scholarly journals Emodin, an 11β-hydroxysteroid dehydrogenase type 1 inhibitor, regulates adipocyte function in vitro and exerts anti-diabetic effect in ob/ob mice

2012 ◽  
Vol 33 (9) ◽  
pp. 1195-1203 ◽  
Author(s):  
Yue-jing Wang ◽  
Su-ling Huang ◽  
Ying Feng ◽  
Meng-meng Ning ◽  
Ying Leng
Keyword(s):  
Hydroxysteroid Dehydrogenase

An in vitro microdialysis methodology to study 11β-hydroxysteroid dehydrogenase type 1 enzyme activity in liver microsomes

2007 ◽  
Vol 370 (1) ◽  
pp. 26-37 ◽  
Author(s):  
Li Sun ◽  
Julie A. Stenken ◽  
Amy Y. Yang ◽  
Jamie J. Zhao ◽  
Donald G. Musson
Keyword(s):  
Enzyme Activity ◽  
Liver Microsomes ◽  
Hydroxysteroid Dehydrogenase

scholarly journals 17β-Hydroxysteroid Dehydrogenase Type 1, 2, 3, and 4 Expression and Enzyme Activity in Human Anterior Pituitary Adenomas

1999 ◽  
Vol 84 (4) ◽  
pp. 1340-1345
Author(s):  
V. L. Green ◽  
V. Speirs ◽  
A. M. Landolt ◽  
P. M. Foy ◽  
S. L. Atkin
Keyword(s):  
Gene Expression ◽  
Enzyme Activity ◽  
Pituitary Adenomas ◽  
Anterior Pituitary ◽  
Estrogenic Activity ◽  
Hydroxysteroid Dehydrogenase ◽  
Messenger Ribonucleic Acid ◽  
Human Anterior Pituitary

17β-Hydroxysteroid dehydrogenase (17βHSD) isoforms reversibly catalyze the final step in the formation of estradiol (E2) from estrone (E1) and the formation of testosterone from androstenedione. We have investigated 17βHSD type 1, 2, 3, and 4 gene expression and 17βHSD estrogenic activity in human anterior pituitary adenomas. 17βHSD messenger ribonucleic acid (mRNA) expression was studied by RT-PCR in 42 pituitary tumors and 3 normal pituitaries, 17βHSD activity was studied in 11 tumors and 17βHSD type 1 was immunolocalized in vitro in 6 tumors. 17βHSD type 1 gene expression was detected in 34 of 42 adenomas in all tumor subtypes; 17βHSD type 2 mRNA was detected in 18 of 42 adenomas, but not in prolactinomas; 17βHSD type 3 mRNA was detected in 12 of 42 adenomas, but not in corticotropinomas; 17βHSD type 4 was expressed in 20 of 42 adenomas by all adenoma subtypes. Reversible 17βHSD activity was found in 9 of 11 adenomas, and 17βHSD type 1 immunopositivity was cytoplasmically distributed in all 6 adenomas in vitro. All 4 17βHSD isoforms are variably expressed in human anterior pituitary adenomas, which also show 17βHSD enzyme activity, suggesting that 17βHSD may play an important role in regulating the local cellular levels of estradiol.

scholarly journals Comparative investigation of the in vitro inhibitory potencies of 13-epimeric estrones and D-secoestrones towards 17β-hydroxysteroid dehydrogenase type 1

2016 ◽  
Vol 31 (sup3) ◽  
pp. 61-69 ◽  
Author(s):  
Bianka Edina Herman ◽  
Johanna Szabó ◽  
Ildikó Bacsa ◽  
János Wölfling ◽  
Gyula Schneider ◽  
...  
Keyword(s):  
Hydroxysteroid Dehydrogenase ◽  
Comparative Investigation

scholarly journals Direct antiproliferative effect of nonsteroidal 17β-hydroxysteroid dehydrogenase type 1 inhibitors in vitro

2012 ◽  
Vol 28 (4) ◽  
pp. 695-703 ◽  
Author(s):  
Ágnes Berényi ◽  
Martin Frotscher ◽  
Sandrine Marchais-Oberwinkler ◽  
Rolf W. Hartmann ◽  
Renáta Minorics ◽  
...  
Keyword(s):  
Hydroxysteroid Dehydrogenase ◽  
Antiproliferative Effect

scholarly journals Functional Effects of Polymorphisms in the Human Gene Encoding 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1): A Sequence Variant at the Translation Start of 11β-HSD1 Alters Enzyme Levels

Endocrinology ◽  
2010 ◽  
Vol 151 (1) ◽  
pp. 195-202 ◽  
Author(s):  
Elise L. V. Malavasi ◽  
Val Kelly ◽  
Nikita Nath ◽  
Alessandra Gambineri ◽  
Rachel S. Dakin ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Hydroxysteroid Dehydrogenase ◽  
In Vitro Translation ◽  
Metabolic Phenotype ◽  
Sequence Variant ◽  
Gene Encoding ◽  
Functional Consequences

Abstract Regeneration of active glucocorticoids within liver and adipose tissue by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) may be of pathophysiological importance in obesity and metabolic syndrome and is a therapeutic target in type 2 diabetes. Polymorphisms in HSD11B1, the gene encoding 11β-HSD1, have been associated with metabolic phenotype in humans, including type 2 diabetes and hypertension. Here, we have tested the functional consequences of two single nucleotide polymorphisms located in contexts that potentially affect tissue levels of 11β-HSD1. We report no effect of allelic variation at rs846910, a polymorphism within the 5′-flanking region of the gene on HSD11B1 promoter activity in vitro. However, compared with the common G allele, the A allele of rs13306421, a polymorphism located two nucleotides 5′ to the translation initiation site, gave higher 11β-HSD1 expression and activity in vitro and was translated at higher levels in in vitro translation reactions, possibly associated with a lower frequency of “leaky scanning.” These data suggest that this polymorphism may have direct functional consequences on levels of 11β-HSD1 enzyme activity in vivo. However, the rs13306421 A sequence variant originally reported in other ethnic groups may be of low prevalence because it was not detected in a population of 600 European Caucasian women.

Design, chemical synthesis, and in vitro biological evaluation of simplified estradiol–adenosine hybrids as inhibitors of 17β-hydroxysteroid dehydrogenase type 1

2009 ◽  
Vol 87 (8) ◽  
pp. 1180-1199 ◽  
Author(s):  
Marie Bérubé ◽  
Donald Poirier
Keyword(s):  
Hydroxysteroid Dehydrogenase ◽  
Acid Group ◽  
Biological Evaluation ◽  
Benzene Derivative ◽  
Coupling Reactions ◽  
Cofactor Binding ◽  
Cross Metathesis ◽  
Key Steps

A series of estradiol (E2) derivatives were designed to interact with both the substrate- and the cofactor-binding sites of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1). These analogues of potent E2–adenosine hybrid inhibitor EM-1745, where the adenosine moiety was replaced by a more stable benzene derivative, were synthesized from estrone using alkene cross-metathesis and Sonogashira coupling reactions as key steps. In vitro biological evaluation of these steroid derivatives revealed that a spacer of 13 methylenes, between the 16β-position of E2 and the adenosine mimic bearing a carboxylic acid group, gave the best inhibition of 17β-HSD1.

scholarly journals Interactions between oestradiol and glucocorticoid regulatory effects on liver-specific glucocorticoid-inducible genes: possible evidence for a role of hepatic 11beta-hydroxysteroid dehydrogenase type 1

1999 ◽  
Vol 160 (1) ◽  
pp. 103-109 ◽  
Author(s):  
PM Jamieson ◽  
MJ Nyirenda ◽  
BR Walker ◽  
KE Chapman ◽  
Keyword(s):  
Phosphoenolpyruvate Carboxykinase ◽  
Hepatic Metabolism ◽  
Hydroxysteroid Dehydrogenase ◽  
Metabolic Functions ◽  
Rate Limiting Step ◽  
Regulatory Effects ◽  
Inducible Genes

In vitro, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) catalyses the interconversion of active corticosterone and inert 11-dehydrocorticosterone. 11beta-HSD-1 is highly expressed in liver, where the reaction direction is 11beta-reduction, thus potentially increasing intrahepatic active glucocorticoid levels. Inhibition of 11beta-HSD-1 increases insulin sensitivity in humans in vivo suggesting that hepatic 11beta-HSD-1 plays a role in the maintenance or control of key glucocorticoid-regulated metabolic functions. We have selectively repressed hepatic 11beta-HSD-1 in rats by oestradiol administration for 42 days. This nearly completely repressed hepatic 11beta-HSD-1 mRNA expression and enzyme activity and reduced expression of hepatic glucocorticoid-inducible genes including phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting step in gluconeogenesis. Similar effects were seen after 3 weeks of oestradiol treatment. To examine whether this was due to any direct effect of oestradiol upon PEPCK, the experiment was repeated in adrenalectomised rats+/-glucocorticoid replacement. In adrenalectomised rats, oestradiol did not attenuate hepatic PEPCK, whilst glucocorticoid replacement restored this action. Oestradiol did not alter hepatic metabolism of corticosterone by pathways other than 11beta-HSD-1. These data suggest 11beta-HSD-1 plays an important role in maintaining expression of key glucocorticoid-regulated hepatic transcripts. Enzyme inhibition may provide a useful therapeutic target for manipulating glucose homeostasis.

scholarly journals Regulation of 11beta-hydroxysteroid dehydrogenase type 1 gene expression by LH and interleukin-1beta in cultured rat granulosa cells

1999 ◽  
Vol 163 (3) ◽  
pp. 417-423 ◽  
Author(s):  
M Tetsuka ◽  
LC Haines ◽  
M Milne ◽  
GE Simpson ◽  
SG Hillier
Keyword(s):  
Gene Expression ◽  
Mrna Expression ◽  
Granulosa Cells ◽  
Hydroxysteroid Dehydrogenase ◽  
Releasing Hormone ◽  
Cell Monolayers ◽  
Interleukin 1Beta ◽  
Lh Releasing Hormone

Granulosa cells from preovulatory follicles show increased expression of 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) at the time of ovulation. As ovulation may be an inflammatory process, this may be a mechanism of local enhancement of the activity of anti-inflammatory glucocorticoids. In this study, we examined direct effects of LH, the proinflammatory cytokine, interleukin-1beta (IL-1beta), and pharmacological activators of protein kinase A (PKA) (forskolin and dibutyryl (db) cAMP) and PKC (LH-releasing hormone and phorbol 12-myristate 13-acetate (PMA)) signalling on the expression of 11betaHSD1 mRNA in vitro. Granulosa cells from immature female rat ovaries were cultured (pretreatment) in serum-free medium 199 containing recombinant human (rh) FSH (1 ng/ml) for 48 h to induce responsiveness to LH. Cell monolayers were then washed and cultured (test treatment) for a further 12 h in the presence of rhLH (0-100 ng/ml), IL-1beta (0-50 ng/ml), or both. Total RNA was extracted from granulosa cell monolayers and taken for quantitative ribonuclease protection analysis of 11betaHSD1 mRNA. The low level of 11betaHSD1 mRNA detectable in unstimulated (control) cultures was increased approximately twofold by the 48-h pretreatment with rhFSH. Subsequent exposure to rhLH (1-100 ng/ml) for a further 12 h dose-dependently increased 11betaHSD1 mRNA expression by an additional two- to threefold. Forskolin (10 microM), db-cAMP (2 mM), LH-releasing hormone (LHRH; 1 microM) and PMA (200 nM) were also stimulatory. IL-1beta (0.05-50 ng/ml) stimulated 11betaHSD1 mRNA expression in a dose-related manner, both in the absence and in the presence of rhLH (3 ng/ml). The interaction between IL-1beta (5 ng/ml) and rhLH (3 ng/ml) was additive. Co-treatment with a 50-fold excess of IL-1 receptor antagonist fully reversed the action of IL-1beta. We conclude that 11betaHSD1 mRNA expression in functionally mature granulosa cells is directly stimulated by gonadotrophins and IL-1beta in vitro, potentially involving post-receptor signalling via PKA- and PKC-mediated pathways. Thus both LH and IL-1beta may serve physiological roles in the upregulation of 11betaHSD1 gene expression by granulosa cells in ovulatory follicles.

scholarly journals Synthesis of novel 13α-estrone derivatives by Sonogashira coupling as potential 17β-HSD1 inhibitors

2017 ◽  
Vol 13 ◽  
pp. 1303-1309 ◽  
Author(s):  
Ildikó Bacsa ◽  
Rebeka Jójárt ◽  
János Wölfling ◽  
Gyula Schneider ◽  
Bianka Edina Herman ◽  
...  
Keyword(s):  
Methyl Ether ◽  
Hydroxysteroid Dehydrogenase ◽  
Coupling Reactions ◽  
Sonogashira Coupling ◽  
Partial Saturation ◽  
Inhibitory Effects ◽  
Microwave Reactor ◽  
Incubation Method

Novel 13α-estrone derivatives were synthesized by Sonogashira coupling. Transformations of 2- or 4-iodo regioisomers of 13α-estrone and its 3-methyl ether were carried out under different conditions in a microwave reactor. The 2-iodo isomers were reacted with para-substituted phenylacetylenes using Pd(PPh3)4 as catalyst and CuI as a cocatalyst. Coupling reactions of 4-iodo derivatives could be achieved by changing the catalyst to Pd(PPh3)2Cl2. The product phenethynyl derivatives were partially or fully saturated. Compounds bearing a phenolic OH group furnished benzofurans under the conditions used for the partial saturation. The inhibitory effects of the compounds on human placental 17β-hydroxysteroid dehydrogenase type 1 isozyme (17β-HSD1) were investigated by an in vitro radiosubstrate incubation method. Certain 3-hydroxy-2-phenethynyl or -phenethyl derivatives proved to be potent 17β-HSD1 inhibitors, displaying submicromolar IC50 values.

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