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1
Mensah-Nyagan, Guy Ayikoe. "Contribution à l'étude des neurostéroïdes dans le cerveau des amphibiens : biosynthèse des Delta(4)-3-cétostéroïdes et des 17β-hydroxystéroïdes, et régulation par les endozépines." Rouen, 1997. http://www.theses.fr/1997ROUES023.
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En utilisant des anticorps dirigés respectivement contre la la 3β-hydroxystéroïde déshydrogénase (3β-HSD) et la 17β-hydroxystéroïde déshydrogénase (17β-HSD) placentaires humaines nous avons montré la présence de ces enzymes dans le système nerveux central (SNC) de la grenouille. Les neurones à 3β-HSD sont localisés dans le diencéphale et la 17β-HSD est exprimée par des épendymocytes du télencéphale. Des quantités importantes de progestérone (P), 17-hydroxyprogestérone (17OH-P), testostérone (T) et dihydrotestostérone (5α-DHT) ont été mesurées dans le télencéphale et le diencéphale de grenouilles mâles et femelles en combinant l'analyse HPLC d'extraits tissulaires au dosage radioimmunologique. La castration des animaux mâles ne modifie pas les concentrations cérébrales de T et de 5α-DHT. La T a été formellement caractérisée dans le télencephale par HPLC et chromatographie en phase gazeuse couplée à une identification par spectrométrie de masse. Les explants d'hypothalamus convertissent la prégnènolone tritiée ([3h]Delta(5)P) en [3h]P et [3H]17OH-P, et la formation de ces deux métabolites est réduite significativement par le trilostane, un inhibiteur spécifique de la 3β-HSD L'incubation des explants de télencephale avec la [3h]Delta(5)P a révélé la synthèse de 15 métabolites tritiés dont 7 coéluent avec la P, la 17OH-P, l'androsténédione, la T, la 5α-DHT et l'oestrone ou l'oestradiol. Par ailleurs, nous avons démontré que de nombreux neurones hypothalamiques à 3β-HSD expriment également des récepteurs périphériques aux benzodiazépines (PBR) localisés à la fois dans le cytoplasme et au niveau de la membrane plasmique. L'incubation des explants d'hypothalamus avec la [3h]Delta(5)P en présence du triakontatétraneuropeptide (TTN) induit une stimulation dose-dépendante de la biosynthèse des neurostéroïdes. L'effet du TTN est mimé par le Ro5-4864 et inhibé par le PK11195 mais n'est pas modifié par le flumazénil. En conclusion, ce travail démontre pour la première fois la biosynthèse des neurostéroïdes dans le SNC des amphibiens. Nos résultats indiquent également que la production des stéroïdes dans les neurones hypothalamiques est activée par le TTN lequel agit probablement via des PBR situés au niveau de la membrane plasmique.
2
Breitling, Rainer. "Phylogenetische und bioinformatische Untersuchung der 17[beta]-Hydroxysteroiddehydrogenasen [17-beta-Hydroxysteroiddehydrogenasen] Struktur, Funktion und Evolution einer komplexen Proteinfamilie /." [S.l. : s.n.], 2001. http://deposit.ddb.de/cgi-bin/dokserv?idn=962139920.
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Green, Andrew Russell. "Regulatory factors in human breast : cytokines and 17#beta#-hydroxysteroid dehydrogenase." Thesis, University of Hull, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.389436.
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Kobayashi, Kaori. "Expression of 17 β-hydroxysteroid dehydrogenase type IV in chick retinal pigment epithelium." Kyoto University, 1997. http://hdl.handle.net/2433/202174.
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Wang, Ruixuan. "Expression and role of 17BETA-hydroxysteroid dehydrogenase type 1, 5 and 7 in epithelial ovarian cancer." Master's thesis, Université Laval, 2018. http://hdl.handle.net/20.500.11794/29632.
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Le cancer de l’ovaire est l’une des cinq causes les plus fréquentes de décès par cancer chez les femmes dans le monde développé. Environ 90% des cancers de l’ovaire proviennent de l’épithélium que l’on nomme cancer de l’ovaire épithélial (EOC). Le EOC est un cancer hormono-dépendant et les stéroïdes sexuels jouent un rôle crucial en favoriant la prolifération et de la survie des cellules. Les 17β-hydroxystéroïdes déshydrogénases (17β-HSDs) jouent un rôle important pour le contrôle de la concentration intracellulaire de tous les stéroïdes sexuels actifs. Le mécanisme qui reculent le fonctionnent et l’expression des 17β-HSDs dans le EOC sont très peu compris. L’inhibition de certains 17β-HSDs pourrait être un traitement de l’EOC et ette approche thérapeutique doit être étudiée. Les résultats de notre étude ont démontré que les 17β- HSD types 1, 5 et 7 sont tous exprimés dans les cellules OOC-3, mais que la type 1 est la plus abondante. L’expression des 17β-HSD types 1 et 7 dans les tumeurs ovariennes épithéliales que dans les ovaires normaux (type 1, 2.2 fois; type 7, 1.9 fois). Mais l’expression de la 17β-HSD 5 est significativement plus faible dans les tumeurs, suite au développement de l’EOC (-5.217 fois). De plus, la prolifération cellulaire a diminué à la suite du knockdown la 17β-HSD type 1 ou type 7 par des siRNAs spécifiques dans les cellules OVCAR-3, mais, le knockdown de la type 5 a un effet contraire. Nous suggérons que la 17β-HSD 5 peut être impliquée dans une signalisation d’hormones stéroïdiennes pour le développement du cancer de l’ovaire épithélial. Les 17β-HSD 1 et 7 pourraient être des biomarqueurs importants pour l’EOC diagnostiqué tôt et ils peuvent également être de nouvelles cibles pour le traitement de l’EOC.Ovarian cancer is one of the top five commonest causes of female cancer death in the developed world. About 90% of ovarian cancer have epithelial origins. Epithelial ovarian cancer (EOC) is a hormone-dependent cancer, in which the sex steroids play a crucial role in maintaining the cell proliferation and survival. The 17β-hydroxysteroid dehydrogenases (17β-HSDs) are important in the control of intracellular concentration of all active sex steroids. The function and expression of 17β-HSDs in EOC is not fully understood. Whether or not 17β-HSDs could be a therapeutic approach for the EOC treatment needs to be studied. Our results showed that 17β-HSD types 1, 5 and 7 are all expressed in EOC cells OVCAR-3 and type 1 is the highest one. The expression of 17β-HSD types 1 and 7 is higher in epithelial ovarian tumor tissues than in normal ovaries (type1, 2.2-fold; type7, 1.9-fold), but the expression of 17β-HSD type 5 is significantly lower in the tumor, following the EOC development (-5.2-fold). We found that cell proliferation was decreased after 17β-HSD type 1 or 7 knockdown by specific siRNAs in OVCAR-3 cells. While knocking down type 5 has the opposite effect. We suggest that 17β- HSD type 5 may be involved in steroid hormone signaling in EOC development. Moreover, 17β-HSD types 1 and 7 could be important biomarkers for early diagnosed EOC and novel targets for EOC treatment.
6
Xu, Dan (Ph D). "Role of 17β-hydroxysteroid dehydrogenase type 5 in breast cancer studied by intracrinology." Doctoral thesis, Université Laval, 2015. http://hdl.handle.net/20.500.11794/27239.
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Dans cette thèse, je présente une étude (1) du rôle de la 17β-HSD5 dans la modulation des taux d'hormones et dans la prolifération, et l'impact de l'expression de la 17β-HSD5 sur d’autres protéines de BC cellules; (2) une étude comparative sur trois enzymes (17β-HSD1, 17β-HSD7 et 3α-HSD3) avec la provision de DHEA et ses substrats directes soit l’E1 ou la DHT. Les principaux résultats obtenus dans cette étude sont les suivants: (1) en utilisant l'ARN d’interférence de la 17β-HSD5, des immunodosages enzymatiques et des tests de prolifération de cellules démontrent que l'expression de la 17β-HSD5 est positivement corrélée à un niveau de T et de DHT dans les BCC, mais négativement corrélée pour l’E2 et la prolifération des cellules de BC (2) les analyses quantitatives de PCR en temps réel et de Western blot ont démontré que l’inhibition de l’expression de la 17β-HSD5 régule à la hausse l'expression de l'aromatase dans les cellules MCF-7. (3) L’analyse d’ELISA de la prostaglandine E2 a vérifié que l'expression accrue de l'aromatase a été modulée par des niveaux élevés de PGE2 après l’inactivation de l’expression du gène de la 17β-HSD5. (4) Le test de cicatrisation a montré que l’inactivation de l’expression du gène de la 17β-HSD5 favorise l’augmentation de la migration cellulaire. (5) L'expression du gène 17β-HSD5 dans des échantillons cliniques, à partir de l'analyse de base de données ONCOMINE, a montré que sa plus faible expression a été corrélée avec le statut de l’HER-2 et de la métastase de la tumeur. (6) Les données protéomiques révèlent également que des protéines impliquées dans les voies métaboliques sont fortement exprimées dans les cellules MCF-7 après l’inactivation de l’expression du gène de la 17β-HSD5. (7) L’étude n'a démontré aucune différence dans la fonction biologique de la 17β-HSD1 et de la 17β-HSD7 lorsqu'elles sont cultivées avec différentes stéroïdes: tel que les niveaux de stéroides, la prolifération cellulaire et les protéines régulées. (8) Toutefois, la supplémentation du milieu de culture se révèle avoir un impact marqué sur l'étude de la 3α-HSD3. (9). Nous avons proposé que l'utilisation de la DHEA comme source d'hormone puisse entraîner une meilleure imitation des conditions physiologiques post-ménopausales en culture cellulaire selon l’intracrinologie.Human 17β-hydroxysteroid dehydrogenase type 5 (17β-HSD5) mainly synthesizes the activate androgen testosterone (T) from △4-androstenedione (4-dione), then 4-dione and T aromatazion to estrone (E1) and estradiol (E2) by the action of aromatase. 17β-HSD1 and 7 catalyze the formation of E2 from E1 and inactivate androgen dihydrotestosterone (DHT). In this thesis, I present the study of (1) the roles of 17β-HSD5 in the modulation of hormone levels and in the proliferation. and the proteomic study of the impact of the 17β-HSD5 knock down in BCC; (2) a comparative study of three enzymes (17β-HSD1，7 and 3α-HSD3) with the provision of DHEA and the direct substrates, E1 or DHT. The main results obtained in this study are as follow: (1) Using RNA interference of 17β-HSD5, enzyme immunoassays, and cell proliferation assays demonstrate that 17β-HSD5 expression is positively correlated with T and DHT levels in BCC, but negatively correlated with E2 levels, and BCC proliferation. (2) Quantitative real-time PCR analyzes and western blot showed that 17β-HSD5 knockdown up-regulates aromatase expression in MCF-7 cells. (3) Prostaglandin E2 ELISA assay verified that aromatase expression increase was modulated by elevated PGE2 levels after 17β-HSD5 knockdown. (4) Wound healing assay showed that with the knockdown of 17β-HSD5 expression, cell migration increased. (5)17β-HSD5 gene expression in clinical samples from ONCOMINE analysis showed its lower expression was correlated with HER-2 status and tumor metastasis. (6) The proteomic data also reveal that proteins involved in metabolic pathways are highly expressed in 17β-HSD5 knockdown MCF-7 cells. (7) Cell biology study showed no difference in biological function for 17β-HSD1 and 17β-HSD7 when cultured with different steroids cell proliferation and estradiol levels decreased, whereas DHT accumulated; cyclin D1, PCNA, and pS2 were down-regulated after knocking down these two enzymes. (8) The culture medium supplementation was found to have a marked impact on the study of 3α-HSD3. (9) We first proposed that using DHEA as hormone source may result in better mimicking of the physiological conditions of post-menopausal in cell culture according intracrinology.
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Shafqat, Naeem. "Substrate specificities and functional properties of human short-chain dehydrogenases/reductases /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7349-829-7.
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Nokelainen, P. (Pasi). "Biosynthesis of estradiol:cloning and characterization of rodent 17β-hydroxysteroid dehydrogenase/17-ketosteroid reductase types 1 and 7." Doctoral thesis, University of Oulu, 2000. http://urn.fi/urn:isbn:9514257510.
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Abstract
17β-Hydroxysteroid dehydrogenases (17HSDs)/17-ketosteroid
reductases (17KSRs) modulate the biological activity of certain
estrogens and androgens by catalyzing dehydrogenase and reductase reactions
between 17β-hydroxy and 17-ketosteroids.
In the present study, cDNAs encoding mouse and rat 17HSD/KSR1
were cloned in order to study the role of rodent type 1 enzyme in
ovarian estradiol (E2) biosynthesis and its
enzymatic characteristics. Both rat and mouse 17HSD/KSR1
were expressed in granulosa cells of developing follicles, where
diethylstilbestrol and follicle-stimulating hormone stimulated follicular
maturation and up-regulated the expression of 17HSD/KSR1,
whereas human chorionic gonadotropin caused luteinization of follicles
and down-regulation of the enzyme. In line with this, the rodent
type 1 enzymes are not expressed in the corpus luteum (CL). Mouse
17HSD/KSR1 showed substrate specificity different from
that of the human counterpart. The mouse type 1 enzyme catalyzed
the reaction from androstenedione to testosterone at least as efficiently
as estrone (E1) to E2,
while human 17HSD/KSR1 clearly preferred the E1 to
E2 reaction.
A mouse mammary epithelial cell line was found to possess
strong estrogenic 17KSR activity. A novel type of 17HSD/KSR
responsible for this activity was expression-cloned on the basis
of its ability to convert E1 to E2 and
it was chronologically named 17HSD/KSR7. Interestingly,
it showed 89 % identity with a rat protein called prolactin
receptor-associated protein (PRAP), which is expressed in the CL.
Enzymatic characterization showed that both mouse 17HSD/KSR7
and PRAP efficiently catalyzed the reaction from E1 to
E2. The mouse type 7 enzyme was most abundantly expressed
in the ovary and placenta. Similar primary structure, enzymatic
characteristics, and tissue distribution of mouse 17HSD/KSR7
and PRAP suggest that PRAP is rat 17HSD/KSR7.
Further studies showed that in rat ovaries 17HSD/KSR7
is primarily expressed in the middle and second half of pregnancy,
in parallel with E2 secretion from the CL.
Using in situ hybridization, cell-specific expression of 17HSD/KSR7
was studied in the mouse ovary, uterus and placenta. In the mouse
ovary, the enzyme was expressed exclusively in the CL. In the uterus
on day 5 post coitum (p.c.), the type 7 enzyme was expressed in
the decidua, mostly in the inner zone of antimesometrial decidua.
Between day 8 and 9 p.c. the enzyme was abundant in decidua capsularis
of the developing placenta, after which expression moved to the
basal zone. On days 12 and 14 p.c., mouse type 7 enzyme was abundantly
expressed in the spongiotrophoblasts, where expression decreased
towards parturition. Altogether, rodent 17HSD/KSR7 is a
new 17HSD/KSR which is involved in the biosynthesis of
E2 in the ovaries. In addition, E2 produced
locally in the decidua and placenta by the type 7 enzyme may have
a role in decidualization and/or implantation and placentation.
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Gunnarsson, Cecilia. "Steroid converting enzymes in breast cancer /." Linköping : Univ, 2005. http://www.bibl.liu.se/liupubl/disp/disp2005/med908s.pdf.
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Olusanjo, Moniola Sarah. "Synthesis and biochemical evaluation of potential steroidal and non-steroidal inhibitors of 17[beta]-hydroxysteroid dehydrogenase (17[beta]-HSD) in the treatment of hormone-dependent cancers." Thesis, Kingston University, 2008. http://eprints.kingston.ac.uk/22361/.
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Enzymes such as aromatase, 17[beta]-hydroxysteroid dehydrogenase [types 1 (17[beta]-HSD1) and 3 (17[beta]-HSD3)] and estrone sulfatase (ES) are all involved in the biosynthesis of steroids via the steroidal cascade. The inhibition of these enzymes may lead to a reduction in the levels of steroids present, thereby leading to a decrease in the stimulation of hormone-dependent tissues, in particular, hormone-dependent breast and prostate cancers. This approach has proved to be successful in postmenopausal women where the use of aromatase inhibitors has led to the decrease in tumour yield and has thus led to the treatment of the disease. Within the current study, the synthesis and biochemical evaluation of a number of compounds of varying structural features has been undertaken, in particular, the synthesis of sulfonate derivatives of 4-hydroxyphenyl ketone - the parent compound having already been shown to be a potent inhibitor of 17[beta]-HSD3 (with good specificity towards 17[beta]-HSD3) and the synthesis of a range of alkyl and cycloalkyl esters of steroids [in particular, testosterone (T) dehydroepiandrosterone (DHEA) and estrone (E10] as probes of the active sites of the HSD family of enzymes. The results show that the sulfonate (methanesulfonate and trifluromethanesulfonate) derivatives of 4-hydroxyphenyl ketone-based compounds were found to possess weak inhibitory activity against all three HSD enzymes considered (namely, 17[beta]-HSD1, 17[beta]-HSD3 and 3[beta]-HSD) in comparison to the parent 4-hydroxyphenyl ketone-based compounds. For example, within the methanesulfonate derivatives, methane sulfonic acid (4-cyclohexane carbonyl)-phenyl ester (164) was found to be the most potent inhibitor against 17[beta]-HSD3, however, it possessed ~30% inhibitory against this enzyme at an inhibitor concentration of 100[mu]M. Against 17[beta]-HSD1, the most potent compound within the same range was also compound 164 which pssessed ~45% inhibitory activity under similar conditions. Within the trifluromethane sulfonate derivatives, the most potent compounds proved to be extremely weak inhibitors of 17[beta]-HSD3, however, against 17[beta]-HSD1, the most potent compound was trifluromethane sulfonic acid 4-benzoyl-phenyl ester (180) which possess 43% inhibitory activity. The molecular modeling of these compounds within representations of the active sites of 17[beta]-HSD1 and 17[beta]-HSD3 shows that the lack of inhibitory activity is due to steric hindrance, in particular, the sulfonate moeity undergoes steric hindrance with groups at the active site which is close to the C(17) area of the natural substrate. The synthesis of the esters of T, DHEA and E1 and the subsequent biochemical evaluation of these compounds resulted in an interesting structure-activity relationship. In general, the compounds based on DHEA were found to be potent inhibitors of 17[beta]-HSD3 with weak inhibitory activity against 17[beta]-HSD1 and 3[beta]-HSD. For example, DHEA acetate (196) was found to possess an IC[sub]50 value of 0.74[mu]M in comparison to the most potent standard, namely 1-(4hydroxy-phenyl)-nonan-1-one (139) which was found to possess an IC[sub]50 value of 12.32[mu]M - this compound was found to possess good selectivity as it possessed ~40% and ~25% inhibitory activity against 17[beta]-HSD1 and 3[beta]-HSD respectively at an inhibitor concentration of 100[mu]M. The esters of E1 and T proved to be weaker inhibitors in comparison to the esters based on DHEA, however, the E1-based esters also showed some selectivity towards 17[beta]-HSD3. For example, E1 hexanoate (216) possessed an IC[sub]50 value of 37.28[mu]M and possessed 45% and 35% inhibitory activity against 17[beta]-HSD1 and 3[beta]-HSD respectively at an inhibitor concentration of 100[mu]M. The modelling of these compounds (using representations of the active sites of 17[beta]-HSD1 and 17[beta]-HSD3) showed that the lack of inhibitory activity was due to steric interactions between the inhibitors and groups within the active site. As such, these compounds proved to be extremely useful probes of the active sites of 17[beta]-HSD1 and 17[beta]-HSD3 and have further enhanced the models used in the design of these compounds.
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Soltani-Khankahdani, Siamak. "Synthesis of biochemical evaluation of potential inhibitors of 17 β-hydroxysteroid dehydrogenase for treatment of hormone-dependent prostate cancer." Thesis, Kingston University, 2011. http://eprints.kingston.ac.uk/26554/.
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It has been shown that the majority of benign prostatic hyperplasia (BPH) and prostate cancers are dependent on androgen production within the body. The biosynthesis of androgens is catalysed by different enzymes however one of the enzymes, 17 beta-hydroxysteroid dehydrogenase type 3 (17 beta-HSD3), converts the C(17)=O carbonyl moiety of androstenedione (1l4-dione) to the corresponding C(17)-OH hydroxyl group of testosterone (T). It has been hypothesised that inhibition of 17 beta-HSD3 may cause a decrease in the level of androgens which in turn leads to a reduction in the genesis of androgen-dependent prostatic diseases. The utilisation of enzyme inhibition as a therapeutic agent, in the treatment of breast cancer, has been tested on postmenopausal women by using aromatase inhibitors (e. g; exemestane, anastrazole and latrazole). This approach has proved to be successful and the impact of enzyme inhibition was led to a reduction in cancer growth. This process has now found a clinical application. From molecular modelling studies it was postulated that any potential inhibitor of 17 beta-HSD3 should contain a carbonyl moiety, mimicking the C(17)=O of the natural substrate, as well as an aromatic ring adjacent to the carbonyl group. With these criteria in mind results from our laboratories showed that from a library of candidates those based upon 4-hydroxyphenyl ketones showed some potential. The main focus of this prestn study was to fine tube the enzyme inhibitor analogues and hence optimise inhibitory activity of 4-hydroxyphenyl ketones. We have successfully synthesised a range of novel derivatives of 4-hydroxyphenyl ketones such as the 4-methanesulfonate and 4-acetate ester derivatives. In general, the reactions have proceeded very well with the yields ranging from 65% to 88% and 91% to 97% respectively. The results of biochemical evaluation studies suggested that the acetate ester derivatives, in particular compounds (149) and (150) exhibited good inhibitory activity against 17 beta-HSD type 3 of about 40% compared to standard inhibitors such as 7-hydroxyflavone and baicalein which resulted in about 13% and 14% inhibitory activity respectively. In addition a range of non-steroidal B, C, D ring mimics of the natural substrate of 17 beta-HSD type 3 were synthesised in good yields (65% to 85%). The biochemical evaluation of these compounds also showed good inhibitory activity; in fact compound (107) exhibited about 43% inhibition in comparison to the above standards which had inhibition of about 25% and 31 % respectively. In conclusion we have successfully synthesised and biochemically evaluated a number of enzyme inhibitors for the enzyme 17 beta-HSD type 3. The two types of active inhibitors were structurally dissimilar suggesting that they may have different modes of binding. This outcome requires further investigation in order to establish and identify how this inhibition is taking place.
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Härkönen, P. (Päivi). "17β-Hydroxysteroid dehydrogenases/17-ketosteroid reductases (17HSD/KSRs) in prostate cancer:the role of 17HSD/KSR types 2, 5, and 7 in steroid hormone action and loss of heterozygosity at chromosome region 16q." Doctoral thesis, University of Oulu, 2005. http://urn.fi/urn:isbn:9514279379.
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Abstract
Prostate cancer is the most frequently diagnosed cancer in men in industrialized countries. Despite the substantial clinical importance of the disease, the mechanisms underlying the development and progression of prostate cancer are poorly understood.
In the present study, fragment analysis of chromosome arm 16q was carried out with the aim of searching for sites of consistent chromosomal deletion, possibly uncovering the location of target genes that become inactivated in prostate carcinogenesis. The highest percentage of loss of heterozygosity (LOH) was found at chromosomal region 16q24.1-q24.2, including the gene for 17β-hydroxysteroid dehydrogenase/17-ketosteroid reductase (17HSD/KSR) type 2, HSD17B2. The data further indicated an association between loss of the most commonly deleted region and clinically aggressive features of the disease. A fragment analysis performed using sequential primary and locally recurrent prostate cancer specimens suggested the location of the genes related to prostate cancer progression to be at 16q24.3 and, further, gave rise to a hypothesis of the potential role of locus HSD17B2 as a prognostic marker for prostate cancer progression. Quantitative real-time polymerase chain reaction (PCR) revealed a decreased HSD17B2 gene copy number in prostate cancer specimens compared to their normal counterparts. A diminished HSD17B2 gene copy number was significantly associated with poor differentiation of the tumor.
The progression of prostate cancer during androgen deprivation is a serious clinical problem, the molecular mechanisms of which largely remain to be clarified. The present data of enzyme activity measurements performed using high-performance liquid chromatography (HPLC) provided evidence of a substantial decrease in oxidative and an increase in reductive 17HSD/KSR activity during the transition of prostate cancer LNCaP cells into an androgen-independent state. Further, the changes detected in the activities largely coincided with the changes in the relative expression levels of genes for the potential 17HSD/KSR isoenzymes; 17HSD/KSR types 2, 5, and 7, as evidenced by relative quantitative reverse transcription PCR (RT-PCR). The data on the expression analysis of mRNA for 17HSD/KSR types 5 and 7 in prostate tissue specimens performed using in situ hybridization showed a moderately low but constitutive level for 17HSD/KSR7 mRNA in tissues of cancerous as well as hyperplastic origin. The expression of mRNA for 17HSD/KSR type 5, instead, varied considerably between different specimens, the highest expressions being strongly associated with aggressive and metastatic prostate cancer. Interestingly, furthermore, the intense expression of 17HSD/KSR5 was significantly associated with the androgen deprivation achieved either surgically or medically.
Since 17HSD/KSRs critically contribute to the control of the bioavailability of active sex steroid hormones locally in the prostate, the variation in intraprostatic 17HSD/KSR activity might be crucially involved in the regulation of the growth and function of the organ.
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Mazumdar, Mausumi. "Reductive 17beta-hydroxysteroid dehydrogenase types 1, 5 and 7 involved in hormone-dependent cancers : 3D-structure, function and inhibition." Thesis, Université Laval, 2010. http://www.theses.ulaval.ca/2010/26794/26794.pdf.
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Li, Tang. "Structure-biological function study of 17B-hydroxysteroid dehydrogenase type 1 and reductive steroid enzymes : inhibitor design targeting estrogen-dependent diseases." Doctoral thesis, Université Laval, 2019. http://hdl.handle.net/20.500.11794/34398.
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La 17β-HSD1 catalyse l’activation de l’oestrogène le plus actif, l’estradiol, ainsi que la désactivation de la dihydrotestosterone, l’androgène le plus puissant. Cette enzyme est considé ré e comme une cible prometteuse pour le traitement des maladies dépendantes des oestrogènes. Malgré des décennies de recherches, aucun inhibiteur ciblant la 17β-HSD1 n’a encore atteint le stade clinique. De plus, le mécanisme de l’inhibition du substrat de la 17β-HSD1, qui peut être utilisé pour faciliter la conception d’inhibiteur, n’est toujours pas bien dé montré de maniè re structurelle. Ici, nous avons Co-cristallisé trois inhibiteurs de différence, à savoir l’EM- 139, le 2-MeO-CC-156 et le PBRM, avec la 17β-HSD1 et avons résolu ces structures cristallines. L’inhibiteur ré versible EM-139 s’est révélé moins stable dans le site de liaison aux stéroïdes, avec seulement la fraction du noyau stéroïdien de l’inhibiteur présentant une densité d’électron définissable. La fraction volumineuse de 7α-alkyle de l’inhibiteur, qui limite son activité anti-oestrogénique, n’est pas dé finie dans la densité électronique, peut compromettre l’effet inhibiteur de l’inhibiteur sur l’enzyme. Quant à l’inhibiteur réversible, le 2-MeO-CC-156, il interagit de maniè re similaire que le CC-156 avec l’enzyme. Cependant, avec la présence du groupe 2-MeO, le pouvoir inhibiteur de la 17β-HSD1 est nettement infé rieur à celui du CC-156. L’analyse du complexe ternaire PBRM avec la 17β-HSD1 montre clairement la formation d’une liaison covalente entre l’His221 et la chaîne laté rale bromoethyl de l’inhibiteur, donnant un aperç u des interactions molé culaires bé né fiques qui favorisent la liaison et l’avè nement de N-alkylation ulté rieur dans le site catalytique de l’enzyme. En outre, le groupe bromoethyl en position C-3 du PBRM justifie son profil non oestrogénique, ralentit son mé tabolisme et assure son action spé cifique de la 17β-HSD1 par la formation d’une liaison covalente avec Nε du ré sidu His221. Nous avons aussi Co-cristallisé la 17β-HSD1 avec l’oestrone ainsi qu’avec l’analogue de l’oestrone et du cofacteur NADP+, la structure a révélé un mode de liaison inversé de l’oestrone dans l’enzyme, jamais trouvé dans les complexes d’estradiol. L’analyse structurale a démontré que His221 est le résidu clé responsable de la réorganisation et de la stabilisation de l’oestrone liée de manière inversée, conduisant à la formation d’un complexe sans issue. Ainsi, sur la base du mécanisme d’inhibition du substrat et de l’analyse computationnelle, une novelle entité chimique (SX7) est proposé e qui peut inhiber la 17β-HSD1 et former un complexe sans issue. De plus, avec un grand nombre d’échantillons cliniques, nous avons dé montré la modulation et la corrélation d’expression significative de plusieurs enzymes clés de conversion des sté roïdes, supportant les 17β-HSD1 et 17β-HSD7 ré ductrices comme cibles prometteuses et la nouvelle thé rapie combiné e ciblant les 11β-HSD2 et 17β- HSD7Human 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyzes the activation of the most potent estrogen estradiol as well as the deactivation of the most active androgen dihydrotestosterone, and is considered as a promising target for the treatment of estrogen-dependent diseases such as endometriosis, breast cancer, endometrial cancer and ovarian cancer. Despite decades of research, no inhibitor targeting 17β-HSD1 has yet reached the stage of clinical trials. Moreover, the structure-biological function of the substrate inhibition of 17β-HSD1, which can be used to facilitate the inhibitor design, is still not well demonstrated. Here we co-crystallized three different inhibitors, namely EM-139, 2-MeO-CC-156 and PBRM, with 17β-HSD1 and solved the structures of these complexes. The reversible inhibitor EM-139 showed high mobility in the steroid binding site with only its steroid core moiety could be defined in the electron density. The bulky 7α-alkyl moiety of the inhibitor, which guarantees its anti-estrogenic activity but unable to be defined in the electron density, may compromise the inhibitory effect of the inhibitor on the enzyme. As for the reversible inhibitor 2-MeO-CC-156, it interacts similarly to CC-156 with the enzyme. However, in the presence of the 2- MeO group, it shows much less inhibitory potency to 17β-HSD1 as compared to the CC-156. The analysis of the PBRM ternary complex with 17β-HSD1 clearly shows an unambiguous continuity of electron density from the side chain of His221 to the bound PBRM, demonstrating the formation of a covalent bond between the Nε of His221 and the C-31 (BrCH2) of the inhibitor. This result provides insight into beneficial molecular interactions that favor the binding and subsequent N-alkylation event in the enzyme catalytic site. Also, the bromoethyl group at position C-3 of the PBRM warrants its non-estrogenic profile, slows down its metabolism, and secures the specific action of 17β-HSD1 through the formation of a covalent bond with Nε of residue His221. Meanwhile, we co-crystallized 17β-HSD1 with estrone as well as with estrone and cofactor analog NADP+, revealed a reversely orientated binding mode of estrone in the enzyme, never found in reported estradiol complexes. Structural analysis demonstrated that His221 is the key residue responsible for the reorganization and stabilization of the reversely bound estrone, leading to the formation of a dead-end complex. Thus, based on the substrate inhibition mechanism and computational analysis, a chemical entity (SX7) is proposed that may inhibit 17β-HSD1 and form a dead-end complex. Furthermore, with large number clinical samples, we demonstrated the significant expression modulation and expression correlation of several key steroidconverting enzymes, supporting the reductive 17β-HSD1 and 17β-HSD7 as promising targets and the new combined therapy targeting 11β-HSD2 and 17β-HSD7.
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Han, Hui. "Substrate inhibition of 17 beta-hydroxysteroid dehydrogenase type 1 in living cells and regulation among the steroid-converting enzymes in breast cancers." Doctoral thesis, Université Laval, 2018. http://hdl.handle.net/20.500.11794/32545.
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Cette étude a permis de démontrer les fonctions et les mécanismes de la 17bêtahydroxystéroïde déshydrogénase de type 1 (17β-HSD1) et de la stéroïde sulfatase (STS) au niveau du cancer du sein, y compris la cinétique moléculaire et cellulaire, la liaison du ligand étudiée par la titration de fluorescence, la régulation des stéroïdes et la régulation mutuelle entre les enzymes stéroïdiennes et les cellules cancéreuses du sein. 1), L’inhibition de la 17β-HSD1 par son substrat a été démontrée par la cinétique enzymatique au niveau cellulaire pour la première fois, soutenant ainsi la fonction biologique de l’inhibition produite par le substrat. 2), En tant qu’inhibiteur, la dihydrotestostérone (DHT) n’a pas affecté la concentration du substrat estrone (E1) à laquelle l’activité enzymatique a commencé à diminuer, mais certaines augmentations de vitesse ont été observées, suggérant une diminution significative de l’inhibition par le substrat. 3), Les résultats de la modulation de l’ARNm ont démontré que la transcription du gène codant la 17β-HSD7 diminuait en réponse à l’inhibition de la 17β-HSD1 ou au knockdown dans les cellules du cancer du sein par la modification estradiol (E2). 4), L’expression de la STS est stimulée par E2 de manière à générer une rétroaction positive, ce qui favorise la biosynthèse de E2 dans les cellules de cancer du sein. 5), L’inhibition conjointe de la STS et de la 17β-HSD7 pourrait bloquer leurs activités enzymatiques, diminuant ainsi la formation de E2, mais rétablissant la formation de DHT, réduisant de façon synergique la prolifération cellulaire et induisant l’arrêt du cycle cellulaire en G0 / G1. 6), Les 17β-HSD7 et STS synthétisent E2 et sont toutes deux régulées par E2. Ainsi, elles forment un groupe fonctionnel d’enzymes mutuellement positivement corrélées, l’inhibition de l’une peut réduire l’expression d’une autre, amplifiant ainsi potentiellement les traitements inhibiteurs. 7), Le recepteur estrogenique α ERα a été non seulement régulés à la baisse par E2, mais également réduits par la DHT grâce à l’activation des récepteurs aux androgènes (AR). En conclusion, la 17β-HSD1 et la 17β-HSD7 jouent des rôles essentiels dans la conversion et la régulation des hormones sexuelles, et l’inhibition conjointe de la STS et de la 17β-HSD7 constitue une nouvelle stratégie pour le traitement hormonal des cancers du sein sensibles aux estrogènes.Human 17beta-hydroxysteroid dehydrogenase type 1 (17β-HSD1), 17betahydroxysteroid dehydrogenase type 7 (17β-HSD7) and steroid sulfatase (STS) play a crucial role in regulating estrogen synthesis for breast cancer (BC). However, mutual regulation of enzymes and the interaction of these steroids (estrogens, androgens and their precursor dehydroepiandrosterone (DHEA)) are not clear. This study demonstrated the functions and mechanisms including kinetics at molecular level and in cells, ligand binding using fluorescence titration, regulation of steroids and mutual regulation between steroid enzymes in BC cells: 1) Substrate inhibition of 17β-HSD1 was shown for the first time by enzyme kinetics at the cell level, supporting the biological function of substrate inhibition. 2) As an inhibitor, dihydrotestosterone (DHT) did not affect the estrone (E1) substrate concentration at which the enzyme activity started to decrease, but some increases in velocity were observed, suggesting a corresponding decrease in substrate inhibition 3) The mRNA modulation results demonstrated that 17β-HSD7 transcription decreased in response to 17β-HSD1 inhibition or knockdown in BC cells due to estradiol (E2) concentration decrease. 4) The expression of STS is stimulated by E2 in a positive-feedback manner which finally promotes E2 biosynthesis within BC cells. 5) The joint inhibition of STS and 17β-HSD7 could block the activities of these enzymes, thus decreasing E2 formation but restoring DHT formation, to synergistically reduce cell proliferation and induce G0/G1 cell cycle arrest. 6) 17β-HSD7 and STS can synthesize E2 and are all regulated by E2. Thus, they form a functional group of enzymes mutually positively correlated, inhibition of one can reduce the expression of the other, thereby potentially amplifying the inhibitory effects. 7) Estrogen Receptor α (ERα) is not only down-regulated by E2, but also reduced by DHT though androgen receptor (AR) activation. In conclusion, 17β-HSD1 and 17β-HSD7 play essential roles in sex-hormone conversion and regulation, and the joint inhibition of STS and 17β-HSD7 constitutes a novel strategy for hormonal treatment of estrogen-receptor positive BC
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Liu, Hong. "Molecular isolation and characterization of Macaca fascicularis hydroxysteroid dehydrogenases involved in sex steroid biosynthesis and metabolism." Thesis, Université Laval, 2007. http://www.theses.ulaval.ca/2007/24499/24499.pdf.
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Wang, Xiao Qiang. "Function and regulation of 17B-hydroxysteroid dehydrogenase type7 (17B-HSD7) in sex hormone biosynthesis and breast cancer : in vitro, in vivo, proteomic and three dimensional co-culture studies." Doctoral thesis, Université Laval, 2015. http://hdl.handle.net/20.500.11794/27483.
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La 17β-hydroxystéroïde déshydrogénase humaine de type 7 (17β-HSD7) a une double fonction dans la cholestérologénèse et la stéroïdogénèse, et qui est impliquée à la fois dans la formation d’estradiol (E2) à partir de l’estrone (E1), et dans la dégradation de la dihydrotestostérone (DHT) en un œstrogène faible (3β-diol). Cependant, sa fonction dans le cancer du sein dépendant des œstrogènes (positif aux récepteurs oestrogéniques (RE+) n’a pas toujours été claire. L’E2 stimule la croissance des cellules cancéreuses du sein (CCS; cellules MCF-7) via les RE tandis que la DHT a un effet antiprolifératif via le récepteur des androgènes. Mes études in vitro, in vivo et de protéomique, ont apporté les résultats suivants : (1) L’inhibition de la 17β-HSD7 par un inhibiteur spécifique (INH7) dans les CCS a entrainé une baisse de l’E2, une augmentation de la DHT, une interruption du cycle cellulaire et une régulation négative de cette enzyme. De plus, l’INH7 a permis de réduire des tumeurs xénogreffes qui a été accompagnées d’une diminution de l’E2 et une augmentation de la DHT sériques. (2) L’INH7 a modulé des protéines impliquant différents processus biologiques. L’INH7 a supprimé l’expression de la protéine 78 régulée par le glucose (Grp78) et de fait a augmenté l’apoptose des CCS envers le Letrozole, un inhibiteur de l’aromatase. (3) Les interactions entre les CCS et les fibroblastes tumoraux montrent que la 17β-HSD7 était l’enzyme la plus régulée dans les CCS tandis que l’aromatase était l’enzyme les plus régulées dans les fibroblastes. De telles régulations ont mené à une augmentation de la conversion de l’E2 à partir de ses précurseurs, et a ainsi encouragé la prolifération cellulaire des CCS. Si l’augmentation de la prolifération cellulaire est bloquée par le Letrozole des résultats plus significatifs ont été observés par l’INH7 qui bloque la dégradation de la DHT. (4) L’analyse des données intégratives basée sur The Cancer Genome Atlas (TCGA) confirme l’amplification significative du gène HSD17B7 dans les divers cancers du sein comparé à des tissus mammaires sains. Ainsi, nous pensons que la 17β-HSD7 devrait être une nouvelle cible thérapeutique des cancers RE+ du sein.Human 17β-hydroxysteroid dehydrogenase type 7 (17β-HSD7) displays a dual function in cholesterogenesis and steroidogenesis. In steroidogenesis, it is both involved in the formation of the estradiol (E2) from estrone (E1) and in the degradation of dihydroterstosterone (DHT) into weak estrogen 5α-androstane-3β, 17β-diol (3β-diol). However, its function in estrogen dependent breast cancer (estrogen receptor positive, ER+) has been unclear for many years. E2 stimulates breast cancer cells (BCCs, MCF-7 cells) growth via estrogen receptor (ER) whereas DHT displays anti-proliferative effects via androgen receptor (AR). In the present thesis, the function of 17β-HSD7 in ER+ breast cancer was studied with in vitro, in vivo, proteomics and three dimensional (3D) co-culture model and results were described: (1) Inhibition of 17β-HSD7 by its selective inhibitor (INH7) in BCCs induced significant lower E2, higher DHT, cell cycle arresting and negative regulating of the same enzyme. Such inhibition induced significant shrinkage of xenograft tumors accompanied by decreased E2 and elevated DHT in plasma. (2) Inhibition of 17β-HSD7modulated 104 proteins involved in different biological processes. INH7 especially suppresses the expression of glucose regulated protein 78 (GRP78) and consequently enhanced apoptosis of MCF-7 towards aromatase inhibitor. (3) The interactions between BCCs and tumor fibroblast modulate steroidogenic enzymes. 17β-HSD7 was the most modulated enzyme in MCF-7 cells whereas aromatase was the most regulated enzyme in fibroblast (Hs578Bst). Such regulations led to an increasing of E2 conversion from precursors and promoted MCF-7 cells’ proliferation. The increased cell proliferation was blocked by aromatase inhibitor in 3D co-culture system, but more significant results were observed with INH7 which blocked DHT degradation. (4) Integrative data analysis with The Cancer Genome Atlas (TCGA) confirmed the significant amplification of 17β-HSD7 in various breast cancers compared to normal breast tissue. Thus, in the present thesis, 17β-HSD7 was characterized as a novel therapeutic target for estrogen dependent breast cancer in postmenopausal women.
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Do, Rego Marie Jean Luc. "Contribution à l'étude des mécanismes de régulation de la biosynthèse des neurostéroïdes : effets des endozépines et du GABA." Rouen, 2000. http://www.theses.fr/2000ROUES047.
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Nous avons récemment démontré qu'une enzyme clé de la stéroïdogénèse, la 3-hydroxystéroïde deshydrogénase (3-HSD) est exprimée dans le diencéphale de la grenouille et nous avons montré que les explants hypothalamiques synthétisent plusieurs neurostéroïdes. Dans la présente étude, nous avons recherché les effets de deux endozépines, le TTN et l'ODN ainsi que les effets du GABA sur l'activité de la 3-HSD dans le cerveau. Des expériences de double marquage révèlent que les neurones hypothalamiques 3-HSD-positifs contiennent également les récepteurs des benzodiazépines de type périphérique (PBR) ainsi que les sous-unités α3, β2 et/ou β3 des récepteurs GABA A. Nous avons aussi observé que les cellules gliales ODN-immunoréactives jouxtent les neurones 3-HSD-positifs. L'incubation d'explants hypothalamique en présence du TTN induit une stimulation de la production de 17OH-delta5P, 17OH-P et d'un nouveau stéroïde. L'effet du TTN est mimé par le Ro5-4864, un agoniste des PBR, et réduit par le PK11195, un antagoniste des PBR. Nous avons ensuite observé que l'ODN, un ligand endogène des récepteurs des benzodiazépines de type central (CBR), stimule également la biosynthèse des neurostéroïdes. Les β-carbolines β-CCM et DMCM, deux agonistes inverses des CBR, miment l'effet de l'ODN, alors que le flumazénil, un antagoniste des CBR réduit significativement l'effet de l'ODN, du β-CCM et du DMCM. Enfin, le GABA induit une inhibition dose-dépendante de la formation des stéroïdes dans le cerveau. L'effet du GABA est mimé par le muscimol, un agoniste des récepteurs GABA A, et bloqué par la bicuculline et le SR95531, deux antagonistes des récepteurs GABA A. En revanche, le baclofène, un agoniste des récepteurs GABA B, n'a aucun effet sur la synthèse des neurostéroïdes. L'ensemble de ces données démontre pour la première fois que l'activité biologique de la 3β-HSD et du cytochrome P450 C17 dans le système nerveux central des vertébrés est régulée par les endozépines et le GABA via les PBR et les récepteurs GABA A.
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Santos, Betânia Rodrigues dos. "Estudo da associação entre polimorfismos do gene do receptor de vitamina D (VDR) e do SNP-71 A/G do gene 17 beta- hidroxiesteróide desidrogenase tipo 5 (HSD17B5) e variáveis clínicas, hormonais e metabólicas em pacientes com pubarca precoce e controles." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2011. http://hdl.handle.net/10183/31696.
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A pubarca precoce (PP) é definida como o desenvolvimento de pêlos pubianos antes dos 8 anos de idade em meninas e 9 anos de idade em meninos. Embora a PP não interfira diretamente com os eventos da puberdade, algumas evidências sugerem que estas meninas tenham maior risco para desenvolver, mais tarde, a Síndrome dos Ovários Policísticos (PCOS). A 17ß-hidroxiesteróide desidrogenase tipo 5 (17ßHSD5) é a principal responsável pela conversão de androstenediona em testosterona. Variações no gene que codifica para essa enzima, em especial os polimorfismos de nucleotídeo único (SNPs), podem estar relacionados com hiperandrogenismo e PCOS. A vitamina D, além dos efeitos sobre metabolismo ósseo, parece modular outras ações extra-esqueléticas, incluindo secreção e sensibilidade tecidual à insulina. A Vitamina D vem sendo associada com resistência insulínica e variantes do gene do receptor da vitamina D (VDR), vem sendo estudadas em populações de risco como no diabetes. No entanto, pouco se sabe sobre o envolvimento destes polimorfismos na PP. Os objetivos do presente trabalho foram: Avaliar os níveis de 25-hidroxivitamina D; determinar a frequência dos polimorfismos FokI, BsmI, ApaI e TaqI do gene do VDR e do SNP-71AG do gene da 17ßHSD5; verificar se existe associação entre esses polimorfismos com variáveis antropométricas, metabólicas e hormonais em uma amostra de pacientes com PP e controles do sul do Brasil. Foram arroladas 36 meninas com PP e 197 controles saudáveis. As genotipagens foram realizadas por PCR em tempo real para os SNPs -71AG, BsmI e FokI e por PCR-RFLP para os SNPs ApaI e TaqI. O SNP -71 AG do gene da 17ßHSD5 apresentou distribuição genotípica de 52,4% AA, 39,1% AG e 8,6% GG, sendo a frequência dos alelos A:G de 0,72:0,28. Analisando os dois grupos, verificamos uma maior freqüência do alelo variante (G) no grupo de meninas com PP quando comparadas aos controles (0,37 e 0,26, respectivamente), no entanto sem diferença estatística (p=0,054); não foram verificadas associações do polimorfismo com os dados clínicos e hormonais. As meninas com PP apresentaram níveis séricos de 25(OH)D inferiores aos das meninas controles (18,08±8,32 versus 21,27±7,03; p=0,032). Na análise dos polimorfismos, observou-se que o genótipo polimórfico GG do SNP ApaI TG, apresentou uma frequência maior em PP (30,6%) do que nas controles (16,2%) (Odds Ratio: 2,269; 95% Intervalo de Confiança: 1,015 – 5,076; p=0,042). Este genótipo foi também associado com níveis mais baixos de estradiol (35,30 (14,80 – 50,48) versus 12,22 (6,49 – 23,69); p=0,030) e testosterona total (0,52 (0,39 – 0,84) versus 0,20 (0,11 – 0,47); p=0,009) nas meninas com PP, mas não foi associado com os níveis de 25(OH)D. Por outro lado, verificou-se associação entre a presença dos polimorfismos TaqI TC (genótipo TC+CC) e BsmI GA (genótipo GA+AA) e níveis séricos de 25(OH)D mais elevados no grupo de meninas saudáveis (19,86±7,16 versus 22,55±6,69, p=0,007; 19,53±6,94 versus 22,88±6,76, p=0,001, respectivamente). Em conclusão, os dados deste estudo indicam que: 1) houve maior freqüência do alelo variante G SNP -71 AG do gene da 17βHSD5, com uma associação limítrofe desse alelo com o diagnóstico clínico de PP; 2) o polimorfismo ApaI TG associou-se com PP e parece estar modulando os processos esteroidogênicos nas meninas com PP; 3) houve uma interação entre os polimorfismos TaqI TC e BsmI GA e concentrações circulantes de vitamina D em meninas do sul do Brasil.Precocious pubarche (PP) is usually defined as the development of pubic hair before the age of 8 in girls and age of 9 in boys. Although the PP does not interfere directly in puberty events, some evidence suggests that these girls have higher risk for the development of Polycystic Ovary Syndrome (PCOS) at later ages. The Type 5 17β-Hydroxysteroid Dehydrogenase (17ßHSD5) is the principal responsible for the conversion of androstenedione to testosterone. Variations in the gene encoding for this enzyme, especially Single Nucleotide polymorphisms (SNPs), may be related with hyperandrogenism, and PCOS. Besides the effects on bone metabolism, vitamin D appears to modulate other extra-skeletal actions, including secretions and tissue sensitivity to insulin. Vitamin D has been associated with insulin resistance and variants in the vitamin D receptor (VDR) gene, have been studied in populations at risk of Diabetes. However, little is known about these polymorphisms in the PP. The aims of this work were: to evaluate the levels of the 25-hydroxyvitamin D; to determine the polymorphisms FokI, BsmI, ApaI and TaqI in VDR gene and SNP -71AG in 17ßHSD5 gene frequencies; to asses if exist association between this SNPs and anthropometric, metabolic and hormonal characteristics in patients with PP and controls of the southern Brazil. Were enrolled 36 girls with PP and 197 healthy controls. Genotypic analyzes were evaluated by Real Time for the SNPs -71AG, BsmI and FokI and by PCR-RFLP for the ApaI e TaqI polymorphisms. Genotype frequency for SNP -71 AG of the 17ßHSD5 gene was 52.4% AA, 39.1% AG and 8.6% GG, A:G allelic frequency was 0.72:0.28. Analyzing both groups, higher frequency of the variant allele (G) in patient PP than controls (0.37 e 0.26, respectively) was found but without statistical difference (p=0.054); there were no associations between this polymorphism and clinical and hormonal features. PP girls have serum levels of 25(OH)D lower than those from control group (18.08±8.32 versus 21.27±7.03; p=0.032). The polymorphism analyze was observed that genotype GG of the SNP ApaI TG showed a higher frequency in PP (30.6%) than controls (16.2%) (Odds Ratio: 2.269; 95% confidence interval: 1.015 – 5.076; p=0.042). The same genotype was associated with lower estradiol (35.30 (14.80 – 50.48) versus 12.22 (6.49 – 23.69); p=0.030) and total testosterone levels (0.52 (0.39 – 0.84) versus 0.20 (0.11 – 0.47); p=0.009), in girls with PP. There were no association between this polymorphism and serum 25(OH)D. On the other hand, there was association between the presence of the polymorphisms TaqI TC (TC + CC genotype) and BsmI GA (GA + AA genotype) and higher serum 25(OH)D in the group of healthy girls (19.86 ± 7.16 versus 6.69 ± 22:55 , p = 0.007; 19:53 ± 6.94 versus 22.88 ± 6.76, p = 0.001, respectively). In conclusion, data from this study indicate that: 1) there was a higher frequency of the variant allele G of the SNP -71 AG of the 17ßHSD5 gene, with a borderline association of this allele with the clinical diagnosis of PP; 2) ApaI TG polymorphism is associated with PP and seems to modulate the processes steroidogenesis in girls with PP; 3) there was an interaction between the polymorphisms TaqI TC and BsmI GA and vitamin D concentrations in girls from southern Brazil.
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Ziegler, Erika [Verfasser]. "Design, Synthese und biologische Evaluierung nichtsteroidaler, potenter und selektiver Inhibitoren der 17β-Hydroxysteroid-Dehydrogenase [17-beta-Hydroxysteroid-Dehydrogenase] Typ 1 (17β-HSD1) [(17-beta-HSD1)] / von Erika Ziegler." 2007. http://d-nb.info/983906009/34.
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Lin, Liang-Yi, and 林良怡. "Expression and Characterization of A Novel 17-beta Hydroxysteroid Dehydrogenase of Human and Zebrafish." Thesis, 2003. http://ndltd.ncl.edu.tw/handle/16224509716232782021.
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碩士中山醫學大學
營養科學研究所
91
ABSTRACT In this study, by using BLAST (Basic Local Alignment Search Tool), a novel 17-beta Hydroxysteroid Dehydrogenase of zebra fish(accession number AI477544) and human(accession number NP_115679) were found from NCBI (National Center for Biotechnology Information) nucleotide database. The novel 17-beta Hydroxysteroid Dehydrogenase cDNA of zebra fish was successfully amplified from the 0-7 days old zebra fish embryo cDNA library by using the combination of PCR and 3’rapid-amplification of cDNA ends (3’RACE) methods. The novel zebra fish cDNA had a 1469 bp open reading frame and 416 deduced amino acid. The novel human cDNA had a 3303bp open reading frame and 345 amino acid. Both enzyme had two domain, i.e. short chain alcohol dehydrogenase(adh_short) and steroid carried protein(SCP2)domain. The initial velocity analysis of both enzyme showed that two substrates, Estriol and 5-Androstene 3β,16α,17β-triol may participate in the catalytic reaction of the novel 17-beta Hydroxysteroid Dehydrogenase.
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Chen, Hsin-Yi, and 陳欣宜. "Cloning and Expression a Novel 17-beta Hydroxysteroid Dehydrogenase TypeⅧ of Human and Zebrafish." Thesis, 2004. http://ndltd.ncl.edu.tw/handle/07514870022419191593.
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碩士中山醫學大學
營養科學研究所
92
In this study, the search tool BLAST (Basic Local Alignment Search Tool), based on NCBI (National Center for Biotechnology Information) was used against nucleotide and protein databases. The analysis found a hydroxysteroid dehydrogenase (HSD) of zebrafish (NCBI accession numberAL672176/ CAD54662) and human (NCBI accession number NM_014234/ NP_055049). The HSD cDNA of zebrafish and human were successfully amplified with a continuous open reading frame of 771 bps and 786 bps encoding a protein of 256 and 261 amino acids with a calculated molecular mass of 26.970 kDa and 26.974 kDa respectively. Zebrafish and human HSD were cloned and expressed with a 6-histidine tag for specific purification. The purified recombinant proteins have mobility of 32 kDa and 29 kDa on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Western and Northern analysis showed that HSD is expressed in the rat tissues, such as brain, heart, intestine, kidney, muscle, lung, liver, spleen, and testis. Following expression, purification and the kinetic studies, using 16α hydroxyestrone and NAD+ as substrates, the specific activities of Ni2+ column purified recombinant zebrafish and human HSD were 62.42 and 311.17 unit/mg respectively. Therefore, we renamed these enzymes 16α-hydroxysteroid dehydrogenase.
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Qiu, Wei. "X-ray crystallographic studies of human estrogenic type 1 and androgenic type 5 17[beta]-hydroxysteroid dehydrogenases /." 2002. http://proquest.umi.com/pqdweb?did=765056441&sid=21&Fmt=2&clientId=9268&RQT=309&VName=PQD.
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Kruchten, Patricia [Verfasser]. "Entwicklung eines Screeningsystems zur Identifizierung hochaktiver und selektiver Hemmstoffe der 17β-Hydroxysteroid-Dehydrogenase [17-Beta-Hydroxysteroid-Dehydrogenase] Typ 1 (17βHSD1) [(17betaHSD1)] / von Patricia Kruchten." 2009. http://d-nb.info/99846984X/34.
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LU, ZHAO-YUAN, and 盧昭元. "The induction of 17▫-hydroxysteroid dehydrogenase by ovariansyeroids of rat endometrial cells in vitro." Thesis, 1990. http://ndltd.ncl.edu.tw/handle/59810338767743870724.
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Mohamed, Bassim. "Role of the 17-beta-hydroxysteroid dehydrogenase type 12 (HSD17B12) in hepatitis C and related flaviviruses replication." Thèse, 2019. http://hdl.handle.net/1866/23512.
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Dans le monde entier, les infections virales causent des problèmes de santé majeurs et récurrents, engendrant de sérieux problèmes socio-économiques. Notamment, les virus de la famille Flaviviridae qui représentent un fardeau considérable sur la santé mondiale et font partie des domaines prioritaires de la virologie médicale selon le rapport 2016 du ‘Global Virus Network’. Bien que le traitement actuel contre le virus de l’hépatite C (VHC) ait un taux de guérison dépassant 98%, d’autres comme le virus de la dengue (DENV) et le virus zika (ZIKV) n’ont pas encore de traitement spécifique autorisé. En prenant avantage de la grande expertise de notre laboratoire dans l’étude du VHC, nous avons utilisé des données d’une étude de biologie des systèmes visant à identifier l’interactome des différentes protéines virales. Les techniques utilisées ont combiné l’immunoprécipitation des protéines virales suivie de l’identification des protéines interacteurs humaines par spectrométrie de masse. Des études de génomique fonctionnelle par ARN interférent (ARNi) ont permis d’étudier l’effet de la diminution de l’expression des protéines identifiées sur la réplication du VHC. Cette étude a conduit à la découverte de l’interactant spécifique 17-bêta-hydroxystéroïde déshydrogénase de type 12 (HSD17B12 ou DHB12) de la protéine virale Core comme facteur cellulaire requis à la réplication du VHC. HSD17B12 est une enzyme cellulaire dont l’activité catalytique est requise pour l’élongation des acides gras à très longue chaîne (VLCFA) lors de la deuxième des quatre réactions du cycle d’élongation. Dans cette étude, nous avons déterminé que les cycles de réplication du VHC, ZIKV et DENV dépendent de l’expression et de l’activité métabolique du facteur cellulaire HSD17B12. Ainsi, nous avons étudié les effets de l’inhibition de l’expression génique par ARNi et de façon pharmacologique sur la réplication de plusieurs flavivirus dans une approche antivirale à large spectre. Nous avons démontré que le silençage de HSD17B12 diminue significativement la réplication virale, l’expression des protéines virales et la production de particules infectieuses de cellules Huh7.5 infectées par la souche JFH1 du VHC. L'analyse de la localisation cellulaire de HSD17B12 dans des ii cellules infectées suggère une colocalisation avec l'ARN double brin (ARNdb) aux sites de réplication virale, ainsi qu’avec la protéine Core (et les gouttelettes lipidiques) aux des sites d’assemblage du virus. Nous avons également observé que le silençage de HSD17B12 réduit considérablement le nombre et la taille des gouttelettes lipidiques. En accord avec ces données, la diminution de l’expression de HSD17B12 par ARNi réduit significativement l’acide oléique et les espèces lipidiques telles que triglycérides et phosphatidyl-éthanolamine dans l'extrait cellulaire total. Ces travaux suggèrent une contribution de la capacité métabolique de HSD17B12 lors de la réplication du VHC. De même, nous avons démontré que le silençage de HSD17B12 réduit significativement les particules infectieuses de cellules infectées par DENV et ZIKV. Ces études supportent le rôle de HSD17B12 dans l’efficacité des processus de la réplication de l'ARN viral et de l’assemblage de particules virales. De plus, l'inhibiteur spécifique de HSD17B12, INH-12, réduit la réplication du VHC à des concentrations pour lesquelles aucune cytotoxicité notable n'est observée. Le traitement avec 20 μM d'INH-12 réduit jusqu'à 1,000 fois les particules infectieuses produite par des cellules Huh-7.5 infectées par DENV et ZIKV lors de plusieurs cycles de réplication, et bloque complètement l'expression des protéines virales. En conclusion, ces travaux ont conduit à une meilleure compréhension du rôle de HSD17B12 lors de la synthèse de VLCFA et de lipides requise à la réplication du VHC, permettant d’explorer l’inhibition de HSD17B12 et de l’élongation d’acides gras à très longue chaîne comme nouvelle approche thérapeutique pour le traitement à large spectre des infections par les virus de la famille Flaviviridae.Infections with viruses are major recurrent socio-economical and health problems worldwide. These include infections by viruses of the Flaviviridae family, which present a substantial global health burden and are among the priority areas of medical virology according to the Global Virus Network 2016 report. While the current treatment regimens for hepatitis C virus (HCV) infection have cure rates of more than 98%, other important members of Flaviviridae like dengue virus (DENV) and zika virus (ZIKV) have no specific licensed treatments. By taking advantage of the most-studied HCV, which our lab has developed a vast expertise in the last 20 years, we used proteomics data of an HCV interactome study, combining viral protein immunoprecipitation (IP) coupled to tandem mass spectrometry identification (IP-MS/MS) and functional genomics RNAi screening. The study uncovered the 17-beta-hydroxysteroid dehydrogenase type 12 (HSD17B12, also named DHB12), as a specific host interactor of core that promotes HCV replication. HSD17B12 catalytic activity is involved in the synthesis of very-long-chain fatty acids (VLCFA) upon the second step of the elongation cycle. In this study, taking HCV as a virus model, we elucidated the dependency of HCV, dengue virus (DENV) and zika virus (ZIKV) replication on expression and metabolic capacity of the host factor HSD17B12. We investigated the effects of the inhibition of gene expression by RNAi and of its pharmacological enzymatic inhibition on flavivirus replication in a broad-spectrum antiviral approach. We showed that silencing expression of HSD17B12 decreases viral replication, viral proteins and iv infectious particle production of the JFH1 strain of HCV in Huh7.5 cells. The cellular localization analysis of HSD17B12 showed a co-staining with double-stranded RNA (dsRNA) at viral replication sites and with core protein (and lipid droplets) at virus assembly sites. Furthermore, HSD17B12 gene silencing drastically reduced the number and size of lipid droplets. In association, the reduced expression of HSD17B12 by RNAi decreases oleic acid levels and lipids such as triglycerides (TG) and phosphatidylethanolamine (PE) in whole-cell extract. The data suggested the requirement of the metabolic capacity of HSD17B12 for HCV replication. Similarly, we provide evidence that HSD17B12 silencing significantly reduces DENV and ZIKV infectious particles. The studies support a role of HSD17B12 for effective viral RNA replication and particle assembly processes. Moreover, the specific HSD17B12 inhibitor, INH-12, reduces HCV replication at concentrations for which no appreciable cytotoxicity is observed. The treatment of DENV- and ZIKV-infected Huh- 7.5 cells with 20 μM of INH-12 dramatically reduces production of infectious particles by up to 3-log10 in infection assays, and completely block viral protein expression. In conclusion, these studies extends our understanding of the role of HSD17B12 in VLCFA synthesis required for the replication of HCV, allowing to explore the inhibition of HSD17B12 and elongation of VLCFA as a novel therapeutic approach for the treatment of a broad-spectrum of viruses of the Flaviviridae family.
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DENG, SU-PING, and 鄧素蘋. "The effects of estrogenic hormones on 17▫-hydroxysteroid dehydrogenase activity in human breast cancer in vitro." Thesis, 1990. http://ndltd.ncl.edu.tw/handle/16561260172466067856.
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ZHANG, WEI-CHEN, and 章偉成. "The induction of 17 B -hydroxysteroid dehydrogenase activity in human breast cancer tissues by estrogen and progesterone in vitro." Thesis, 1993. http://ndltd.ncl.edu.tw/handle/67299684319905789685.
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Bey, Emmanuel [Verfasser]. "Development of a new class of potent and selective non-steroidal inhibitors of 17β-hydroxysteroid [17-beta-hydroxysteroid] dehydrogenase type 1 : bis(hydroxyphenyl)substituted azoles, thiophenes, benzenes and aza-benzenes / von Emmanuel Bey." 2008. http://d-nb.info/1010643576/34.
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Lämmermann, Nicole [Verfasser]. "Die 17β-Hydroxysteroid-Dehydrogenase [17-beta-Hydroxysteroid-Dehydrogenase] 4 in der gesunden Brustdrüse - Expression von Östrogen- und Progesteronrezeptoren in der gesunden Brustdrüse : Untersuchungen im Verlauf des normalen ovariellen Zyklus und bei hormoneller Antikonzeption / vorgelegt von Nicole Laemmermann." 2004. http://d-nb.info/979914833/34.
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Shi, Rong. "Estrogen and androgen discrimination by human 17[beta]-hydroxysteroid dehydrogenase type 1 and a conserv ed cofactor binding more in the short-chain dehydrogenase/reductase family /." 2004. http://proquest.umi.com/pqdweb?did=765362621&sid=12&Fmt=2&clientId=9268&RQT=309&VName=PQD.
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