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1.
Sci Total Environ ; 712: 134406, 2020 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-31927438

RESUMO

Plasticiser di-(2-ethylhexyl) phthalate (DEHP) is associated with female reproductive endocrine toxicity. Our previous study found that mono-(2-ethylhexyl) phthalate (MEHP), the metabolite of DEHP, can interfere with ovarian function via dysregulation of 17ß-hydroxysteroid dehydrogenase (17ß-HSD) in vitro. The aim of this study was to verify this hypothesis in vivo. The present study tested the hypothesis that subacute exposure to DEHP induced ovarian dysfunction by dysregulating 17ß-HSD signalling. 48 adult female Wistar rats were divided into 4 groups randomly: control group, low-dose group, medium-dose group, and high-dose group. DEHP was intragastrically administrated at the dosage of 0, 300, 1000 and 3000 mg/kg/d (body weight) for 4 weeks. Rats were executed, and the detection of the pathological changes of ovaries, steroid hormone levels, steroid receptor expression, and steroidogenic enzyme expression in sex hormone synthesis pathway and the apoptosis of GCs were performed. This study showed that DEHP could prolong the estrous cycle, increase follicular atresia, inhibit sex hormone secretion, reduce the expression of steroidogenic enzymes, and promote GCs apoptosis associating with ovarian dysfunction. In conclusion, these results indicate that DEHP can disturb ovarian function through the 17ß-HSD signalling pathway.


Assuntos
Dietilexilftalato/farmacologia , 17-Hidroxiesteroide Desidrogenases , Animais , Feminino , Ratos , Ratos Wistar
2.
Cell Mol Life Sci ; 77(6): 1153-1175, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31302749

RESUMO

Metabolic reprogramming of tumor cells involves upregulation of fatty acid (FA) synthesis to support high bioenergetic demands and membrane synthesis. This has been shown for cytosolic synthesis of FAs with up to 16 carbon atoms. Synthesis of long-chain fatty acids (LCFAs), including ω-6 and ω-3 polyunsaturated FAs, takes place at the endoplasmic reticulum. Despite increasing evidence for an important role of LCFAs in cancer, the impact of their synthesis in cancer cell growth has scarcely been studied. Here, we demonstrated that silencing of 17ß-hydroxysteroid dehydrogenase type 12 (17ß-HSD12), essentially catalyzing the 3-ketoacyl-CoA reduction step in LCFA production, modulates proliferation and migration of breast cancer cells in a cell line-dependent manner. Increased proliferation and migration after 17ß-HSD12 knockdown were partly mediated by metabolism of arachidonic acid towards COX2 and CYP1B1-derived eicosanoids. Decreased proliferation was rescued by increased glucose concentration and was preceded by reduced ATP production through oxidative phosphorylation and spare respiratory capacity. In addition, 17ß-HSD12 silencing was accompanied by alterations in unfolded protein response, including a decrease in CHOP expression and increase in eIF2α activation and the folding chaperone ERp44. Our study highlights the significance of LCFA biosynthesis for tumor cell physiology and unveils unknown aspects of breast cancer cell heterogeneity.


Assuntos
17-Hidroxiesteroide Desidrogenases/metabolismo , Neoplasias da Mama/metabolismo , 17-Hidroxiesteroide Desidrogenases/genética , Acil Coenzima A/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Ácidos Graxos/metabolismo , Feminino , Inativação Gênica , Humanos , Lipogênese , Células MCF-7
3.
Nat Rev Gastroenterol Hepatol ; 17(1): 40-52, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31641249

RESUMO

Nonalcoholic fatty liver disease (NAFLD) affects around a quarter of the global population, paralleling worldwide increases in obesity and metabolic syndrome. NAFLD arises in the context of systemic metabolic dysfunction that concomitantly amplifies the risk of cardiovascular disease and diabetes. These interrelated conditions have long been recognized to have a heritable component, and advances using unbiased association studies followed by functional characterization have created a paradigm for unravelling the genetic architecture of these conditions. A novel perspective is to characterize the shared genetic basis of NAFLD and other related disorders. This information on shared genetic risks and their biological overlap should in future enable the development of precision medicine approaches through better patient stratification, and enable the identification of preventive and therapeutic strategies. In this Review, we discuss current knowledge of the genetic basis of NAFLD and of possible pleiotropy between NAFLD and other liver diseases as well as other related metabolic disorders. We also discuss evidence of causality in NAFLD and other related diseases and the translational significance of such evidence, and future challenges from the study of genetic pleiotropy.


Assuntos
Hepatopatia Gordurosa não Alcoólica/genética , 17-Hidroxiesteroide Desidrogenases/genética , Aciltransferases/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Carcinoma Hepatocelular/genética , Causalidade , Progressão da Doença , Pleiotropia Genética , Predisposição Genética para Doença , Humanos , Lipase/genética , Cirrose Hepática Alcoólica/genética , Neoplasias Hepáticas/genética , Proteínas de Membrana/genética , Análise da Randomização Mendeliana , Síndrome Metabólica/genética , Biologia de Sistemas
4.
BMB Rep ; 53(1): 47-55, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31818365

RESUMO

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease and has become a major socioeconomic issue in many developed countries. Currently available therapeutic agents for AD provide only symptomatic treatments, mainly because the complete mechanism of the AD pathogenesis is still unclear. Although several different hypotheses have been proposed, mitochondrial dysfunction has gathered interest because of its profound effect on brain bioenergetics and neuronal survival in the pathophysiology of AD. Various therapeutic agents targeting the mitochondrial pathways associated with AD have been developed over the past decade. Although most of these agents are still early in the clinical development process, they are used to restore mitochondrial function, which provides an alternative therapeutic strategy that is likely to slow the progression of the disease. In this mini review, we will survey the AD-related mitochondrial pathways and their small-molecule modulators that have therapeutic potential. We will focus on recently reported examples, and also overview the current challenges and future perspectives of ongoing research. [BMB Reports 2020; 53(1): 47-55].


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , 17-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , 17-Hidroxiesteroide Desidrogenases/metabolismo , 3-Hidroxiacil-CoA Desidrogenases/antagonistas & inibidores , 3-Hidroxiacil-CoA Desidrogenases/metabolismo , Animais , Progressão da Doença , Dinaminas/metabolismo , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/enzimologia , Proteínas de Transporte da Membrana Mitocondrial/antagonistas & inibidores , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Neuroesteroides/química , Neuroesteroides/metabolismo , Neuroesteroides/farmacologia , Estresse Oxidativo/genética , Estresse Oxidativo/fisiologia , Proteínas Quinases/química , Proteínas Quinases/metabolismo , Receptores de GABA/metabolismo
5.
Reprod Biol Endocrinol ; 17(1): 111, 2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31878927

RESUMO

BACKGROUND: Previous studies of expression profiles of major endometrial effectors of steroid physiology in endometriosis have yielded markedly conflicting conclusions, presumably because the relative effects of type of endometriosis, fertility history and menstrual cycle phases on the measured variables were not considered. In the present study, endometrial mRNA and protein levels of several effectors of steroid biosynthesis and action in patients with stage III-IV ovarian endometriosis (OE) with known fertility and menstrual cycle histories were compared with the levels in control endometrium to test this concept. METHODS: Endometrial samples were collected from patients without endometriosis (n = 32) or OE stages III-IV (n = 52) with known fertility and cycle histories. qRT-PCR and immunoblotting experiments were performed to measure levels of NR5A1, STAR, CYP19A1, HSD17Bs, ESRs and PGR transcripts and proteins, respectively. Tissue concentrations of steroids (P4, T, E1 and E2) were measured using ELISAs. RESULTS: The levels of expression of aromatase and ERß were lower (P < 0.0001) and 17ß-HSD1 (P < 0.0001) and PRA (P < 0.01) were higher in OE endometrium. Lower aromatase levels and higher 17ß-HSD1 levels were detected in fertile (aromatase: P < 0.05; 17ß-HSD1: P < 0.0001) and infertile (aromatase: P < 0.0001; 17ß-HSD1: P < 0.0001) OE endometrium than in the matched control tissues. Both proliferative (PP) and secretory (SP) phase OE samples expressed aromatase (P < 0.0001) and ERß (PP: P < 0.001; SP: P < 0.01) at lower levels and 17ß-HSD1 (P < 0.0001) and PRA (PP: P < 0.01; SP: P < 0.0001) at higher levels than matched controls. Higher 17ß-HSD1 (P < 0.01) and E2 (P < 0.05) levels and a lower (P < 0.01) PRB/PRA ratio was observed in infertile secretory phase OE endometrium than in control. CONCLUSIONS: We report that dysregulated expression of 17ß-HSD1 and PGR resulting in hyperestrogenism and progesterone resistance during the secretory phase of the menstrual cycle, rather than an anomaly in aromatase expression, was the hallmark of eutopic endometrium from infertile OE patients. Furthermore, the results provide proof of concept that the fertility and menstrual cycle histories exerted relatively different effects on steroid physiology in the endometrium from OE patients compared with the control subjects.


Assuntos
Endometriose/metabolismo , Endométrio/metabolismo , Hormônios Esteroides Gonadais/metabolismo , Doenças Ovarianas/metabolismo , Receptores de Esteroides/metabolismo , 17-Hidroxiesteroide Desidrogenases/análise , 17-Hidroxiesteroide Desidrogenases/genética , Adolescente , Adulto , Aromatase/análise , Aromatase/genética , Endométrio/química , Estradiol/análise , Feminino , Expressão Gênica , Humanos , Infertilidade Feminina/metabolismo , Ciclo Menstrual , Progesterona/análise , Receptores Estrogênicos/análise , Receptores de Progesterona/análise , Receptores de Esteroides/genética , Adulto Jovem
6.
Aquat Toxicol ; 217: 105327, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31703940

RESUMO

Numerous anthropogenic sources, such as pulp mill and sewage treatment effluents, contain androgenic endocrine disrupting compounds that alter the reproductive status of aquatic organisms. The current study injected adult male mummichog (Fundulus heteroclitus) with 0 (control), 1 pg/g, 1 ng/g or 1 µg/g body weight of the model androgen 5α-dihydrotestosterone (DHT) with the intent to induce a period of plasma sex hormone depression, a previously-observed effect of DHT in fish. A suite of gonadal steroidogenic genes were assessed during sex hormone depression and recovery. Fish were sampled 6, 12, 16, 18, 24, 30 and 36 h post-injection, and sections of testis tissue were either snap frozen immediately or incubated for 24 h at 18 °C to determine in vitro gonadal hormone production and then frozen. Plasma testosterone (T) and 11-ketotestosterone (11KT) were depressed beginning 24 h post-injection. At 36 h post-injection plasma T remained depressed while plasma 11KT had recovered. In snap frozen tissue there was a correlation between plasma sex hormone depression and downregulation of key steroidogenic genes including steroidogenic acute regulatory protein (star), cytochrome P450 17a1 (cyp17a1), 3ß-hydroxysteroid dehydrogenase (3ßhsd), 11ß-hydroxysteroid dehydrogenase (11ßhsd) and 17ß-hydroxysteroid dehydrogenase (17ßhsd). Similar to previous studies, 3ßhsd was the first and most responsive gene during DHT exposure. Gene responses from in vitro tissue were more variable and included the upregulation of 3ßhsd, 11ßhsd and star during the period of hormone depression. The differential expression of steroidogenic genes from the in vitro testes compared to the snap frozen tissues may be due to the lack of regulators from the hypothalamo-pituitary-gonadal axis present in whole-animal systems. Due to these findings it is recommended to use snap frozen tissue, not post-incubation tissue from in vitro analysis, for gonadal steroidogenic gene expression to more accurately reflect in vivo responses.


Assuntos
Di-Hidrotestosterona/toxicidade , Fundulidae/fisiologia , 17-Hidroxiesteroide Desidrogenases/metabolismo , Animais , Di-Hidrotestosterona/sangue , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Gônadas/efeitos dos fármacos , Masculino , Fosfoproteínas/metabolismo , Reprodução/efeitos dos fármacos , Esteroide 17-alfa-Hidroxilase/metabolismo , Testículo/efeitos dos fármacos , Testosterona/análogos & derivados , Testosterona/metabolismo , Poluentes Químicos da Água/toxicidade
7.
J Steroid Biochem Mol Biol ; 195: 105483, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31550505

RESUMO

Hydroxysteroid 17-Beta Dehydrogenase 3 (Hsd17b3), primarily expressed in Leydig cells (LCs) of the mammalian testes, is essential for testosterone biosynthesis and male fertility. The aim of our study was to profile the expression, splice variants (SV) and novel insertion/deletion (indel) of Hsd17b3 in boars. Quantitative analysis showed that the expression level of Hsd17b3 in the testis was significantly highest. Among different testicular cell types, the Hsd17b3 mRNA expression level of LCs was significantly higher than that of SSCs (spermatogonial stem cells) and SCs (Sertoli cells). Furthermore, the SV was firstly identified in pigs and it was highly expressed in LCs comparing with SSCs and SCs. In addition, two mutations were identified in pig Hsd17b3 gene promotor and intron, respectively, which were associated with male reproductive traits (P <  0.05). In conclusion, both transcripts of Hsd17b3 gene were highly expressed in pig testes and LCs; the two novel indel variants of Hsd17b3 gene can be used as potential DNA makers for the marker-assisted selection in pigs. All these findings would enrich the study of Hsd17b3 gene in pig genetic breeding.


Assuntos
17-Hidroxiesteroide Desidrogenases/genética , Células Intersticiais do Testículo/metabolismo , Reprodução/genética , Sus scrofa/genética , Células-Tronco Germinativas Adultas/metabolismo , Processamento Alternativo , Animais , Variação Genética , Mutação INDEL , Masculino , Regiões Promotoras Genéticas , Células de Sertoli/metabolismo
8.
Anim Genet ; 50(6): 705-711, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31476086

RESUMO

The genetic background of disorders of sex development (DSD) in dogs with a normal male sex chromosome set (78,XY) is poorly described. In this study, we present for the first time, an analysis of six genes of the testosterone pathway, encoding enzymes (CYP17A1, HSD3B2, HSD17B3, SRD5A2) and transcription factors (NR5A1, AR). The entire coding sequence and flanking regions of the introns, 5'-UTR and 3'-UTR were analyzed in five DSD dogs (78,XY, SRY-positive) with ambiguous external genitalia and in 15 control dogs. A homozygous deletion of 2 bp in exon 2 of HSD17B3 (hydroxysteroid 17-beta dehydrogenase 3) was found in a Dachshund dog with enlarged clitoris, vulva and abdominal gonads and decreased serum testosterone level. In silico analysis revealed that this deleterious variant causes truncation of the encoded polypeptide (from 306 to 65 amino acids) and deprivation of the active site of the encoded enzyme. Genotyping of 23 control Dachshund dogs showed a normal homozygous genotype. Thus, we assumed that the 2-bp deletion is the causative variant. Moreover, 24 SNPs (four in CYP17A1, three in HSD3B2, six in HSD17B3, five in SRD5A2, one in AR and five in NR5A1), two intronic indels (one in HSD3B2 and one in SRD5A2) and two microsatellite polymorphisms in exon 1 of AR were found. Six SNPs appeared to be novel. No association with DSD phenotype was observed. Identification of the first case of DSD in domestic animals caused by a deleterious variant of a gene involved in testosterone synthesis showed that these genes are important candidates in such studies.


Assuntos
Transtornos do Desenvolvimento Sexual/veterinária , Doenças do Cão/genética , Testosterona/biossíntese , 17-Hidroxiesteroide Desidrogenases/genética , Animais , Códon de Terminação , Transtornos do Desenvolvimento Sexual/genética , Transtornos do Desenvolvimento Sexual/patologia , Cães , Feminino , Deleção de Genes , Genitália/patologia , Masculino , Testosterona/sangue
9.
Acta Histochem ; 121(7): 833-840, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31420111

RESUMO

Diabetes Mellitus (DM) is a kind of metabolic endocrine diseases, which has various effects on the gonadal system. The current study aimed to examine the effect of Stevia rebaudiana Bertoni extract on the mRNA expression involved in testosterone synthesis, and stereological parameters in rat testes, for improving diabetes complications. In this study, 48 rats were randomly classified into control, diabetic (streptozocin 60 mg/kg + nicotinamide 120 mg/kg), diabetic + Stevia (400 mg/kg), and diabetic + metformin (500 mg/kg) groups. Finally, Fasting Blood Sugar (FBS) level, the serum level of LH and testosterone, the Star, Cyp11a1, and Hsd17b3 gene expressions, and changes in the testis histology were evaluated. The results indicated a decrease in body weight, serum LH and testosterone level, the star gene expression, stereological changes of testes, and an increase in the FBS level in diabetic group, compared with the control group (P<0.05). Nonetheless, Stevia significantly reduced the FBS and increased the serum LH level, in comparison with diabetic rats (P<0.05), but no significant differences in the serum testosterone level and the Star gene expression has been found. Stevia also resulted in an increase in weight, testis volume, the number of sexual lineage cells, and sperm count and motility, compared to diabetic rats (P<0.05). Due to its antioxidant properties, Stevia enhanced the alteration in spermatogenesis and stereological characteristics in diabetic rat testes. Hence, Stevia could diminish the reproductive system problems and improve infertility in diabetic male rats.


Assuntos
17-Hidroxiesteroide Desidrogenases/biossíntese , Enzima de Clivagem da Cadeia Lateral do Colesterol/biossíntese , Diabetes Mellitus Experimental/metabolismo , Hormônio Luteinizante/metabolismo , Extratos Vegetais/farmacologia , Stevia/química , Testículo/metabolismo , Testosterona/metabolismo , Animais , Diabetes Mellitus Experimental/patologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Masculino , Extratos Vegetais/química , Ratos , Ratos Wistar , Espermatogênese/efeitos dos fármacos , Testículo/patologia
10.
Molecules ; 24(15)2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31362457

RESUMO

: It has long been established that mitochondrial dysfunction in Alzheimer's disease (AD) patients can trigger pathological changes in cell metabolism by altering metabolic enzymes such as the mitochondrial 17ß-hydroxysteroid dehydrogenase type 10 (17ß-HSD10), also known as amyloid-binding alcohol dehydrogenase (ABAD). We and others have shown that frentizole and riluzole derivatives can inhibit 17ß-HSD10 and that this inhibition is beneficial and holds therapeutic merit for the treatment of AD. Here we evaluate several novel series based on benzothiazolylurea scaffold evaluating key structural and activity relationships required for the inhibition of 17ß-HSD10. Results show that the most promising of these compounds have markedly increased potency on our previously published inhibitors, with the most promising exhibiting advantageous features like low cytotoxicity and target engagement in living cells.


Assuntos
17-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , 17-Hidroxiesteroide Desidrogenases/química , Benzotiazóis/química , Ureia/química , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Linhagem Celular , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Mitocôndrias/metabolismo , Estrutura Molecular , Relação Estrutura-Atividade
12.
J Pharm Pharmacol ; 71(10): 1565-1575, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31385305

RESUMO

OBJECTIVES: This study was designed to assess the role of caffeine on fertility parameters in testicular and epididymal tissues of scopolamine-induced model of amnesia in rats. METHODS: Adult male rats were treated with scopolamine with or without caffeine. The modulatory effects of caffeine or scopolamine on fertility parameters were assessed in rats' testicular and epididymal homogenates. KEY FINDINGS: Scopolamine-induced sperm abnormalities, reduced steroidogenic enzyme 3ß-Hydroxysteroid dehydrogenase (3ß-HSD) and 17ß-Hydroxysteroid dehydrogenase (17ß-HSD) activities and serum testosterone levels in rats' testicular tissues. Treatment with caffeine increased 3ß-HSD and 17ß-HSD as well as testosterone levels. Caffeine also reversed sperm viability, sperm motility and sperm count in testicular tissues of scopolamine-treated rats. Furthermore, scopolamine-induced oxidative damage in rats' epididymal and testicular tissues via reduction of thiol and non-protein thiol content as well as increase in reactive oxygen species (ROS) and malondialdehyde (MDA) levels. Caffeine attenuated oxidative stress in testicular and epididymal tissues of rats treated with scopolamine via increase in non-protein and protein thiol levels with concomitant reduction in ROS and MDA levels. CONCLUSION: This study revealed that caffeine (5 and 25 mg/kg) improved sperm quality, increased steroidogenic enzyme activities and attenuated oxidative damage in testis and epididymis of rats treated with scopolamine.


Assuntos
Amnésia/tratamento farmacológico , Cafeína/farmacologia , Epididimo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Testículo/efeitos dos fármacos , Testosterona/metabolismo , 17-Hidroxiesteroide Desidrogenases/metabolismo , Amnésia/induzido quimicamente , Amnésia/metabolismo , Animais , Modelos Animais de Doenças , Epididimo/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Oxirredução/efeitos dos fármacos , Ratos , Ratos Wistar , Escopolamina/farmacologia , Motilidade Espermática/efeitos dos fármacos , Testículo/metabolismo
13.
PLoS One ; 14(7): e0220492, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31348804

RESUMO

Rhodococcus ruber Chol-4 is a potent steroid degrader that has a great potential as a biotechnological tool. As proof of concept, this work presents testosterone production from 4-androstene-3,17-dione by tailoring innate catabolic enzymes of the steroid catabolism inside the strain. A R. ruber quadruple mutant was constructed in order to avoid the breakage of the steroid nucleus. At the same time, an inducible expression vector for this strain was developed. The 17-ketoreductase gene from the fungus Cochliobolus lunatus was cloned and overexpressed in this vector. The engineered strain was able to produce testosterone from 4-androstene-3,17-dione using glucose for cofactor regeneration with a molar conversion of 61%. It is important to note that 91% of the testosterone was secreted outside the cell after 3 days of cell biotransformation. The results support the idea that Rhodococcus ruber Chol-4 can be metabolically engineered and can be used for the production of steroid intermediates.


Assuntos
17-Hidroxiesteroide Desidrogenases/metabolismo , Proteínas de Bactérias/metabolismo , Engenharia Metabólica/métodos , Rhodococcus/genética , Rhodococcus/metabolismo , Testosterona/metabolismo , 17-Hidroxiesteroide Desidrogenases/genética , Proteínas de Bactérias/genética , Biotransformação , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Rhodococcus/crescimento & desenvolvimento
14.
J Strength Cond Res ; 33(9): 2344-2351, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31343553

RESUMO

Pickering, C, Suraci, B, Semenova, EA, Boulygina, EA, Kostryukova, ES, Kulemin, NA, Borisov, OV, Khabibova, SA, Larin, AK, Pavlenko, AV, Lyubaeva, EV, Popov, DV, Lysenko, EA, Vepkhvadze, TF, Lednev, EM, Leonska-Duniec, A, Pajak, B, Chycki, J, Moska, W, Lulinska-Kuklik, E, Dornowski, M, Maszczyk, A, Bradley, B, Kana-ah, A, Cieszczyk, P, Generozov, EV, and Ahmetov, II. A genome-wide association study of sprint performance in elite youth football players. J Strength Cond Res 33(9): 2344-2351, 2019-Sprint speed is an important component of football performance, with teams often placing a high value on sprint and acceleration ability. The aim of this study was to undertake the first genome-wide association study to identify genetic variants associated with sprint test performance in elite youth football players and to further validate the obtained results in additional studies. Using micro-array data (600 K-1.14 M single nucleotide polymorphisms [SNPs]) of 1,206 subjects, we identified 12 SNPs with suggestive significance after passing replication criteria. The polymorphism rs55743914 located in the PTPRK gene was found as the most significant for 5-m sprint test (p = 7.7 × 10). Seven of the discovered SNPs were also associated with sprint test performance in a cohort of 126 Polish women, and 4 were associated with power athlete status in a cohort of 399 elite Russian athletes. Six SNPs were associated with muscle fiber type in a cohort of 96 Russian subjects. We also examined genotype distributions and possible associations for 16 SNPs previously linked with sprint performance. Four SNPs (AGT rs699, HSD17B14 rs7247312, IGF2 rs680, and IL6 rs1800795) were associated with sprint test performance in this cohort. In addition, the G alleles of 2 SNPs in ADRB2 (rs1042713 & rs1042714) were significantly over-represented in these players compared with British and European controls. These results suggest that there is a genetic influence on sprint test performance in footballers, and identifies some of the genetic variants that help explain this influence.


Assuntos
Desempenho Atlético/fisiologia , Grupo com Ancestrais do Continente Europeu/genética , Corrida/fisiologia , Futebol/fisiologia , 17-Hidroxiesteroide Desidrogenases/genética , Aceleração , Adolescente , Alelos , Angiotensinogênio/genética , Criança , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Fator de Crescimento Insulin-Like II/genética , Interleucina-6/genética , Masculino , Polônia , Polimorfismo de Nucleotídeo Único , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/genética , Receptores Adrenérgicos beta 2/genética , Federação Russa , Reino Unido , Adulto Jovem
15.
J Steroid Biochem Mol Biol ; 193: 105420, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31283987

RESUMO

Mutations in the X-linked androgen receptor (AR) gene cause complete androgen insensitivity syndrome (CAIS). CAIS may cause congenital sexual development disorder, which frequently develops into testicular tumors. Here, we describe a novel splice-site intron 1 mutation in AR leading to improper splicing and AR protein absence in CAIS gonads. We characterized a patient's postpubertal gonadal steroidogenic enzyme expression profile. Localization of both CYP11A1 and CYP17A1 enzymes was restricted to both Leydig tumor cells and adjacent to tumor gonadal tissues. Sertoli cells of the CAIS gonad showed abundant HSD17B3 protein, which is an adult Leydig cell marker that enables the conversion of androstenedione to testosterone. Such HSD17B3 expression is typical for fetal-type Sertoli cells in rodents. The postpubertal CAIS gonad of our patient was completely devoid of androgen signaling pathway activity. Plausibly, the postpubertal Leydig cells consisted of two distinct cell populations: postpubertal fetal-type Leydig cells that persisted as androgen-independent cells and immature adult Leydig cells that failed to differentiate. Taken together, in this CAIS postpubertal testis, both Leydig and fetal-type Sertoli cells participated in testosterone production. Our results indicate the importance of molecular analysis as well as the characterization of steroidogenic enzyme profiling in the CAIS patient's gonad.


Assuntos
Síndrome de Resistência a Andrógenos/genética , Receptores Androgênicos/genética , 17-Hidroxiesteroide Desidrogenases/metabolismo , Síndrome de Resistência a Andrógenos/metabolismo , Androgênios/metabolismo , Feminino , Feto/metabolismo , Gônadas/metabolismo , Hormônios/sangue , Humanos , Íntrons , Masculino , Mutação , Receptores Androgênicos/metabolismo
16.
J Enzyme Inhib Med Chem ; 34(1): 1271-1286, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31307240

RESUMO

17ß-Hydroxysteroid dehydrogenase type 1 (17ß-HSD1) is a key enzyme in the biosynthesis of 17ß-estradiol. Novel estrone-based compounds bearing various 15ß-oxa-linked substituents and hydroxy, methoxy, benzyloxy, and sulfamate groups in position C3 as potential 17ß-HSD1 inhibitors have been synthesized. In addition, in vitro inhibitory potentials measured in the presence of excess amount of NADPH or NADH were investigated. We observed substantial inhibitory potentials for several derivatives (IC50 < 1 µM) and increased binding affinities compared to unsubstituted core molecules. Binding and inhibition were found to be cofactor-dependent for some of the compounds and we propose structural explanations for this phenomenon. Our results may contribute to the development of new 17ß-HSD1 inhibitors, potential drug candidates for antiestrogen therapy of hormone-dependent gynecological cancers.


Assuntos
17-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Estrona/farmacologia , 17-Hidroxiesteroide Desidrogenases/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Estrona/síntese química , Estrona/química , Humanos , Conformação Molecular , Relação Estrutura-Atividade
17.
J Steroid Biochem Mol Biol ; 193: 105411, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31207361

RESUMO

Reductive 17ß-hydroxysteroid dehydrogenases (17ß-HSDs) and 11ß-hydroxysteroid dehydrogenase 2 (11ß-HSD2) play crucial roles in respectively regulating steroids and glucocorticoids for the progression of hormone-dependent breast cancer. Most studies focused on the function and individual regulation of these enzymes. However, mutual regulation of these enzymes and the induced modulation on the estrogen and androgen receptors for breast cancer promotion are not yet clear. In this study, MCF-7 and T47D cells were treated with inhibitors of 17ß-HSD1, 17ß-HSD7, aromatase or steroid sulfatase (STS), then mRNA levels of 17ß-HSD7, STS, 11ß-HSD 2, estrogen receptors α (ERα) and androgen receptor (AR) were determined by Q-PCR. ER negative cell line MDA-MB-231 was used as a negative control. Our results demonstrate that 17ß-HSD7, STS and 11ß-HSD2 are all regulated by the same estrogen estradiol via ERα. When the gene of ERα (ESR1) was knocked down, there was no longer significant mutual regulation of these enzymes. Our results demonstrate that important steroidogenic enzymes transcriptionally regulated by ERα, can be mutually closely correlated. Inhibition of one of them can reduce the expression of another, thereby amplifying the role of the inhibition. Furthermore, inhibition of 17ß-HSD7 increases the expression of AR gene which is considered as a marker for better prognosis in ER + breast cancer, while maintaining ERα level. Thus, our mechanistic finding provides a base for further improving the endocrine therapy of ER + breast cancer, e.g., for selecting the target steroid enzymes, and for the combined targeting of human 17ß-HSD7 and ERα.


Assuntos
17-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , Neoplasias da Mama/genética , Receptor alfa de Estrogênio/genética , Receptores Androgênicos/genética , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/antagonistas & inibidores , 17-Hidroxiesteroide Desidrogenases/genética , Inibidores da Aromatase/farmacologia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Di-Hidrotestosterona/metabolismo , Estradiol/metabolismo , Feminino , Humanos , Esteril-Sulfatase/antagonistas & inibidores , Esteril-Sulfatase/genética , Esteril-Sulfatase/metabolismo
18.
J Steroid Biochem Mol Biol ; 192: 105405, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31185280

RESUMO

Hormone replacement therapy is a viable option to protect bone from postmenopausal osteoporosis. Systemically elevated estrogen levels, however, are disadvantageous because of the risk of harmful side effects in other organs. The rationale of the study presented here is to target a key enzyme in estradiol (E2) and testosterone (T) metabolism to increase E2 levels in an organ-specific manner, thereby avoiding the disadvantages of systemically increased E2 levels. The 17ß-hydroxysteroid dehydrogenase (17ß-HSD2), which is e.g. expressed in bone, catalyzes the oxidation of E2 and T into estrone (E1) and androstenedione. We postulate that inhibiting 17ß-HSD2 should lead to elevated E2 and T levels in organs expressing the enzyme. Therefore, we can use the benefits of E2 directly, or those of T following aromatization into E2, in the bone without affecting systemic levels. We tested for the first time, the novel and potent 17ß-HSD2 inhibitor, compound 24 (C24), to explore the therapeutic potential of a 17ß-HSD2 inhibition in an ovariectomy (ovx)-induced rat model of bone loss. We tested the inhibitor alone and, together with low dose estrogen supplementation to model estrogen levels in the postmenopausal situation. Female mature Wistar-Hannover rats were treated for 8 weeks with doses of 2, 10, 50 mg C24 per kg body weight per day alone or in the presence of estradiol benzoate (E2B) supplementation to alleviate ovx-induced bone loss. Ovx placebo and sham operated animals served as negative and positive controls. The experiment was evaluated regarding aspects of efficacy and safety: Bone was analyzed to evaluate bone protective effects, and uterus for potential, unwanted E2-mediated side effects. We observed a good bioavailability of C24 as very high plasma concentrations were measured, up to a group mean of 15,412 nM for the ovx C24-high group. Histomorphometrical analyses and in vivo &ex vivo µCT revealed significant bone protective effects for the lowest inhibitor concentration used. Irrespective of the plasma concentration, no proliferative effects in the uterus could be observed. These results support our approach of intracellular targeting key enzymes of E2 and T metabolism to increase E2 and T levels in an organ specific manner.


Assuntos
17-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , Osso e Ossos/efeitos dos fármacos , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Osteoporose/tratamento farmacológico , Animais , Osso e Ossos/enzimologia , Osso e Ossos/patologia , Inibidores Enzimáticos/farmacocinética , Feminino , Humanos , Tamanho do Órgão , Osteoporose/enzimologia , Osteoporose/patologia , Ovariectomia , Ratos , Ratos Wistar , Distribuição Tecidual , Útero/efeitos dos fármacos
19.
Eur J Med Chem ; 178: 93-107, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31176098

RESUMO

Estrogens are the major female sex steroid hormones, estradiol (E2) being the most potent form in humans. Disturbing the balance between E2 and its weakly active oxidized form estrone (E1) leads to diverse types of estrogen-dependent diseases such as endometriosis or osteoporosis. 17ß-Hydroxysteroid dehydrogenase type 1 (17ß-HSD1) catalyzes the biosynthesis of E2 by reduction of E1 while the type 2 enzyme catalyzes the reverse reaction. Thus, 17ß-HSD1 and 17ß-HSD2 are attractive targets for treatment of estrogen-dependent diseases. Recently, we reported the first proof-of-principle study of a 17ß-HSD2 inhibitor in a bone fracture mouse model, using subcutaneous administration. In the present study, our aim was to improve the in vitro ADME profile of the most potent 17ß-HSD1 and 17ß-HSD2 inhibitors described so far. The optimized compounds show strong and selective inhibition of both the human enzymes and their murine orthologs. In addition, they display good metabolic stability in human liver microsomes (S9 fraction), low in vitro cytotoxicity as well as better aqueous solubility and physicochemical properties compared to the lead compounds. These achievements make the compounds eligible for testing in preclinical in vivo animal model studies on the effects of inhibition of 17ß-HSD1 and 17ß-HSD2.


Assuntos
17-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , Inibidores Enzimáticos/farmacocinética , Estradiol Desidrogenases/antagonistas & inibidores , Fenóis/farmacocinética , Tiofenos/farmacocinética , Animais , Sítios de Ligação , Desenho de Fármacos , Estabilidade de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Estradiol Desidrogenases/química , Estradiol Desidrogenases/metabolismo , Células HEK293 , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Fenóis/síntese química , Fenóis/química , Fenóis/metabolismo , Ligação Proteica , Solubilidade , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química , Tiofenos/metabolismo
20.
Chemosphere ; 231: 60-71, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31128353

RESUMO

Paraquat, a widely used nonselective herbicide, is a serious hazard to human health. However, the effects of paraquat on the male reproductive system remain unclear. In this study, adult male Sprague Dawley rats were intraperitoneally injected ethane dimethane sulfonate (EDS, 75 mg/kg) to initiate a regeneration of Leydig cells. EDS-treated rats were orally exposed to paraquat (0.5, 2, 8 mg/kg/day) from post-EDS day 17 to day 28 and effects of paraquat on Leydig and Sertoli cell functions on post-EDS day 35 and day 56 were investigated. Paraquat significantly decreased serum testosterone levels at 2 and 8 mg/kg. Paraquat lowered Leydig cell Hsd17b3, Srd5a1, and Hsd11b1 mRNA levels but increased Hsd3b1 on post-EDS day 35. Paraquat lowered Cyp11a1, Cyp17a1, and Hsd11b1 but increased Srd5a1 on post-EDS day 56. However, paraquat did not alter Leydig cell number and PCNA labeling index. Epididymal staining showed that few sperms were observed in paraquat-treated rats. Primary culture of adult Leydig cells showed that paraquat diminished testosterone output and induced reactive oxygen species generation at 1 and 10 µM and apoptosis rate at 10 µM. In conclusion, a short-term exposure to paraquat delays Leydig cell regeneration from stem/progenitor Leydig cells, causing low production of testosterone and an arrest of spermatogenesis.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Herbicidas/toxicidade , Células Intersticiais do Testículo/citologia , Paraquat/toxicidade , Regeneração/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/análise , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/genética , 17-Hidroxiesteroide Desidrogenases/análise , 17-Hidroxiesteroide Desidrogenases/genética , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/análise , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Animais , Apoptose/efeitos dos fármacos , Células Intersticiais do Testículo/efeitos dos fármacos , Masculino , Proteínas de Membrana/análise , Proteínas de Membrana/genética , Mesilatos/farmacologia , Progesterona Redutase/análise , RNA Mensageiro/biossíntese , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Esteroide 17-alfa-Hidroxilase/análise , Testosterona/sangue
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