabolismo Spheniscidae/metabolismo Estrigiformes/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 36-88-4 (Carotenoids); 9035-51-2 (Cytochrome P-450 Enzyme System) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180226 [Lr] Data última revisão: 180226 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170926 [St] Status: MEDLINE

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[PMID]: 28747362 [Au] Autor: Travers S; Martinerie L; Boileau P; Lombès M; Pussard E [Ad] Endereço: Inserm, U1185, Le Kremlin-Bicêtre, France. [Ti] Título: Alterations of adrenal steroidomic profiles in preterm infants at birth. [So] Source: Arch Dis Child Fetal Neonatal Ed;103(2):F143-F151, 2018 Mar. [Is] ISSN: 1468-2052 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: OBJECTIVE: Preterm infants have relative adrenal and kidney immaturity. Recently, we linked their urine sodium loss to a hypoaldosteronism at variance with an appropriate stimulation of the renin-angiotensin system. To investigate this defective aldosterone secretion, we analyse the biosynthesis pathways of adrenal steroids in neonates according to gestational age (GA). DESIGN: Multicentre study (Premaldo) including 152 neonates classified into three groups: group 1 (very preterm (VPT)): <33 gestational weeks (GW); group 2 (preterm (PT)): 33-36 GW and group 3 (term (T)): ≥GW. METHOD: Steroidomic profiles of mineralocorticoids, glucocorticoids and adrenal androgens were established from umbilical cord at birth (n=152) and peripheral blood at day 3 (n=70) using a recently developed liquid chromatography mass spectrometry method (LC-MS/MS). The enzymatic activity of each biosynthesis step was estimated by the product-to-substrate ratio. RESULTS: At birth, VPT infants exhibit a global defect in adrenal steroid synthesis pathways leading to lower levels of aldosterone, cortisol and androstenedione than in term infants. This defect was strongly related to GA. On day 3, steroid precursors (progesterone, 11-deoxycorticosterone (DOC), 17-hydroxyprogesterone(17-OH-P) and 11-deoxycortisol (S)) were higher in VPT and negatively correlated with GA. Despite of precursors' accumulation, aldosterone and cortisol were similar in the three groups. At birth and day 3, a low cortisol/11-deoxycortisol ratio was found in preterm infants, suggesting an 11-beta-hydroxylase activity ( ) deficiency. CONCLUSIONS: At birth, VPT infants exhibit a global deficit in mineralocorticoids, glucocorticoids and adrenal androgens that attenuates on day 3 of life. Steroid profiling using LC-MS/MS provides evidence for a partial defect in 11-hydroxylase along with prematurity. [Mh] Termos MeSH primário: Corticosteroides/metabolismo Recém-Nascido Prematuro [Mh] Termos MeSH secundário: Corticosteroides/sangue Androgênios/metabolismo Cromatografia Líquida Sistema Enzimático do Citocromo P-450/metabolismo Sangue Fetal/química Idade Gestacional Glucocorticoides/metabolismo Seres Humanos Hipoaldosteronismo/metabolismo Lactente Extremamente Prematuro Recém-Nascido Mineralocorticoides/metabolismo Espectrometria de Massas em Tandem [Pt] Tipo de publicação: JOURNAL ARTICLE; MULTICENTER STUDY [Nm] Nome de substância: 0 (Adrenal Cortex Hormones); 0 (Androgens); 0 (Glucocorticoids); 0 (Mineralocorticoids); 9035-51-2 (Cytochrome P-450 Enzyme System) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180226 [Lr] Data última revisão: 180226 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 170728 [St] Status: MEDLINE [do] DOI: 10.1136/archdischild-2016-312457

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[PMID]: 29202140 [Au] Autor: Nawrot U; Sulik-Tyszka B; Kurzyk E; Mroczynska M; Wlodarczyk K; Wróblewska M; Basak GW; Brillowska-Dabrowska A [Ad] Endereço: Department of Pharmaceutical Microbiology and Parasitology, Faculty of Pharmacy, Wroclaw Medical University, Wroclaw, Poland. [Ti] Título: Relation of the polymorphism of cyp51A sequence and the susceptibility of Aspergillus fumigatus isolates to triazoles determined by commercial gradient test (Etest) and by reference methods. [So] Source: Acta Biochim Pol;64(4):631-634, 2017. [Is] ISSN: 1734-154X [Cp] País de publicação: Poland [La] Idioma: eng [Ab] Resumo: The aim of this study was to evaluate the accuracy of commercial gradient test (Etest) in the detection of triazole resistant Aspergillus fumigatus isolates using reference microdilution methods and the analysis of sequences of the cyp 51A gene. The study was performed on twenty clinical isolates which were identified as Aspergillus fumigatus based on the DNA sequences of the ITS1-2 fragment of ribosomal DNA and the ß-tubulin gene, out of them seventeen isolates showed wild-type cyp51A sequence and three were positive for the mutation TR34/L98H. All isolates were tested for the susceptibility to itraconazole (ITZ), voriconazole (VOR) and posaconasole (POS) using microdilution methods, according to EUCAST and CLSI protocols, as well as using Etest. The results of microdilution and Etests were analysed separately according to clinical breakpoints (CBP) defined by EUCAST version 7.0 and epidemiological cut off values (ECV). Etest as well as reference methods excellently recognised the WT isolates, which were susceptible to all tested triazoles, regardless of the method and CBP or ECV criteria used. The Etest recognized three non-WT isolates as resistant or intermediately sensitive to ITZ and POS and one as resistant to VOR. The categorical concordance between Etests and EUCAST and Etests and the CLSI method ranged from 90 to 100%. The interpretation of the results obtained from routine A. fumigatus Etests requires great caution. The use of the confirmative examinations with reference AST methods as well as with molecular tests is recommended. [Mh] Termos MeSH primário: Antifúngicos/farmacologia Aspergillus fumigatus/efeitos dos fármacos Sistema Enzimático do Citocromo P-450/genética Testes de Sensibilidade a Antimicrobianos por Disco-Difusão/métodos Farmacorresistência Fúngica/efeitos dos fármacos Proteínas Fúngicas/genética [Mh] Termos MeSH secundário: Aspergillus fumigatus/genética Farmacorresistência Fúngica/genética Itraconazol/farmacologia Testes de Sensibilidade Microbiana/métodos Polimorfismo Genético Triazóis/farmacologia Voriconazol/farmacologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antifungal Agents); 0 (Fungal Proteins); 0 (Triazoles); 304NUG5GF4 (Itraconazole); 9035-51-2 (Cytochrome P-450 Enzyme System); EC 1.14.14.- (cytochrome P-450 CYP51A, Aspergillus); JFU09I87TR (Voriconazole) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180223 [Lr] Data última revisão: 180223 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171205 [St] Status: MEDLINE [do] DOI: 10.18388/abp.2017_1571

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MEDLINE

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[PMID]: 29227934 [Au] Autor: Zabela V; Hettich T; Schlotterbeck G; Wimmer L; Mihovilovic MD; Guillet F; Bouaita B; Shevchenko B; Hamburger M; Oufir M [Ad] Endereço: Pharmaceutical Biology Laboratory, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: volha.zabela@unibas.ch. [Ti] Título: GABA receptor activity modulating piperine analogs: In vitro metabolic stability, metabolite identification, CYP450 reaction phenotyping, and protein binding. [So] Source: J Chromatogr B Analyt Technol Biomed Life Sci;1072:379-389, 2018 Jan 01. [Is] ISSN: 1873-376X [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: In a screening of natural products for allosteric modulators of GABA receptors (γ-aminobutyric acid type A receptor), piperine was identified as a compound targeting a benzodiazepine-independent binding site. Given that piperine is also an activator of TRPV1 (transient receptor potential vanilloid type 1) receptors involved in pain signaling and thermoregulation, a series of piperine analogs were prepared in several cycles of structural optimization, with the aim of separating GABA and TRPV1 activating properties. We here investigated the metabolism of piperine and selected analogs in view of further cycles of lead optimization. Metabolic stability of the compounds was evaluated by incubation with pooled human liver microsomes, and metabolites were analyzed by UHPLC-Q-TOF-MS. CYP450 isoenzymes involved in metabolism of compounds were identified by reaction phenotyping with Silensomes™. Unbound fraction in whole blood was determined by rapid equilibrium dialysis. Piperine was the metabolically most stable compound. Aliphatic hydroxylation, and N- and O-dealkylation were the major routes of oxidative metabolism. Piperine was exclusively metabolized by CYP1A2, whereas CYP2C9 contributed significantly in the oxidative metabolism of all analogs. Extensive binding to blood constituents was observed for all compounds. [Mh] Termos MeSH primário: Alcaloides Benzodioxóis Inibidores das Enzimas do Citocromo P-450 Sistema Enzimático do Citocromo P-450 Piperidinas Alcamidas Poli-Insaturadas Receptores de GABA-A/metabolismo [Mh] Termos MeSH secundário: Alcaloides/análise Alcaloides/química Alcaloides/metabolismo Benzodioxóis/análise Benzodioxóis/química Benzodioxóis/metabolismo Cromatografia Líquida de Alta Pressão Inibidores das Enzimas do Citocromo P-450/análise Inibidores das Enzimas do Citocromo P-450/química Inibidores das Enzimas do Citocromo P-450/metabolismo Sistema Enzimático do Citocromo P-450/análise Sistema Enzimático do Citocromo P-450/classificação Sistema Enzimático do Citocromo P-450/metabolismo Seres Humanos Microssomos Hepáticos/metabolismo Piperidinas/análise Piperidinas/química Piperidinas/metabolismo Alcamidas Poli-Insaturadas/análise Alcamidas Poli-Insaturadas/química Alcamidas Poli-Insaturadas/metabolismo Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Alkaloids); 0 (Benzodioxoles); 0 (Cytochrome P-450 Enzyme Inhibitors); 0 (Piperidines); 0 (Polyunsaturated Alkamides); 0 (Receptors, GABA-A); 9035-51-2 (Cytochrome P-450 Enzyme System); U71XL721QK (piperine) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180221 [Lr] Data última revisão: 180221 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171212 [St] Status: MEDLINE

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