Showing papers on "Hydroxysteroid dehydrogenase published in 2017"

First Dual Inhibitors of Steroid Sulfatase (STS) and 17β-Hydroxysteroid Dehydrogenase Type 1 (17β-HSD1): Designed Multiple Ligands as Novel Potential Therapeutics for Estrogen-Dependent Diseases

Abstract: STS and 17β-HSD1 are attractive targets for the treatment of estrogen-dependent diseases like endometriosis and breast cancer. The simultaneous inhibition of both enzymes appears more promising than blockage of either protein alone. We describe a designed multiple ligand approach resulting in highly potent dual inhibitors. The most interesting compound 9 showed nanomolar IC50 values for both proteins, membrane permeability, and no interference with estrogen receptors. It efficiently reversed E1S- and E1-induced T47D cell proliferation.

Liver X receptor α induces 17β-hydroxysteroid dehydrogenase-13 expression through SREBP-1c

Abstract: Liver X receptors, including LXRα and LXRβ, are known to be master regulators of liver lipid metabolism. Activation of LXRα increases hepatic lipid storage in lipid droplets (LDs). 17β-Hydroxystero...

Potential Antiosteoporotic Natural Product Lead Compounds That Inhibit 17β-Hydroxysteroid Dehydrogenase Type 2

Abstract: 17β-Hydroxysteroid dehydrogenase type 2 (17β-HSD2) converts the active steroid hormones estradiol, testosterone, and 5α-dihydrotestosterone into their weakly active forms estrone, Δ4-androstene-3,17-dione, and 5α-androstane-3,17-dione, respectively, thereby regulating cell- and tissue-specific steroid action. As reduced levels of active steroids are associated with compromised bone health and onset of osteoporosis, 17β-HSD2 is considered a target for antiosteoporotic treatment. In this study, a pharmacophore model based on 17β-HSD2 inhibitors was applied to a virtual screening of various databases containing natural products in order to discover new lead structures from nature. In total, 36 hit molecules were selected for biological evaluation. Of these compounds, 12 inhibited 17β-HSD2 with nanomolar to low micromolar IC50 values. The most potent compounds, nordihydroguaiaretic acid (1), IC50 0.38 ± 0.04 μM, (−)-dihydroguaiaretic acid (4), IC50 0.94 ± 0.02 μM, isoliquiritigenin (6), IC50 0.36 ± 0.08 μM, a...

Class-Specific Histone Deacetylase Inhibitors Promote 11-Beta Hydroxysteroid Dehydrogenase Type 2 Expression in JEG-3 Cells.

Abstract: Exposure to maternal cortisol plays a crucial role in fetal organogenesis. However, fetal overexposure to cortisol has been linked to a range of short- and long-term adverse outcomes. Normally, this is prevented by the expression of an enzyme in the placenta called 11-beta hydroxysteroid dehydrogenase type 2 (11β-HSD2) which converts active cortisol to its inactive metabolite cortisone. Placental 11β-HSD2 is known to be reduced in a number of adverse pregnancy complications, possibly through an epigenetic mechanism. As a result, a number of pan-HDAC inhibitors have been examined for their ability to promote 11β-HSD2 expression. However, it is not known if the effects of pan-HDAC inhibition are a general phenomenon or if the effects are dependent upon a specific class of HDACs. Here, we examined the ability of pan- and class-specific HDAC inhibitors to regulate 11β-HSD2 expression in JEG3 cells. We find that pan-, class I, or class IIa HDAC inhibition promoted 11β-HSD2 expression and prevented cortisol or interleukin-1β-induced decrease in its expression. These results demonstrate that targeting a specific class of HDACs can promote 11β-HSD2 expression in JEG3 cells. This adds to the growing body of evidence suggesting that HDACs may be crucial in maintaining normal fetal development.

Investigation of the In Vitro and In Vivo efficiency of RM-532-105, a 17β-hydroxysteroid dehydrogenase type 3 inhibitor, in LAPC-4 prostate cancer cell and tumor models.

Abstract: In the fight against androgen-sensitive prostate cancer, the enzyme 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) is an attractive therapeutic target considering its key role in the formation of androgenic steroids. In this study, we attempted to assess the in vivo efficacy of the compound RM-532-105, an androsterone derivative developed as an inhibitor of 17β-HSD3, in the prostate cancer model of androgen-sensitive LAPC-4 cells xenografted in nude mice. RM-532-105 did not inhibit the tumor growth induced by 4-androstene-3,17-dione (4-dione); rather, the levels of the androgens testosterone (T) and dihydrotestosterone (DHT) increased within the tumors. In plasma, however, DHT levels increased but T levels did not. In troubleshooting experiments, the non-androgenic potential of RM-532-105 was confirmed by two different assays (LAPC-4 proliferation and androgen receptor transcriptional activity assays). The enzyme 5α-reductase was also revealed to be the predominant enzyme metabolizing 4-dione in LAPC-4 cells, yielding 5α-androstane-3,17-dione and not T. Other 17β-HSDs than 17β-HSD3 seem responsible in the androgen synthesis. From experiments with LAPC-4 cells, we fortuitously came across the interesting finding that 17β-HSD3 inhibitor RM-532-105 is concentrated inside tumors.

46,XY Disorder of Sex Development due to 17-Beta Hydroxysteroid Dehydrogenase Type 3 Deficiency in an Infant of Greek Origin.

Abstract: 17-beta hydroxysteroid dehydrogenase type 3 (17βHSD-3) enzyme catalyzes the conversion of androstenedione (Δ4) to testosterone (T) in the testes of the developing fetus, thus playing a crucial role in the differentiation of the gonads and in establishing the male sex phenotype. Any mutation in the encoding gene (HSD17B3) can lead to varying degrees of undervirilization of the affected male, ranging from completely undervirilized external female genitalia to predominantly male with micropenis and hypospadias. We present here an infant who was referred to our clinic because of ambiguous genitalia at birth. Gonads were palpable in the inguinal canal bilaterally and no Mullerian structures were identified on pelvic ultrasound. Because of a low T/Δ4 ratio after a human chorionic gonadotropin stimulation test, a tentative diagnosis of 17βHSD-3 deficiency was made which was confirmed after genetic analysis of the HSD17B3 gene of the patient. The molecular analysis identified compound heterozygosity of two previously described mutations and could offer some further validation for the idea of a founder effect for 655-1;G→A mutation in the Greek population.

Clostridium sardiniense 7alpha-hydroxysteroid dehydrogenase mutant T145S

Abstract: The invention relates to hydroxysteroid dehydrogenase and particularly relates to a clostridium sardiniense 7alpha-hydroxysteroid dehydrogenase mutant T145S. The amino acid sequence of the clostridium sardiniense 7alpha-hydroxysteroid dehydrogenase mutant T145S is shown by SEQ ID No:2 and obtained by changing the 145th-site amino acid of the 7alpha-hydroxysteroid dehydrogenase with an amino acid sequence of SEQ ID No:1 from Thr into Ser. The mutant is 4.85 times of a wild type in the catalysis efficiency against the substrates TCDCA and NADP and has a huge application potential in a biotransformation process of CDCA/TCDCA for obtaining UDCA/TUDCA.

Hydroxysteroid dehydrogenase HSD1L is localised to the pituitary–gonadal axis of primates

Abstract: Steroid hormones play clinically important and specific regulatory roles in the development, growth, metabolism, reproduction and brain function in human. The type 1 and 2 11-beta hydroxysteroid dehydrogenase enzymes (11β-HSD1 and 2) have key roles in the pre-receptor modification of glucocorticoids allowing aldosterone regulation of blood pressure, control of systemic fluid and electrolyte homeostasis and modulation of integrated metabolism and brain function. Although the activity and function of 11β-HSDs is thought to be understood, there exists an open reading frame for a distinct 11βHSD-like gene; HSD11B1L, which is present in human, non-human primate, sheep, pig and many other higher organisms, whereas an orthologue is absent in the genomes of mouse, rat and rabbit. We have now characterised this novel HSD11B1L gene as encoded by 9 exons and analysis of EST library transcripts indicated the use of two alternate ATG start sites in exons 2 and 3, and alternate splicing in exon 9. Relatively strong HSD11B1L gene expression was detected in human, non-human primate and sheep tissue samples from the brain, ovary and testis. Analysis in non-human primates and sheep by immunohistochemistry localised HSD11B1L protein to the cytoplasm of ovarian granulosa cells, testis Leydig cells, and gonadatroph cells in the anterior pituitary. Intracellular localisation analysis in transfected human HEK293 cells showed HSD1L protein within the endoplasmic reticulum and sequence analysis suggests that similar to 11βHSD1 it is membrane bound. The endogenous substrate of this third HSD enzyme remains elusive with localisation and expression data suggesting a reproductive hormone as a likely substrate.

DISTURBANCE OF 20α-HYDROXYSTEROID DEHYDROGENASE ACTIVITY IN VILLOUS CHORION SYNCIOTHYTHROPHOBLAST AT REACTIVATION OF CYTOMEGALOVIRUS INFECTION DURING PREGNANCY

Abstract: Цель работы – оценка характера влияния цитомегаловирусной инфекции на активность 20α-гидроксистероиддегидрогеназы в синцитиотрофобласте ворсинчатого хориона в первом триместре беременности. Материалом для исследования послужили 48 ворсинчатых хорионов, взятых при самопроизвольных абортах в срок 8-10 недель от женщин с реактивацией хронической цитомегаловирусной инфекции во время беременности (основная группа). Контрольную группу составили 35 ворсинчатых хорионов беременных с хронической цитомегаловирусной инфекцией в латентной стадии, взятых при проведении медицинских абортов на том же сроке гестации. Результаты обследования беременных женщин анализировали с позиции активности цитомегаловирусной инфекции иммуноферментным методом по наличию антител IgM или по величине четырехкратного и более нарастания титра антител IgG в парных сыворотках в динамике через 10 дней. Активность 20α-гидроксистероиддегидрогеназы оценивали гистохимическим методом. Количественная оценка продуктов реакции на срезах проводилась под микроскопом МТ (Япония), связанным с программноаппаратным комплексом SCION Corporation (США). На гистохимических препаратах ворсинчатого хориона беременных основной группы, перенесших обострение хронической цитомегаловирусной инфекции, отмечалось снижение цитофотометрического показателя активности 20α-гидроксипрогестерондегидрогеназы до 30,1±2,12 пикселей/мкм2 (р<0,001) по сравнению с контрольной группой. Снижение активности реакции в синцитиотрофобласте ворсинок плаценты указывало на уменьшение содержания 20α-дигидропрогестерона в плаценте, что способствовало, по нашему мнению, прерыванию беременности. Ключевые слова: цитомегаловирус, ворсинчатый хорион, беременность, прогестерон, 20α-дигидропрогестерон.

NOVEL 7β-HYDROXYSTEROID DEHYDROGENASE MUTANTS AND PROCESSES FOR PREPARING URSODEOXYCHOLIC ACID

Abstract: PROBLEM TO BE SOLVED: To provide further improved 7β-HSDH, in particular, to provide enzyme mutants for more convenient enzymatic or microbial preparation of UDCA via stereoselective reduction of DHCA in position 7 to 3, 12-diketo-7β-CA.SOLUTION: Provided is a 7β-hydroxysteroid dehydrogenase (7β-HSDH) mutant that catalyzes conversion of 7-ketosteroid to corresponding 7-hydroxysteroid at least by stereospecific enzymatic reduction, where the mutant comprises at least one mutation in a sequence motif VMVGRRE at positions 36-42 of SEQ ID NO:2, and has at least 90% sequence identity to SEQ ID NO:2.SELECTED DRAWING: None

Novel 7beta-hydroxysteroid dehydrogenase gene Y1-b-1

Abstract: The invention relates to a hydroxysteroid dehydrogenase and particularly relates to a novel 7beta-hydroxysteroid dehydrogenase gene Y1-b-1 A nucleotide sequence of the gene is as shown in SEQ ID NO2; a novel 7beta-hydroxysteroid dehydrogenase is encoded and an amino acid sequence thereof is as shown in SEQ ID NO1 Epimerization of 7-hydroxy of ursodesoxycholic acid (UDCA) and tauroursodeoxycholic acid (TUDCA) can be catalyzed to generate intermediates 7-ketone lithocholic acid (7K-LCA) and taurine 7-ketone lithocholic acid (T7K-LCA) of chenodeoxycholic acid (CDCA) and taurochenodeoxycholic acid (TCDCA) The specific activity of the novel 7beta-hydroxysteroid dehydrogenase gene Y1-b-1 on the UDCA and the TUDCA is equivalent to that of existing clostridium sardiniense 7beta-HSDH, but the novel 7beta-hydroxysteroid dehydrogenase gene Y1-b-1 has better heat stability and a great industrial application prospect

New 7alpha-hydroxysteroid dehydrogenase gene Y1-a-1

Abstract: The invention relates to hydroxysteroid dehydrogenase, in particular to a new 7alpha-hydroxysteroid dehydrogenase gene Y1-a-1. The nucleotide sequence of the gene is as shown in SEQ ID NO. 2. New 7alpha-hydroxysteroid dehydrogenase is coded, and the amino acid sequence of new 7alpha-hydroxysteroid dehydrogenase is as shown in SEQ ID NO.1; new 7alpha-hydroxysteroid dehydrogenase can catalyze chenodeoxycholic acid (CDCA) and taurochenodeoxycholic acid (TCDCA) to generate 7-ketone lithocholic acid (7K-LCA) and tauro 7-ketone lithocholic acid (T7K-LCA); the catalysis activity for CDCA or TCDCA is more than two times that of existing Sardinia clostridium 7alpha-HSDH, and the new 7alpha-hydroxysteroid dehydrogenase gene Y1-a-1 has an extremely large industrial application value.

Novel 7alpha-hydroxysteroid dehydrogenase gene S1-a-2

Abstract: The invention relates to hydroxysteroid dehydrogenase, in particular to a novel 7alpha-hydroxysteroid dehydrogenase gene S1-a-2. A nucleotide sequence of the gene is shown as SEQ ID NO.2. A novel 7alpha-hydroxysteroid dehydrogenase with an amino acid sequence shown as SEQ ID NO.1 is coded and is capable of catalyzing CDCA (chenodeoxycholic acid) and TCDCA (taurochenodeoxycholic acid) to generate 7K-LCA (7-ketone lithocholic acid) and T7K-LCA (tauro-7-keto lithocholic acid), catalytic activity of the novel 7alpha-hydroxysteroid dehydrogenase for the CDCA or TCDCA is about twice of that of Clostridium sardiniense 7alpha-HSDH for the same, and accordingly the novel 7alpha-hydroxysteroid dehydrogenase is high in industrial application value.

Gene S1-a-1 of novel 7 alpha-HSDH (hydroxysteroid dehydrogenase)

Abstract: The invention relates to HSDH (hydroxysteroid dehydrogenase), in particular to a gene S1-a-1 of novel 7 alpha-HSDH. A nucleotide sequence of the gene is shown as SEQ ID NO.2, the novel 7 alpha-HSDH is encoded, a nucleotide sequence of the novel 7 alpha-HSDH is shown as SEQ ID NO.1, the novel 7 alpha-HSDH can be used for catalyzing CDCA (chenodeoxycholic acid) and TCDCA (taurochenodeoxycholic acid) to generate 7K-LCA (7-ketone lithocholic acid) and T7K-LCA (taurine-7-ketone lithocholic acid), wherein the catalytic activity of the novel 7 alpha-HSDH for CDCA is about 5 times of that of 7 alpha-HSDH of Sardinia clostridium, and the catalytic activity of the novel 7 alpha-HSDH for TCDCA is about over 2.5 times of that of 7 alpha-HSDH of Sardinia clostridium, therefore, the novel 7 alpha-HSDH has a great industrial application value.