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[PMID]:29017851
[Au] Autor:Priyadarshini; Lal B
[Ad] Endereço:Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi 221 005, India.
[Ti] Título:Seasonal ovarian immunolocalization of neuropeptide Y and its role in steriodogenesis in Asian catfish, Clarias batrachus.
[So] Source:Gen Comp Endocrinol;255:32-39, 2018 Jan 01.
[Is] ISSN:1095-6840
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The present study was undertaken to examine the cellular localization and potential steroidogenic role of neuropeptide Y (NPY) in the ovary of the freshwater catfish, Clarias batrachus. NPY-immunoreaction was observed in the follicular cells (granulosa and thecal cells) in the growing ovarian follicles, and the intensity of staining increased steadily from the initiation of follicular development until follicles were fully grown. Thereafter as follicles matured the stain intensity decreased. Positive correlations were found between NPY expression and the ovarian levels of 17ß-estradiol, testosterone, and activities of 3ß-hydroxysteroid dehydrogenase (3ß-HSD) and 17ß-hydroxysteroid dehydrogenase (17ß-HSD) in the ovary. In vitro NPY treatment stimulated the production of the two steroids and the activities of two enzymes. This is the first report of NPY immunoreactivity at the cellular level in the fish ovary and implicates this orexigenic peptide in the modulation of ovarian steroidogenesis.
[Mh] Termos MeSH primário: Peixes-Gato/metabolismo
Neuropeptídeo Y/metabolismo
Ovário/metabolismo
Estações do Ano
Esteroides/biossíntese
[Mh] Termos MeSH secundário: 17-Hidroxiesteroide Desidrogenases/metabolismo
3-Hidroxiesteroide Desidrogenases/metabolismo
Animais
Peixes-Gato/sangue
Estradiol/sangue
Estradiol/metabolismo
Feminino
Imuno-Histoquímica
Ovário/anatomia & histologia
Reprodução
Testosterona/sangue
Testosterona/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Neuropeptide Y); 0 (Steroids); 3XMK78S47O (Testosterone); 4TI98Z838E (Estradiol); EC 1.1.- (17-Hydroxysteroid Dehydrogenases); EC 1.1.- (3-Hydroxysteroid Dehydrogenases); EC 1.1.1.51 (3 (or 17)-beta-hydroxysteroid dehydrogenase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180216
[Lr] Data última revisão:
180216
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171012
[St] Status:MEDLINE


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[PMID]:28454766
[Au] Autor:Rieke S; Heise T; Schmidt F; Haider W; Bednarz H; Niehaus K; Mentz A; Kalinowski J; Hirsch-Ernst KI; Steinberg P; Niemann L; Marx-Stoelting P
[Ad] Endereço:Bundesinstitut für Risikobewertung (BfR), Department for Pesticides Safety, Max-Dohrn-Str. 8-10, 10589 Berlin, Germany.
[Ti] Título:Mixture effects of azole fungicides on the adrenal gland in a broad dose range.
[So] Source:Toxicology;385:28-37, 2017 06 15.
[Is] ISSN:1879-3185
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Consumers are exposed to low concentrations of a variety of pesticide residues in or on food. Some of them might interfere with the endocrine system. While each individual active substance has been extensively tested for toxicity and safety, potential combination effects possibly resulting from combined exposure to different pesticides have seldomly been tested so far, especially in vivo. Since the adrenal gland is a key endocrine organ, we investigated if and how substances of a group of fungicides presumed to interfere with the biosynthesis of steroid hormones affect this organ when applied individually and in combination in a broad dose range. A 28-day feeding study was conducted in Wistar rats by using three (tri)azole fungicides considered to potentially affect the endocrine system (cyproconazole, epoxiconazole and prochloraz) individually at five dose levels, ranging from 0.9ppm to 2400ppm, and in combination at three dose levels. The parameters analysed included classical toxicology (pathology, histopathology, clinical chemistry) and molecular toxicology endpoints (gene expression arrays and quantitative real time PCR e.g. of Star, HSD3ß, Cyp11a1, Cyp11b1, Cyp11b2, Cyp 21, ApoE), as well as hormone analysis. A dose-dependent decrease in the adrenal gland weight of rats treated with epoxiconazole alone, which was accompanied by an atrophy of the adrenal gland as well as by an increase in the serum cholesterol level and which only became statistically significant at the top dose levels, was observed. These effects were attenuated in the combination experiments, although the same epoxiconazole concentration was used.
[Mh] Termos MeSH primário: Glândulas Suprarrenais/efeitos dos fármacos
Azóis/toxicidade
Fungicidas Industriais/toxicidade
[Mh] Termos MeSH secundário: 3-Hidroxiesteroide Desidrogenases/genética
Glândulas Suprarrenais/metabolismo
Glândulas Suprarrenais/patologia
Aldosterona/sangue
Animais
Apolipoproteínas E/genética
Colesterol/sangue
Corticosterona/sangue
Sistema Enzimático do Citocromo P-450/genética
Interações Medicamentosas
Expressão Gênica/efeitos dos fármacos
Masculino
Nível de Efeito Adverso não Observado
Tamanho do Órgão/efeitos dos fármacos
Fosfoproteínas/genética
Progesterona/sangue
Ratos Wistar
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Apolipoproteins E); 0 (Azoles); 0 (Fungicides, Industrial); 0 (Phosphoproteins); 0 (steroidogenic acute regulatory protein); 4964P6T9RB (Aldosterone); 4G7DS2Q64Y (Progesterone); 9035-51-2 (Cytochrome P-450 Enzyme System); 97C5T2UQ7J (Cholesterol); EC 1.1.- (3-Hydroxysteroid Dehydrogenases); W980KJ009P (Corticosterone)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:180122
[Lr] Data última revisão:
180122
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170430
[St] Status:MEDLINE


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[PMID]:28457968
[Au] Autor:Xu D; Aka JA; Wang R; Lin SX
[Ad] Endereço:Laboratory of Molecular Endocrinology and Oncology, Centre Hospitalier Universitaire de Québec Research Centre (CHUQ, CHUL) and Department of Molecular Medicine, Laval University, 2705 Boulevard Laurier, Quebec City, Québec G1V 4G2, Canada.
[Ti] Título:17beta-hydroxysteroid dehydrogenase type 5 is negatively correlated to apoptosis inhibitor GRP78 and tumor-secreted protein PGK1, and modulates breast cancer cell viability and proliferation.
[So] Source:J Steroid Biochem Mol Biol;171:270-280, 2017 07.
[Is] ISSN:1879-1220
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:17beta-hydroxysteroid dehydrogenase type 5 (17ß-HSD5) is an important enzyme associated with sex steroid metabolism in hormone-dependent cancer. However, reports on its expression and its prognostic value in breast cancer are inconsistent. Here, we demonstrate the impact of 17ß-HSD5 expression modulation on the proteome of estrogen receptor-positive (ER+) breast cancer cells. RNA interference technique (siRNA) was used to knock down 17ß-HSD5 gene expression in the ER+ breast cancer cell line MCF-7 and the proteome of the 17ß-HSD5-knockdown cells was compared to that of MCF-7 cells using two-dimensional (2-D) gel electrophoresis followed by mass spectrometry analysis. Ingenuity pathway analysis (IPA) was additionally used to assess functional enrichment analyses of the proteomic dataset, including protein network and canonical pathways. Our proteomic analysis revealed only four differentially expressed protein spots (fold change > 2, p<0.05) between the two cell lines. The four spots were up-regulated in 17ß-HSD5-knockdown MCF-7 cells, and comprised 21 proteins involved in two networks and in functions that include apoptosis inhibition, regulation of cell growth and differentiation, signal transduction and tumor metastasis. Among the proteins are nucleoside diphosphate kinase A (NME1), 78kDa glucose-regulated protein (GRP78) and phosphoglycerate kinase 1 (PGK1). We also showed that expression of 17ß-HSD5 and that of the apoptosis inhibitor GRP78 are strongly but negatively correlated. Consistent with their opposite regulation, GRP78 knockdown decreased MCF-7 cell viability whereas 17ß-HSD5 knockdown or inhibition increased cell viability and proliferation. Besides, IPA analysis revealed that ubiquitination pathway is significantly affected by 17ß-HSD5 knockdown. Furthermore, IPA predicted the proto-oncogene c-Myc as an upstream regulator linked to the tumor-secreted protein PGK1. The latter is over-expressed in invasive ductal breast carcinoma as compared with normal breast tissue and its expression increased following 17ß-HSD5 knockdown. Our present results indicate a 17ß-HSD5 role in down-regulating breast cancer development. We thus propose that 17ß-HSD5 may not be a potent target for breast cancer treatment but its low expression could represent a poor prognosis factor.
[Mh] Termos MeSH primário: 3-Hidroxiesteroide Desidrogenases/metabolismo
Neoplasias da Mama/metabolismo
Regulação Neoplásica da Expressão Gênica
Proteínas de Choque Térmico/metabolismo
Hidroxiprostaglandina Desidrogenases/metabolismo
Proteínas de Neoplasias/metabolismo
Fosfoglicerato Quinase/metabolismo
[Mh] Termos MeSH secundário: 3-Hidroxiesteroide Desidrogenases/antagonistas & inibidores
3-Hidroxiesteroide Desidrogenases/química
3-Hidroxiesteroide Desidrogenases/genética
Membro C3 da Família 1 de alfa-Ceto Redutase
Neoplasias da Mama/patologia
Proliferação Celular
Sobrevivência Celular
Ativação Enzimática
Feminino
Perfilação da Expressão Gênica
Proteínas de Choque Térmico/antagonistas & inibidores
Proteínas de Choque Térmico/química
Proteínas de Choque Térmico/genética
Seres Humanos
Hidroxiprostaglandina Desidrogenases/antagonistas & inibidores
Hidroxiprostaglandina Desidrogenases/química
Hidroxiprostaglandina Desidrogenases/genética
Processamento de Imagem Assistida por Computador
Células MCF-7
Nucleosídeo NM23 Difosfato Quinases/química
Nucleosídeo NM23 Difosfato Quinases/genética
Nucleosídeo NM23 Difosfato Quinases/metabolismo
Proteínas de Neoplasias/antagonistas & inibidores
Proteínas de Neoplasias/química
Proteínas de Neoplasias/genética
Fosfoglicerato Quinase/química
Fosfoglicerato Quinase/genética
Proteômica/métodos
Proteínas Proto-Oncogênicas c-myc/química
Proteínas Proto-Oncogênicas c-myc/genética
Proteínas Proto-Oncogênicas c-myc/metabolismo
Interferência de RNA
Receptores Estrogênicos/metabolismo
Eletroforese em Gel Diferencial Bidimensional
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Heat-Shock Proteins); 0 (MYC protein, human); 0 (NM23 Nucleoside Diphosphate Kinases); 0 (Neoplasm Proteins); 0 (Proto-Oncogene Proteins c-myc); 0 (Receptors, Estrogen); 0 (molecular chaperone GRP78); EC 1.1.- (3-Hydroxysteroid Dehydrogenases); EC 1.1.1.- (Hydroxyprostaglandin Dehydrogenases); EC 1.1.1.357 (AKR1C3 protein, human); EC 1.1.1.357 (Aldo-Keto Reductase Family 1 Member C3); EC 2.7.2.3 (PGK1 protein, human); EC 2.7.2.3 (Phosphoglycerate Kinase); EC 2.7.4.6 (NME1 protein, human)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171208
[Lr] Data última revisão:
171208
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE


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[PMID]:29031687
[Au] Autor:Pham JH; Will CM; Mack VL; Halbert M; Conner EA; Bucholtz KM; Thomas JL
[Ad] Endereço:Department of Biomedical Sciences, Macon, GA, 31207, USA.
[Ti] Título:Structure-function relationships for the selective inhibition of human 3ß-hydroxysteroid dehydrogenase type 1 by a novel androgen analog.
[So] Source:J Steroid Biochem Mol Biol;174:257-264, 2017 Nov.
[Is] ISSN:1879-1220
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:3ß-Hydroxysteroid dehydrogenase type 1 (3ß-HSD1) is selectively expressed in human placenta, mammary glands and breast tumors in women. Human 3ß-HSD2 is selectively expressed in adrenal glands and ovaries. Based on AutoDock 3 and 4 results, we have exploited key differences in the amino acid sequences of 3ß-HSD1 (Ser194, Arg195) and 3ß-HSD2 (Gly194, Pro195) by designing a selective inhibitor of 3ß-HSD1. 2,16-Dicyano-4,5-epoxy-androstane-3,17-dione (16-cyano-17-keto-trilostane or DiCN-AND) was synthesized in a 4-step procedure from androstenedione. In purified 3ß-HSD inhibition studies, DiCN-AND competitively inhibited 3ß- HSD1 with K =4.7µM and noncompetitively inhibited 3ß-HSD2 with a 6.5-fold higher K =30.7µM. We previously reported similar isoenzyme-specific inhibition profiles for trilostane. Based on our docking results, we created, expressed and purified the chimeric S194G-1 mutant of 3ß-HSD1. Trilostane inhibited S194G-1 (K =0.67µM) with a noncompetitive mode compared to its 6.7-fold higher affinity, competitive inhibition of 3ß-HSD1 (K =0.10µM). DiCN-AND inhibited S194G-1 with a 6.3-fold higher K (29.5µM) than measured for 3ß-HSD1 (K =4.7µM) but with the same competitive mode for both enzyme species. Since DiCN-AND noncompetitively inhibits 3ß-HSD2, which has the Gly194 and Pro195 of 3ß-HSD2 in place of the Ser194 and Arg195 in 3ß-HSD1, this suggests that Arg195 alone in 3ß-HSD1 or S194G-1 is required to bind DiCN-AND in the substrate binding site (competitive inhibition). However, both Ser194 and Arg195 are required to bind trilostane in the 3ß-HSD1 substrate site based on its noncompetitive inhibition of S194G-1 and 3ß-HSD2. In support of this hypothesis, DiCN-AND inhibited our chimeric R195P-1 mutant noncompetitively with a K =41.3µM (similar to the 3ß-HSD2 inhibition profile). Since DiCN-AND competitively inhibited S194G-1 that still contains R195 but noncompetitively inhibited R195P-1 that still contains S194, our data provides strong evidence that the Arg195 being mutated to Pro195 (as present in 3ß-HSD2) shifts the inhibition mode from competitive to noncompetitive in 3ß-HSD1. This supports the key role of Arg195 in 3ß-HSD1 for the high affinity, competitive binding of the trilostane analogs. Our new structure/function information for the design of targeted 3ß-HSD1 inhibitors may lead to important new treatments for the prevention of spontaneous premature birth.
[Mh] Termos MeSH primário: 3-Hidroxiesteroide Desidrogenases/antagonistas & inibidores
3-Hidroxiesteroide Desidrogenases/metabolismo
Arginina/metabolismo
Di-Hidrotestosterona/análogos & derivados
Di-Hidrotestosterona/metabolismo
[Mh] Termos MeSH secundário: 3-Hidroxiesteroide Desidrogenases/química
3-Hidroxiesteroide Desidrogenases/genética
Androgênios
Ligação Competitiva
Seres Humanos
Modelos Moleculares
Mutagênese Sítio-Dirigida
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Androgens); 08J2K08A3Y (Dihydrotestosterone); 94ZLA3W45F (Arginine); EC 1.1.- (3-Hydroxysteroid Dehydrogenases)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171017
[St] Status:MEDLINE


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[PMID]:28881288
[Au] Autor:Pippione AC; Giraudo A; Bonanni D; Carnovale IM; Marini E; Cena C; Costale A; Zonari D; Pors K; Sadiq M; Boschi D; Oliaro-Bosso S; Lolli ML
[Ad] Endereço:Department of Science and Drug Technology, University of Torino, Via Pietro Giuria 9, 10125 Torino, Italy.
[Ti] Título:Hydroxytriazole derivatives as potent and selective aldo-keto reductase 1C3 (AKR1C3) inhibitors discovered by bioisosteric scaffold hopping approach.
[So] Source:Eur J Med Chem;139:936-946, 2017 Oct 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:The aldo-keto reductase 1C3 isoform (AKR1C3) plays a vital role in the biosynthesis of androgens, making this enzyme an attractive target for castration-resistant prostate cancer therapy. Although AKR1C3 is a promising drug target, no AKR1C3-targeted agent has to date been approved for clinical use. Flufenamic acid, a non-steroidal anti-inflammatory drug, is known to potently inhibit AKR1C3 in a non-selective manner as COX off-target effects are also observed. To diminish off-target effects, we have applied a scaffold hopping strategy replacing the benzoic acid moiety of flufenamic acid with an acidic hydroxyazolecarbonylic scaffold. In particular, differently N-substituted hydroxylated triazoles were designed to simultaneously interact with both subpockets 1 and 2 in the active site of AKR1C3, larger for AKR1C3 than other AKR1Cs isoforms. Through computational design and iterative rounds of synthesis and biological evaluation, novel compounds are reported, sharing high selectivity (up to 230-fold) for AKR1C3 over 1C2 isoform and minimal COX1 and COX2 off-target inhibition. A docking study of compound 8, the most interesting compound of the series, suggested that its methoxybenzyl substitution has the ability to fit inside subpocket 2, being involved in π-π staking interaction with Trp227 (partial overlapping) and in a T-shape π-π staking with Trp86. This compound was also shown to diminish testosterone production in the AKR1C3-expressing 22RV1 prostate cancer cell line while synergistic effect was observed when 8 was administered in combination with abiraterone or enzalutamide.
[Mh] Termos MeSH primário: 3-Hidroxiesteroide Desidrogenases/antagonistas & inibidores
Inibidores Enzimáticos/farmacologia
Hidroxiprostaglandina Desidrogenases/antagonistas & inibidores
Triazóis/farmacologia
[Mh] Termos MeSH secundário: 3-Hidroxiesteroide Desidrogenases/metabolismo
Membro C3 da Família 1 de alfa-Ceto Redutase
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/química
Seres Humanos
Hidroxiprostaglandina Desidrogenases/metabolismo
Modelos Moleculares
Estrutura Molecular
Relação Estrutura-Atividade
Triazóis/síntese química
Triazóis/química
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Triazoles); EC 1.1.- (3-Hydroxysteroid Dehydrogenases); EC 1.1.1.- (Hydroxyprostaglandin Dehydrogenases); EC 1.1.1.357 (AKR1C3 protein, human); EC 1.1.1.357 (Aldo-Keto Reductase Family 1 Member C3)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170908
[St] Status:MEDLINE


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[PMID]:28771887
[Au] Autor:Migita T; Takayama KI; Urano T; Obinata D; Ikeda K; Soga T; Takahashi S; Inoue S
[Ad] Endereço:Departments of Anti-Aging Medicine and Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
[Ti] Título:ACSL3 promotes intratumoral steroidogenesis in prostate cancer cells.
[So] Source:Cancer Sci;108(10):2011-2021, 2017 Oct.
[Is] ISSN:1349-7006
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Long-chain acyl-coenzyme A (CoA) synthetase 3 (ACSL3) is an androgen-responsive gene involved in the generation of fatty acyl-CoA esters. ACSL3 is expressed in both androgen-sensitive and castration-resistant prostate cancer (CRPC). However, its role in prostate cancer remains elusive. We overexpressed ACSL3 in androgen-dependent LNCaP cells and examined the downstream effectors of ACSL3. Furthermore, we examined the role of ACSL3 in the androgen metabolism of prostate cancer. ACSL3 overexpression led to upregulation of several genes such as aldo-keto reductase 1C3 (AKR1C3) involved in steroidogenesis, which utilizes adrenal androgen dehydroepiandrosterone sulfate (DHEAS) as substrate, and downregulated androgen-inactivating enzyme UDP-glucuronosyltransferase 2 (UGT2B). Exposure to DHEAS significantly increased testosterone levels and cell proliferative response in ACSL3-overexpressing cells when compared to that in control cells. A public database showed that ACSL3 level was higher in CRPC than in hormone-sensitive prostate cancer. CRPC cells showed an increased expression of ACSL3 and an expression pattern of AKR1C3 and UGT2B similar to ACSL3-overexpressing cells. DHEAS stimulation significantly promoted the proliferation of CRPC cells when compared to that of LNCaP cells. These findings suggest that ACSL3 contributes to the growth of CRPC through intratumoral steroidogenesis (i.e. promoting androgen synthesis from DHEAS and preventing the catabolism of active androgens).
[Mh] Termos MeSH primário: Coenzima A Ligases/genética
Coenzima A Ligases/metabolismo
Sulfato de Desidroepiandrosterona/farmacologia
Neoplasias de Próstata Resistentes à Castração/metabolismo
Testosterona/metabolismo
[Mh] Termos MeSH secundário: 3-Hidroxiesteroide Desidrogenases/metabolismo
Membro C3 da Família 1 de alfa-Ceto Redutase
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Glucuronosiltransferase/metabolismo
Seres Humanos
Hidroxiprostaglandina Desidrogenases/metabolismo
Lipogênese
Masculino
Neoplasias de Próstata Resistentes à Castração/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
3XMK78S47O (Testosterone); 57B09Q7FJR (Dehydroepiandrosterone Sulfate); EC 1.1.- (3-Hydroxysteroid Dehydrogenases); EC 1.1.1.- (Hydroxyprostaglandin Dehydrogenases); EC 1.1.1.357 (AKR1C3 protein, human); EC 1.1.1.357 (Aldo-Keto Reductase Family 1 Member C3); EC 2.4.1.17 (Glucuronosyltransferase); EC 6.2.1.- (Coenzyme A Ligases); EC 6.2.1.3 (long-chain-fatty-acid-CoA ligase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170804
[St] Status:MEDLINE
[do] DOI:10.1111/cas.13339


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[PMID]:28645211
[Au] Autor:O'Reilly MW; Kempegowda P; Walsh M; Taylor AE; Manolopoulos KN; Allwood JW; Semple RK; Hebenstreit D; Dunn WB; Tomlinson JW; Arlt W
[Ad] Endereço:Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.
[Ti] Título:AKR1C3-Mediated Adipose Androgen Generation Drives Lipotoxicity in Women With Polycystic Ovary Syndrome.
[So] Source:J Clin Endocrinol Metab;102(9):3327-3339, 2017 Sep 01.
[Is] ISSN:1945-7197
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Context: Polycystic ovary syndrome (PCOS) is a prevalent metabolic disorder occurring in up to 10% of women of reproductive age. PCOS is associated with insulin resistance and cardiovascular risk. Androgen excess is a defining feature of PCOS and has been suggested as causally associated with insulin resistance; however, mechanistic evidence linking both is lacking. We hypothesized that adipose tissue is an important site linking androgen activation and metabolic dysfunction in PCOS. Methods: We performed a human deep metabolic in vivo phenotyping study examining the systemic and intra-adipose effects of acute and chronic androgen exposure in 10 PCOS women, in comparison with 10 body mass index-matched healthy controls, complemented by in vitro experiments. Results: PCOS women had increased intra-adipose concentrations of testosterone (P = 0.0006) and dihydrotestosterone (P = 0.01), with increased expression of the androgen-activating enzyme aldo-ketoreductase type 1 C3 (AKR1C3) (P = 0.04) in subcutaneous adipose tissue. Adipose glycerol levels in subcutaneous adipose tissue microdialysate supported in vivo suppression of lipolysis after acute androgen exposure in PCOS (P = 0.04). Mirroring this, nontargeted serum metabolomics revealed prolipogenic effects of androgens in PCOS women only. In vitro studies showed that insulin increased adipose AKR1C3 expression and activity, whereas androgen exposure increased adipocyte de novo lipid synthesis. Pharmacologic AKR1C3 inhibition in vitro decreased de novo lipogenesis. Conclusions: These findings define an intra-adipose mechanism of androgen activation that contributes to adipose remodeling and a systemic lipotoxic metabolome, with intra-adipose androgens driving lipid accumulation and insulin resistance in PCOS. AKR1C3 represents a promising therapeutic target in PCOS.
[Mh] Termos MeSH primário: 3-Hidroxiesteroide Desidrogenases/metabolismo
Adipócitos/efeitos dos fármacos
Desidroepiandrosterona/farmacologia
Hidroxiprostaglandina Desidrogenases/metabolismo
Síndrome do Ovário Policístico/metabolismo
Gordura Subcutânea/metabolismo
[Mh] Termos MeSH secundário: Adipócitos/metabolismo
Adolescente
Adulto
Membro C3 da Família 1 de alfa-Ceto Redutase
Análise de Variância
Androgênios/metabolismo
Área Sob a Curva
Biomarcadores/sangue
Estudos de Casos e Controles
Células Cultivadas
Feminino
Seres Humanos
Resistência à Insulina
Metabolismo dos Lipídeos
Lipólise
Síndrome do Ovário Policístico/patologia
Reação em Cadeia da Polimerase em Tempo Real/métodos
Valores de Referência
Estatísticas não Paramétricas
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Androgens); 0 (Biomarkers); 459AG36T1B (Dehydroepiandrosterone); EC 1.1.- (3-Hydroxysteroid Dehydrogenases); EC 1.1.1.- (Hydroxyprostaglandin Dehydrogenases); EC 1.1.1.357 (AKR1C3 protein, human); EC 1.1.1.357 (Aldo-Keto Reductase Family 1 Member C3)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170625
[St] Status:MEDLINE
[do] DOI:10.1210/jc.2017-00947


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[PMID]:28594751
[Au] Autor:Riquelme P; Amodio G; Macedo C; Moreau A; Obermajer N; Brochhausen C; Ahrens N; Kekarainen T; Fändrich F; Cuturi C; Gregori S; Metes D; Schlitt HJ; Thomson AW; Geissler EK; Hutchinson JA
[Ad] Endereço:1 Department of Surgery, University Hospital Regensburg, Regensburg, Germany. 2 San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy. 3 Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA. 4 INSERM UMR1064, Center for Research in Transplantation and Immunology, Nantes, France. 5 CHU de Nantes, Institut de Transplantation Urologie Nephrologie (ITUN), Nantes, France. 6 Université de Nantes, Nantes, France. 7 Division of Surgical Oncology, University of Pittsburgh, Hillman Cancer Center, Pittsburgh, PA. 8 Institute of Pathology, University Hospital Regensburg, Regensburg, Germany. 9 Department of Transfusion Medicine, University Hospital Regensburg, Regensburg, Germany. 10 Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland. 11 FinVector Vision Therapies Oy, Microkatu 1S, Kuopio, Finland. 12 Institute for Applied Cell Therapy, University Hospital of Schleswig-Holstein, Campus Kiel, Kiel, Germany.
[Ti] Título:DHRS9 Is a Stable Marker of Human Regulatory Macrophages.
[So] Source:Transplantation;101(11):2731-2738, 2017 Nov.
[Is] ISSN:1534-6080
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The human regulatory macrophage (Mreg) has emerged as a promising cell type for use as a cell-based adjunct immunosuppressive therapy in solid organ transplant recipients. In this brief report, dehydrogenase/reductase 9 (DHRS9) is identified as a robust marker of human Mregs. METHODS: The cognate antigen of a mouse monoclonal antibody raised against human Mregs was identified as DHRS9 by immunoprecipitation and MALDI-MS sequencing. Expression of DHRS9 within a panel of monocyte-derived macrophages was investigated by quantitative PCR, immunoblotting and flow cytometry. RESULTS: DHRS9 expression discriminated human Mregs from a panel of in vitro derived macrophages in other polarisation states. Likewise, DHRS9 expression distinguished Mregs from a variety of human monocyte-derived tolerogenic antigen-presenting cells in current development as cell-based immunotherapies, including Tol-DC, Rapa-DC, DC-10, and PGE2-induced myeloid-derived suppressor cells. A subpopulation of DHRS9-expressing human splenic macrophages was identified by immunohistochemistry. Expression of DHRS9 was acquired gradually during in vitro development of human Mregs from CD14 monocytes and was further enhanced by IFN-γ treatment on day 6 of culture. Stimulating Mregs with 100 ng/mL lipopolysaccharide for 24 hours did not extinguish DHRS9 expression. Dhrs9 was not an informative marker of mouse Mregs. CONCLUSION: DHRS9 is a specific and stable marker of human Mregs.
[Mh] Termos MeSH primário: 3-Hidroxiesteroide Desidrogenases/metabolismo
Ativação de Macrófagos
Macrófagos/enzimologia
[Mh] Termos MeSH secundário: 3-Hidroxiesteroide Desidrogenases/genética
Animais
Biomarcadores/metabolismo
Células Cultivadas
Regulação Enzimológica da Expressão Gênica
Seres Humanos
Interferon gama/farmacologia
Lipopolissacarídeos/farmacologia
Ativação de Macrófagos/efeitos dos fármacos
Macrófagos/efeitos dos fármacos
Macrófagos/imunologia
Camundongos
Camundongos Endogâmicos C57BL
Fenótipo
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
Especificidade da Espécie
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (IFNG protein, human); 0 (Lipopolysaccharides); 0 (RNA, Messenger); 82115-62-6 (Interferon-gamma); EC 1.1.- (3-Hydroxysteroid Dehydrogenases); EC 1.1.- (DHRS9 protein, human)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171106
[Lr] Data última revisão:
171106
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170609
[St] Status:MEDLINE
[do] DOI:10.1097/TP.0000000000001814


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[PMID]:28414027
[Au] Autor:Alamdar A; Xi G; Huang Q; Tian M; Eqani SAMAS; Shen H
[Ad] Endereço:Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, PR China.
[Ti] Título:Arsenic activates the expression of 3ß-HSD in mouse Leydig cells through repression of histone H3K9 methylation.
[So] Source:Toxicol Appl Pharmacol;326:7-14, 2017 Jul 01.
[Is] ISSN:1096-0333
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Arsenic exposure has been associated with male reproductive dysfunction by disrupting steroidogenesis; however, the roles of epigenetic drivers, especially histone methylation in arsenic-induced steroidogenic toxicity remain not well documented. In this study, we investigated the role of histone H3 lysine 9 (H3K9) methylation in steroidogenesis disturbance in mouse Leydig cells (MLTC-1) due to arsenic exposure. Our results indicated that mRNA and protein expression levels of 3ß-hydroxysteroid dehydrogenase (3ß-HSD) were both significantly up-regulated while the rest of key genes involved in steroidogenesis were down-regulated. Moreover, arsenic exposure significantly decreased the histone H3K9 di- and tri-methylation (H3K9me2/3) levels in MLTC-1 cells. Since H3K9 demethylation leads to gene activation, we further investigated whether the induction of 3ß-HSD expression was ascribed to reduced H3K9 methylation. The results showed that H3K9me2/3 demethylase (JMJD2A) inhibitor, quercetin (Que) significantly attenuated the decrease of H3K9me2/3 and increase of 3ß-HSD expression induced by arsenic. To further elucidate the mechanism for the activation of 3ß-HSD, we determined the histone H3K9 methylation levels in Hsd3b gene promoter, which also showed significant decrease of H3K9me2/3 in the investigated region after arsenic exposure. Considering these results, we conclude that arsenic exposure induced 3ß-HSD up-regulation by suppressing H3K9me2/3 status, which is suggested as a compensatory mechanism for steroidogenic disturbance in MLTC-1 cells.
[Mh] Termos MeSH primário: 3-Hidroxiesteroide Desidrogenases/biossíntese
Arsenitos/toxicidade
Metilação de DNA/efeitos dos fármacos
Histonas/metabolismo
Células Intersticiais do Testículo/efeitos dos fármacos
Compostos de Sódio/toxicidade
[Mh] Termos MeSH secundário: 3-Hidroxiesteroide Desidrogenases/genética
Animais
Linhagem Celular
Sobrevivência Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Regulação para Baixo
Indução Enzimática
Inibidores Enzimáticos/farmacologia
Epigênese Genética/efeitos dos fármacos
Histona Desmetilases/antagonistas & inibidores
Histona Desmetilases/metabolismo
Concentração Inibidora 50
Células Intersticiais do Testículo/enzimologia
Masculino
Metilação
Camundongos
Progesterona/metabolismo
Regiões Promotoras Genéticas
Quercetina/farmacologia
RNA Mensageiro/biossíntese
RNA Mensageiro/genética
Testosterona/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Arsenites); 0 (Enzyme Inhibitors); 0 (Histones); 0 (RNA, Messenger); 0 (Sodium Compounds); 3XMK78S47O (Testosterone); 48OVY2OC72 (sodium arsenite); 4G7DS2Q64Y (Progesterone); 9IKM0I5T1E (Quercetin); EC 1.1.- (3-Hydroxysteroid Dehydrogenases); EC 1.14.11.- (Histone Demethylases)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170606
[Lr] Data última revisão:
170606
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170418
[St] Status:MEDLINE


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[PMID]:28300557
[Au] Autor:Zhang Z; Yu Y; Xu H; Wang C; Ji M; Gu J; Yang L; Zhu J; Dong H; Wang SL
[Ad] Endereço:State Key Lab of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, PR China; Key Lab of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, PR China.
[Ti] Título:High-fat diet aggravates 2,2',4,4'-tetrabromodiphenyl ether-inhibited testosterone production via DAX-1 in Leydig cells in rats.
[So] Source:Toxicol Appl Pharmacol;323:1-8, 2017 May 15.
[Is] ISSN:1096-0333
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Growing evidence has revealed that a high-fat diet (HFD) could lead to disorders of glycolipid metabolism and insulin-resistant states, and HFDs have been associated with the inhibition of testicular steroidogenesis. Our previous study demonstrated that 2,2',4,4'-tetrabromodiphenyl ether (BDE47) could increase the risk of diabetes in humans and reduce testosterone production in rats. However, whether the HFD affects BDE47-inhibited testosterone production by elevating insulin levels and inducing related pathways remains unknown. In male rats treated with BDE47 by gavage for 12 weeks, the HFD significantly increased the BDE47 content of the liver and testis and increased the weight of the adipose tissue; increased macrovesicular steatosis in the liver and the levels of triglycerides, fasting glucose and insulin; further aggravated the disruption of the seminiferous epithelium; and lowered the level of testosterone, resulting in fewer sperm in the epididymis. Of note, the HFD enhanced BDE47-induced DAX-1 expression and decreased the expression levels of StAR and 3ß-HSD in the testicular interstitial compartments in rats. In isolated primary Leydig cells from rats, BDE47 or insulin increased DAX-1 expression, decreased the expression of StAR and 3ß-HSD, and reduced testosterone production, which was nearly reversed by knocking down DAX-1. These results indicated that the HFD aggravates BDE47-inhibited testosterone production through hyperinsulinemia, and the accumulation of testicular BDE47 that induces the up-regulation of DAX-1 and the subsequent down-regulation of steroidogenic proteins, i.e., StAR and 3ß-HSD, in Leydig cells.
[Mh] Termos MeSH primário: Receptor Nuclear Órfão DAX-1/metabolismo
Dieta Hiperlipídica/efeitos adversos
Poluentes Ambientais/toxicidade
Éteres Difenil Halogenados/toxicidade
Células Intersticiais do Testículo/efeitos dos fármacos
Testosterona/metabolismo
[Mh] Termos MeSH secundário: 3-Hidroxiesteroide Desidrogenases/metabolismo
Animais
Biomarcadores/sangue
Glicemia/metabolismo
Células Cultivadas
Receptor Nuclear Órfão DAX-1/genética
Relação Dose-Resposta a Droga
Regulação para Baixo
Epididimo/efeitos dos fármacos
Epididimo/metabolismo
Epididimo/patologia
Fígado Gorduroso/induzido quimicamente
Fígado Gorduroso/metabolismo
Hiperinsulinismo/induzido quimicamente
Hiperinsulinismo/metabolismo
Insulina/sangue
Células Intersticiais do Testículo/metabolismo
Células Intersticiais do Testículo/patologia
Fígado/efeitos dos fármacos
Fígado/metabolismo
Masculino
Fosfoproteínas/metabolismo
Interferência de RNA
Ratos Sprague-Dawley
Transdução de Sinais/efeitos dos fármacos
Testosterona/sangue
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Blood Glucose); 0 (DAX-1 Orphan Nuclear Receptor); 0 (Environmental Pollutants); 0 (Halogenated Diphenyl Ethers); 0 (Insulin); 0 (Nr0b1 protein, rat); 0 (Phosphoproteins); 0 (steroidogenic acute regulatory protein); 0N97R5X10X (2,2',4,4'-tetrabromodiphenyl ether); 3XMK78S47O (Testosterone); EC 1.1.- (3-Hydroxysteroid Dehydrogenases)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170424
[Lr] Data última revisão:
170424
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170317
[St] Status:MEDLINE



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