| 1. |
- Almokhtar, Mokhtar, et al.
(författare)
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Motor neuron-like NSC-34 cells as a new model for the study of vitamin D metabolism in the brain.
- 2016
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Ingår i: Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier BV. - 0960-0760 .- 1879-1220. ; 158, s. 178-188
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Tidskriftsartikel (refereegranskat)abstract
- Vitamin D-3 is a pro-hormone, which is sequentially activated by 25- and 1 alpha-hydroxylation to form 25-hydroxyvitamin D-3 [25(OH)D-3] and 1 alpha,25-dihydroxyvitamin D-3 [1 alpha,25(OH)2D(3)], respectively. Subsequent inactivation is performed by 24-hydroxylation. These reactions are carried out by a series of CYP450 enzymes. The 25-hydroxylation involves mainly CYP2R1 and CYP27A1, whereas 1 alpha-hydroxylation and 24-hydroxylation are catalyzed by CYP27B1 and CYP24A1, respectively, and are tightly regulated to maintain adequate levels of the active vitamin D hormone, 1 alpha,25(OH)(2)D-3. Altered circulating vitamin D levels, in particular 25(OH)D-3, have been linked to several disorders of the nervous system, e.g., schizophrenia and Parkinson disease. However, little is known about the mechanisms of vitamin D actions in the neurons. In this study, we examined vitamin D metabolism and its regulation in a murine motor neuron-like hybrid cell line, NSC-34. We found that these cells express mRNAs for the four major CYP450 enzymes involved in vitamin D activation and inactivation, and vitamin D receptor (VDR) that mediates vitamin D actions. We also found high levels of CYP24A1-dependent 24,25-dihydroxyvitamin D-3 [24,25(OH)(2)D-3] production, that was inhibited by the well-known CYP enzyme inhibitor ketoconazole and by several inhibitors that are more specific for CYP24A1. Furthermore, CYP24A1 mRNA levels in NSC-34 cells were up-regulated by 1 alpha,25(OH)(2)D-3 and its synthetic analogs, EB1089 and tacalcitol. Our results suggest that NSC-34 cells could be a novel model for the studies of neuronal vitamin D metabolism and its mechanism of actions.
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| 2. |
- Amzaleg, Y., et al.
(författare)
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Estrogens and selective estrogen receptor modulators differentially antagonize Runx2 in ST2 mesenchymal progenitor cells
- 2018
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Ingår i: Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier BV. - 0960-0760 .- 1879-1220. ; 183, s. 10-17
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Tidskriftsartikel (refereegranskat)abstract
- Estrogens attenuate bone turnover by inhibiting both osteoclasts and osteoblasts, in part through antagonizing Runx2. Apparently conflicting, stimulatory effects in osteoblast lineage cells, however, sway the balance between bone resorption and bone formation in favor of the latter. Consistent with this dualism, 17 beta-estradiol (E2) both stimulates and inhibits Runx2 in a locus-specific manner, and here we provide evidence for such locus specific regulation of Runx2 by E2 in vivo. We also demonstrate dual, negative and positive, regulation of Runx2-driven alkaline phosphatase (ALP) activity by increasing E2 concentrations in ST2 osteoblast progenitor cells. We further compared the effects of E2 to those of the Selective Estrogen Receptor Modulators (SERMs) raloxifene (ral) and lasofoxifene (las) and the phytoestrogen puerarin. We found that E2 at the physiological concentrations of 0.1-1 nM, as well as ral and las, but not puerarin, antagonize Runx2-driven ALP activity. At >= 10 nM, E2 and puerarin, but not ral or las, stimulate ALP relative to the activity measured at 0.1-1 nM. Contrasting the difference between E2 and SERMs in ST2 cells, they all shared a similar dose-response profile when inhibiting preosteoclast proliferation. That ral and las poorly mimic the locus-and concentration-dependent effects of E2 in mesenchymal progenitor cells may help explain their limited clinical efficacy.
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| 3. |
- Ankarberg-Lindgren, Carina, 1963, et al.
(författare)
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High-sensitivity quantification of serum androstenedione, testosterone, dihydrotestosterone, estrone and estradiol by gas chromatography-tandem mass spectrometry with sex- and puberty-specific reference intervals.
- 2018
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Ingår i: The Journal of steroid biochemistry and molecular biology. - : Elsevier BV. - 1879-1220 .- 0960-0760. ; 183, s. 116-124
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Tidskriftsartikel (refereegranskat)abstract
- Androgen and estrogen determinations serve as important diagnostic markers in a variety of clinical conditions. However, one challenge is to enhance assay sensitivity for determination in the lowest range, such as in prepubertal children. We here present a recently developed gas chromatography-tandem mass spectrometry (GC-MS/MS) method for determination of androstenedione (A4), dihydrotestosterone (DHT), testosterone (T), estrone (E1), and estradiol (E2) in children, which we have compared with the sensitive radioimmunoassays; E2 extraction-RIA and T-RIA.Steroids were extracted in ethyl acetate n-hexane solution from serum spiked with isotopically labeled internal standard and derivatized sequentially with pentafluorobenzyl bromide, pentafluorobenzyl hydroxylamine and pentafluoropropionic acid anhydride and analyzed by GC-MS/MS using a triple quadrupole mass spectrometer operated in negative chemical ionization mode. Leftover routine samples (n=414) were used to evaluate the concordance between GC-MS/MS and RIAs and the validity of GC-MS/MS for pediatrics; of these samples, 101 were from seemingly healthy children. Pubertal stage was recorded for reference interval evaluation.Lower limit of detection for A4, T, DHT, E1, and E2 were 0.1nmol/L, 0.1nmol/L, 27pmol/L, 9pmol/L, and 2pmol/L, respectively. Good agreement was found between GC-MS/MS and T-RIA (r=0.98) as well as between GC-MS/MS and E2 extraction-RIA (r=0.98, for E2 concentrations above 14pmol/L). In boys, T and DHT increased significantly from prepuberty throughout pubertal development, and in girls the same increase was observed for E1 and E2. The greatest increase in A4 for both genders, as well as E1 and E2 in boys and T and DHT in girls, occurred in mid to late puberty.We report the development of a GC-MS/MS method sensitive enough to accurately determine serum levels of androgens and estrogens in children.
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| 4. |
- Asnake, Solomon, 1985-, et al.
(författare)
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Species differences in ligand interaction and activation of estrogen receptors in fish and human
- 2019
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Ingår i: Journal of Steroid Biochemistry and Molecular Biology. - : Pergamon Press. - 0960-0760 .- 1879-1220. ; 195
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Tidskriftsartikel (refereegranskat)abstract
- Estrogen receptor (ER) sequences vary between species and this suggests that there are differences in the ligand-specificity, leading to species-specific effects. This would indicate that it is not possible to generalize effects across species. In this study, we investigated the differences in activation potencies and binding affinities of ER´s alpha (α) and beta (β) in human, zebrafish and sea bream to elucidate species differences in response to estradiol, estrone, estriol and methyltestosterone. In vitro analysis showed that estradiol had the highest activity for all the ER´s except for human ERβ and seabream ERβ2. Alignment of the ligand binding domain and ligand binding pocket (LBP) residues of the three species showed that different residues were involved in the LBPs which led to differences in pocket volume, affected binding affinity and orientation of the ligands. By combining in silico and in vitro results, it was possible to identify the ligand specificities of ER´s. The results demonstrated that the human ER´s show lower resolution in ligand-dependent activation, suggesting higher promiscuity, than the zebrafish and seabream ER´s. These results show species-specificity of ER´s and suggest that species-specific differences must be taken into consideration when studying different exposure scenarios.
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| 5. |
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| 6. |
- Björk, Anne, et al.
(författare)
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Variations in the vitamin D receptor gene are not associated with measures of muscle strength, physical performance, or falls in elderly men : Data from MrOS Sweden
- 2019
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Ingår i: Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier BV. - 0960-0760 .- 1879-1220. ; 187, s. 160-165
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Tidskriftsartikel (refereegranskat)abstract
- The vitamin D receptor (VDR) has been proposed as a candidate gene for several musculoskeletal phenotypes. However, previous results on the associations between genetic variants of the VDR with muscle strength and falls have been contradictory. The MrOS Sweden survey, a prospective population-based cohort study of 3014 elderly men (mean age 75 years, range 69-81) offered the opportunity to further investigate these associations. At baseline, data were collected on muscle strength and also the prevalence of falls during the previous 12 months. Genetic association analysis was performed for 7 Single Nucleotide Polymorphisms (SNPs), covering the genetic region surrounding the VDR gene in 2924 men with available samples of DNA. Genetic variations in the VDR were not associated with five different measurements of muscle strength or physical performance (hand grip strength right and left, 6 m walking test (easy and narrow) and timed-stands test). However, one of the 7 SNPs of the gene for the VDR receptor, rs7136534, was associated with prevalence of falls (33.6% of the AA, 14.6% of the AG and 16.5% of the GG allele). In conclusion, VDR genetic variants are not related to muscle strength or physical performance in elderly Swedish men. The role of the rs7136534 SNP for the occurrence of falls is not clear.
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| 7. |
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| 8. |
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| 9. |
- Gustafsson, JA, et al.
(författare)
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Editorial
- 2016
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Ingår i: The Journal of steroid biochemistry and molecular biology. - : Elsevier BV. - 1879-1220 .- 0960-0760. ; 157, s. 1-2
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 10. |
- Gustafsson, JA
(författare)
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Historical overview of nuclear receptors
- 2016
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Ingår i: The Journal of steroid biochemistry and molecular biology. - : Elsevier BV. - 1879-1220 .- 0960-0760. ; 157, s. 3-6
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Tidskriftsartikel (refereegranskat)
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| 11. |
- Heverin, Maura, et al.
(författare)
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On the regulatory importance of 27-hydroxycholesterol in mouse liver
- 2017
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Ingår i: Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier. - 0960-0760 .- 1879-1220. ; 169, s. 10-21
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Forskningsöversikt (refereegranskat)abstract
- 27-Hydroxycholesterol (27OH) is a strong suppressor of cholesterol synthesis and a weak activator of LXR in vitro. The regulatory importance of 27OH in vivo is controversial. Here we utilized male mice with increased levels of 27OH either due to increased production (CYP27A1 transgenic mice) or reduced metabolism (Cyp7b1-/- mice). We also used mice lacking 27OH due to a knockout of Cyp27a1. The latter mice were treated with cholic acid to compensate for reduced bile acid synthesis. The effects of the different levels of 27OH on Srebp- and other LXR-regulated genes in the liver were investigated. In the liver of CYP27tg mice we found a modest increase of the mRNA levels corresponding to the LXR target genes Cyp7b1 and Abca1. A number of other LXR-regulated genes were not affected. The effect on Abca1 mRNA was not seen in the liver of Cyp7b1-/- mice. There were little or no effects on cholesterol synthesis. In the liver of the Cyp27-/- mice treated with 0.025% cholic acid there was no significant effect of the knockout on the LXR target genes. In a previous work triple-knockout mice deficient in the biosynthesis of 24S-hydroxycholesterol, 25-hydroxycholesterol and 27OH were shown to have impaired response to dietary cholesterol, suggesting side-chain oxidized oxysterols to be mediators in cholesterol-induced effects on LXR target genes at a transcriptional level (Chen W. et al., Cell Metab. 5 (2007) 73-79). The hydroxylated oxysterol responsible for the effect was not defined. We show here that treatment of wildtype mice with dietary cholesterol under the same conditions as in the above study induced the LXR target genes Lpl, Abcg8 and Srebp1c in wild type mice but failed to activate the same genes in mice lacking 27-hydroxycholesterol due to a knockout of Cyp27. We failed to demonstrate the above effects at the protein level (Abcg8) or at the activity level (Lpl). The results suggest that 27OH is not an important regulator of Srebp- or LXR regulated genes under basal conditions in mouse liver. On the other hand 27OH appears to mediate cholesterol-induced effects on some LXR target genes at a transcriptional level under some in vivo conditions.
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| 12. |
- Johansson, Maja, et al.
(författare)
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GABAA receptor modulating steroid antagonists (GAMSA) are functional in vivo
- 2016
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Ingår i: Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier. - 0960-0760 .- 1879-1220. ; 160:SI, s. 98-105
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Tidskriftsartikel (refereegranskat)abstract
- GABAA receptor modulating steroid antagonists (GAMSA) selectively inhibit neurosteroid-mediated enhancement of GABA-evoked currents at the GABAA receptor. 3α-hydroxy-neurosteroids, notably allopregnanolone and tetrahydrodeoxycorticosterone (THDOC), potentiate GABAA receptor-mediated currents. On the contrary, various 3β-hydroxy-steroids antagonize this positive neurosteroid-mediated modulation. Importantly, GAMSAs are specific antagonists of the positive neurosteroid-modulation of the receptor and do not inhibit GABA-evoked currents. Allopregnanolone and THDOC have both negative and positive actions. Allopregnanolone can impair encoding/consolidation and retrieval of memories. Chronic administration of a physiological allopregnanolone concentration reduces cognition in mice models of Alzheimer's disease. In humans an allopregnanolone challenge impairs episodic memory and in hepatic encephalopathy cognitive deficits are accompanied by increased brain ammonia and allopregnanolone. Hippocampal slices react in vitro to ammonia by allopregnanolone synthesis in CA1 neurons, which blocks long-term potentiation (LTP). Thus, allopregnanolone may impair learning and memory by interfering with hippocampal LTP. Contrary, pharmacological treatment with allopregnanolone can promote neurogenesis and positively influence learning and memory of trace eye-blink conditioning in mice. In rat the GAMSA UC1011 inhibits an allopregnanolone-induced learning impairment and the GAMSA GR3027 restores learning and motor coordination in rats with hepatic encephalopathy. In addition, the GAMSA isoallopregnanolone antagonizes allopregnanolone-induced anesthesia in rats, and in humans it antagonizes allopregnanolone-induced sedation and reductions in saccadic eye velocity. 17PA is also an effective GAMSA in vivo, as it antagonizes allopregnanolone-induced anesthesia and spinal analgesia in rats. In vitro the allopregnanolone/THDOC-increased GABA-mediated GABAA receptor activity is antagonized by isoallopregnanolone, UC1011, GR3027 and 17PA, while the effect of GABA itself is not affected.
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| 13. |
- Kushnir, Mark M., et al.
(författare)
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Exploratory study of the association of steroid profiles in stimulated ovarian follicular fluid with outcomes of IVF treatment
- 2016
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Ingår i: Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier BV. - 0960-0760 .- 1879-1220. ; 162, s. 126-133
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Forskningsöversikt (refereegranskat)abstract
- Steroid concentrations in stimulated follicular fluid (sFF) samples have been linked to the quality of oocytes used in IVF treatments. Most of the published studies focused on evaluating the association of the IVF outcomes with only a few of the steroids, measured by immunoassays (IA). We performed a treatment outcome, prospective cohort study using stimulated FF sampled from 14 infertile women undergoing IVF treatment; single oocyte was used per IVF cycle. Fourteen endogenous steroids were analyzed in 22 ovarian follicle aspirations, which corresponded to the embryos used in the IVF. Ten oocytes were associated with live birth (LB) and 12 with no pregnancy (NP). Steroids were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. Differences in distribution of concentrations in association with the pregnancy outcome (LB or NP), and receiver operating characteristic (ROC) curves analysis were performed for the entire cohort and for within-women data. The predominant androgen and estrogen in stimulated sFF were androstenedione (A4) and estradiol (E2), respectively. Lower concentrations of pregnenolone (Pr), lower ratios of A4/ dehydroepiandrosterone (DHEA), testosterone (Te)/DHEA, and greater ratios of E2/Te, and estrone/A4 were observed in sFF samples associated with LB. Among the oocytes associated with NP, in four out of 12 samples total concentration of androgens was above the distribution of the concentrations in the oocytes corresponding to the LB group. Observations of the study indicated increased consumption of precursors and increased biosynthesis of estrogens in the follicles associated with LB. Our data suggest that potentially steroid profiles in sFF obtained during oocyte retrieval may serve as biomarkers for selection of the best embryo to transfer after IVF.
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| 14. |
- Lindström, Helena, et al.
(författare)
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Characterization of equine GST A3-3 as a steroid isomerase
- 2018
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Ingår i: Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier BV. - 0960-0760 .- 1879-1220. ; 178, s. 117-126
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Tidskriftsartikel (refereegranskat)abstract
- Glutathione transferases (GSTs) comprise a superfamily of enzymes prominently involved in detoxication by making toxic electrophiles more polar and therefore more easily excretable. However some GSTs have developed alternative functions. Thus, a member of the Alpha class GSTs in pig and human tissues is involved in steroid hormone biosynthesis, catalyzing the obligatory double-bond isomerization of Δ5-androstene-3,17-dione to Δ4-androstene-3,17-dione and of Δ5-pregnene-3,20-dione to Δ4-pregnene-3,20-dione on the biosynthetic pathways to testosterone and progesterone. The human GST A3-3 is the most efficient steroid double-bond isomerase known so far in mammals. The current work extends discoveries of GST enzymes that act in the steroidogenic pathways in large mammals. The mRNA encoding the steroid isomerase GST A3-3 was cloned from testis of the horse (Equus ferus caballus). The concentrations of GSTA3 mRNA were highest in hormone-producing organs such as ovary, testis and adrenal gland. EcaGST A3-3 produced in E. coli has been characterized and shown to have highly efficient steroid double-bond isomerase activity, exceeding its activities with conventional GST substrates. The enzyme now ranks as one of the most efficient steroid isomerases known in mammals and approaches the activity of the bacterial ketosteroid isomerase, one of the most efficient enzymes of all categories known today. The high efficiency and the tissue distribution of EcaGST A3-3 support the view that the enzyme plays a physiologically significant role in the biosynthesis of steroid hormones.
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| 15. |
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| 16. |
- Lundell, Anna-Carin, 1976, et al.
(författare)
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Umbilical Cord Blood Androgen Levels in Girls and Boys Assessed by Gas Chromatography-Tandem Mass Spectrometry.
- 2017
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Ingår i: The Journal of steroid biochemistry and molecular biology. - : Elsevier BV. - 1879-1220 .- 0960-0760. ; 171, s. 195-200
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Tidskriftsartikel (refereegranskat)abstract
- Androgen exposure of the fetus during gestation plays an important role in human physiology and pathophysiology, but assessment of androgens, in particular dihydrotestosterone (DHT), in human umbilical cord blood is technically challenging. The aim of this study was to assess umbilical cord androgen levels, including DHT, at birth by a highly sensitive assay, and study their association with sex of the infant, sex-hormone-binding globulin (SHBG) levels, and gestational age at delivery. Swedish infants (27 girls, 26 boys) were recruited at maternity care clinics in Southern Sweden. Umbilical cord blood levels of dehydroepiandrosterone (DHEA), androstenedione, testosterone and DHT at delivery were assessed by a gas chromatography-tandem mass spectrometry assay. Cord blood levels of DHT were 2.4-fold higher in boys (median 27.8pg/mL) than in girls (11.5pg/mL), while the sex difference was less pronounced for testosterone (1.3-fold higher in boys) and non-significant for DHEA and androstenedione. Gestational age at delivery associated inversely with DHT levels in boys and with DHEA levels in girls. There was a strong inverse correlation between SHBG and DHEA in both sexes, while there were no associations between SHBG and testosterone or DHT levels. In conclusion, using state of the art technology, we report that there is a pronounced sexual dimorphism in human umbilical cord blood DHT levels. The possibility to assess a complete androgen profile in human cord blood opens up for future increased understanding of the biological impact of the fetal androgen milieu.
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| 17. |
- Lundqvist, Johan, et al.
(författare)
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Resveratrol, piceatannol and analogs inhibit activation of both wild-type and T877A mutant androgen receptor
- 2017
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Ingår i: Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier BV. - 0960-0760 .- 1879-1220. ; 174, s. 161-168
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Tidskriftsartikel (refereegranskat)abstract
- Prostate cancer growth and progression are mainly dependent on androgens and many current prostate cancer treatment options target the synthesis or function of androgens. We have previously reported that resveratrol and synthetic analogs of resveratrol with a higher bioavailability inhibit the synthesis of androgens in human adrenocortical H295R cells. Now we have studied the antiandrogenic properties of resveratrol, piceatannol and analogs in two different prostate cell lines; LNCaP and RWPE. LNCaP carry a T877A mutation in the androgen receptor while RWPE has a wild-type androgen receptor. We found that resveratrol, piceatannol and all studied analogs were able to inhibit a dihydrotestosterone-induced activation of the androgen receptor, showing that they act as antiandrogens. In LNCaP cells, all studied compounds were able to statistically significantly decrease the androgenic signaling in concentrations >= 1 mu M and the synthetic analogs trimethylresveratrol (RSVTM) and tetramethylpiceatannol (PICTM) were the most potent compounds. RWPE cells were not as responsive to the studied compounds as the LNCaP cells. A statistically significant decrease in the androgenic signaling was observed at concentrations 5 5 M for most compounds and RSVTM was found to be the most potent compound. Further, we studied the effects of resveratrol, piceatannol and analogs on the levels of prostate-specific antigen (PSA) in LNCaP cells and found that all studied compounds decreased the level of PSA and that the synthetic analogs diacetylresveratrol (RSVDA), triacetylresveratrol (RSVTA) and RSVTM were the most potent compounds, decreasing the PSA level by approx. 50% at concentrations >= 10 mu M. In a cell-free receptor binding assay we were unable to show binding of resveratrol or analogs to the ligand binding domain of the androgen receptor, indicating that the observed effects are mediated via other mechanisms than direct ligand competition. We conclude that the resveratrol, piceatannol and analogs are highly interesting for chemoprevention of prostate cancer, since they have a high potency both as inhibitors of androgen synthesis and androgen receptor activation.
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| 18. |
- Lundqvist, Johan
(författare)
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Williams syndrome transcription factor (WSTF) acts as an activator of estrogen receptor signaling in breast cancer cells and the effect can be abrogated by 1 alpha,25-dihydroxyvitamin D-3
- 2018
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Ingår i: Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier BV. - 0960-0760 .- 1879-1220. ; 177, s. 171-178
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Tidskriftsartikel (refereegranskat)abstract
- majority of estrogen receptor positive (ER +) breast cancers are growth stimulated by estrogens. The ability to inhibit the ER signaling pathway is therefore of critical importance in the current treatment of ER + breast cancers. It has been reported that l alpha,25-dihydroxyvitamin D-3 down-regulates the expression of the CYP19A1 gene, encoding the aromatase enzyme that catalyzes the synthesis of estradiol. Furthermore, l alpha,25-dihydroxyvitamin D-3 has also been reported to down-regulate the expression of estrogen receptor alpha (ER alpha), the main mediator of ER signaling.This study reports a novel transcription factor critical to l alpha,25-dihydroxyvitamin D-3-mediated regulation of estrogenic signaling in MCF-7 breast cancer cells. We have investigated the molecular mechanisms for the la,25-dihydroxyvitamin D-3-mediated down-regulation of CYP19A1 and ERa gene expression in human MCF-7 breast cancer cells and found that Williams syndrome transcription factor (WSTF) plays a key role by binding to the promoters of CYP19A1 and ERa. Although sometimes reported as an inhibitor of gene expression, we found that WSTF acts as an activator of the promoter activity of both CYP19A1 and ER alpha. Silencing of WSTF by siRNA transfection resulted in decreased aromatase-dependent cell growth as well as decreased ER signaling in the cells. When cells were treated with l alpha,25-dihydroxyvitamin D-3, WSTF was dissociated from the promoters and the promoter activities of CYP19A1 and ERa were decreased. We have measured the expression of WSTF in ER positive tumor-samples from breast cancer patients and found that WSTF is expressed in the majority of the investigated samples and that the expression is higher in cancer tissue than in normal tissue. However, we were not able to show any significant association between the WSTF expression in the tumor and the disease free and overall survival in this patient group who have received adjuvant tarnoxifen treatment, nor between the WSTF expression and the expression of ERa, progesterone receptor or HER2. The major conclusions of this study are that WSTF acts as an activator of ER signaling in MCF-7 breast cancer cells, that this action can be inhibited by l alpha,25-dihydroxyvitamin D-3, and that the expression of WSTF is higher in breast cancer tissue than in normal tissue. WSTF may by a new target for treatment of estrogen-dependent breast cancer cell growth.
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| 19. |
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| 20. |
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| 21. |
- Ohlsson, Claes, 1965, et al.
(författare)
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DHEA and mortality: What is the nature of the association?
- 2015
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Ingår i: The Journal of steroid biochemistry and molecular biology. - : Elsevier BV. - 1879-1220 .- 0960-0760. ; 145C, s. 248-253
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Tidskriftsartikel (refereegranskat)abstract
- Although very little is known about the importance of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S) in human physiology and pathophysiology, emerging observations imply pivotal roles of DHEA/-S. One such observation is the association between serum DHEA/-S levels and mortality risk. In this review, we focus on the literature addressing DHEA/-S and mortality with the aim to describe and discuss patterns and potential underlying mechanisms. Although the literature reports somewhat inconsistent results, we conclude that several larger population-based studies support an association between low DHEA/-S and risk of death, at least in elderly men. In women, the association may not be present; alternatively, there may be a U-shaped association. In men, most available evidence suggests an association with cardiovascular (CV) mortality rather than cancer mortality. Further, there are biologically plausible mechanisms for an effect of DHEA/-S on the development of CV disease. On the other hand, there is also strong evidence supporting that any disease may lower DHEA/-S. Thus, the cause-effect relation of this association is less clear. Future studies may employ a mendelian randomization approach using genetic determinants of DHEA-S levels as predictors of clinical outcomes, to delineate the true nature of the association between DHEA/-S and mortality.
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| 22. |
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| 23. |
- Siekkeri Vandikas, Maria, 1980, et al.
(författare)
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Imaging of vitamin D in psoriatic skin using time-of-flight secondary ion mass spectrometry (ToF-SIMS): A pilot case study
- 2019
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Ingår i: Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier BV. - 0960-0760 .- 1879-1220. ; 189, s. 154-160
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Tidskriftsartikel (refereegranskat)abstract
- Recently it has been recognized that there is a need of investigating in detail the vitamin D synthesis and metabolism directly in the skin with respect to its possible autocrine and paracrine actions. The potential effects the active metabolite of vitamin D exerts in pathological skin conditions like psoriasis needs to be clarified. Under ultraviolet B (UVB) irradiation skin can autonomously synthesize, activate and degrade vitamin D. In this pilot case study, we used for the first time Time-of-flight secondary ion mass spectrometry (ToF-SIMS) in the analysis of skin biopsies from a patient with psoriasis before and after UVB phototherapy. We were able to visualize vitamin D 3 and its metabolites in the skin and subcutaneous tissue. At the same time information about their localization at subcellular level and morphology of the skin was received. This study proves that ToF-SIMS is a promising powerful tool to be used when investigating vitamin D´s role in dermatological diseases through skin biopsies.
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| 24. |
- Wicher, Grzegorz, et al.
(författare)
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Estrogen-mediated regulation of steroid metabolism in rat glial cells; effects on neurosteroid levels via regulation of CYP7B1-mediated catalysis
- 2015
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Ingår i: Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier BV. - 0960-0760 .- 1879-1220. ; 145, s. 21-27
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Tidskriftsartikel (refereegranskat)abstract
- Many neuroactive steroids, including dehydroepiandrosterone (DHEA), pregnenolone, 27-hydroxycholesterol and 17 beta-estradiol, are known to affect development and function of the brain and nervous system. These and other steroids can undergo tissue and/or cell-specific enzymatic conversions into steroid metabolites. Carefully regulated production of steroids with various physiological effects is important for cells of the nervous system. Astrocytes express many steroidogenic enzymes and are considered important producers of brain steroids. The quantitative roles of different pathways for steroid metabolism in rat astrocytes are not clear. In the current study we examined effects of estrogens on steroid metabolism catalyzed by CYP7B1 and other enzymes in primary cultures of rat astrocytes. The CYP7B1 enzyme, which has been linked to neurodegenerative disease, is involved in the metabolism of several important neurosteroids. In the present study, we found that 7 alpha-hydroxylation, performed by CYP7B1, is the quantitatively most important pathway for DHEA metabolism in rat astrocytes. In addition, our present experiments on catalytic steroid conversions revealed that estrogens significantly suppress the CYP7B1-catalyzed metabolism of not only DHEA but also of pregnenolone and 27-hydroxycholesterol in rat astrocytes. These novel findings point to a regulatory mechanism for control of the cellular levels of these neurosteroids via CYP7B1. Our hypothesis that estrogens can regulate neurosteroid levels via this enzymatic reaction was supported by experiments using ELISA to assay levels of DHEA and pregnenolone in the presence or absence of estrogen. Furthermore, the present results show that estrogen suppresses CYP7B1-catalyzed 7 alpha-hydroxylation also in primary cultures of rat Schwann cells, indicating that regulation by estrogen via this enzyme may be of relevance in both the CNS and the PNS.
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| 25. |
- Bärebring, Linnea, et al.
(författare)
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Serum cortisol and vitamin D status are independently associated with blood pressure in pregnancy
- 2019
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Ingår i: Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier BV. - 0960-0760. ; 189:May, s. 259-264
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Tidskriftsartikel (refereegranskat)abstract
- The aim was to study if serum cortisol during pregnancy was associated with blood pressure and development of gestational hypertensive disorders. Additionally, associations between 25-hydroxyvitamin D (25OHD) and cortisol, including confounding effects and interactions in their relation to blood pressure were investigated. In total, 1413 pregnant women from the prospective Swedish GraviD cohort were included. Serum was collected in the first (T1) and third trimester (T3) and analyzed for 25OHD by liquid chromatography mass spectrometry and cortisol using an electro-chemiluminescence immunoassay. The main outcome measures were T1 blood pressure and development of gestational hypertensive disorders (gestational hypertension or preeclampsia). Gestational hypertensive disorders were defined as new onset hypertension, with or without proteinuria, after gestational week 20. Mean ± SD cortisol increased significantly from T1 to T3 (312 ± 123 vs. 659 ± 201 nmol/L, p < 0.001) and this increase was influenced by ethnicity. Serum concentrations of cortisol and 25OHD correlated in both T1 (B = 0.35, p < 0.001) and T3 (B = 0.30, p < 0.001). Cortisol and 25OHD were positively associated with T1 blood pressure, and there were non-significant trends for associations with gestational hypertensive disorders. Cortisol and 25OHD did not display any confounding effect or effect modification in their relationships with blood pressure. In conclusion, there was a positive correlation between serum cortisol and 25OHD in both early and late pregnancy. Both cortisol and 25OHD were positively associated with early pregnancy blood pressure. These results imply that the two hormones might be on different paths in their relationship with blood pressure. © 2019
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| 26. |
- Walsh, Meabh, et al.
(författare)
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Avoiding maternal vitamin D deficiency may lower blood glucose in pregnancy
- 2019
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Ingår i: Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier BV. - 0960-0760. ; 186, s. 117-121
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Tidskriftsartikel (refereegranskat)abstract
- Background: Vitamin D status is hypothesised to play a role in gestational glucose control. No studies to date have examined vitamin D in relation to changes in blood glucose in pregnancy. Thus, the aim was to examine if vitamin D in early pregnancy and vitamin D trajectory associate with blood glucose trajectory over pregnancy in a Swedish cohort. We also investigated the relation between maternal vitamin D status and excessive fetal growth. Methods: In 2013-2014, pregnant women were recruited to the GraviD cohort study when registering at the antenatal clinics in south-west Sweden. In the present analysis, 1928 women were included. Women with preexisting diabetes and multifetal pregnancy were excluded. Random blood glucose was assessed according to routine practice, in first trimester (T1, gestational week 4-16), second trimester (T2, gestational week 17-27), early (T3a, gestational week 28-35) and late third trimester (T3b, gestational week 36-41). In Ti and T3a, serum 25-hydroxyvitamim D (25OHD) was analyzed by liquid chromatography tandem mass spectrometry. Large for gestational age (LGA), as a proxy of excessive fetal growth, was defined as body weight at birth above 2 standard deviations of the gender specific population mean. Adjusted linear regression, linear mixed models analysis and logistic regression analysis were used to study 25OHD in relation to Ti blood glucose, glucose trajectory and LGA, respectively. Results: Mean blood glucose increased during pregnancy (5.21 mmol/L in Tl, 5.27 mmol/L in T2, 5.31 mmol/L in T3a and 5.34 mmol/L in T3b; p = 0.003). In T1, 25OHD was negatively associated with blood glucose, i.e. 25OHD > 30 nmol/L was associated with 0.25-0.35 mmol/L lower glucose. Ti 25OHD was also negatively associated with blood glucose trajectory. Higher T3 25OHD was associated with higher odds of LGA (p = 0.032). Conclusion: Avoiding maternal vitamin D deficiency in early pregnancy is associated with lower blood glucose in early pregnancy and throughout pregnancy. Higher 25OHD in late pregnancy was associated with higher odds of LGA at birth.
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| 27. |
- Chaturvedi, Sarika, et al.
(författare)
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Assessment of the quality of clinical documentation in India's JSY cash transfer program for facility births in Madhya Pradesh
- 2016
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Ingår i: International Journal of Gynecology & Obstetrics. - : Wiley. - 0020-7292 .- 1879-3479. ; 132:2, s. 179-183
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To gain insight into the quality of care in facilities implementing the Janani Suraksha Yojana (JSY) cash transfer program in Madhya Pradesh, India, by reviewing the level of documentation in the clinical records of women who delivered.Methods: The present retrospective, descriptive study reviewed case records of women who delivered at 73 primary, secondary, and tertiary level facilities in three districts of Madhya Pradesh between 2012 and 2013. Twenty elements of care were assessed encompassing clinical history and admission details, care during delivery and postnatal period, and discharge details.Results: A total of 1239 records were reviewed. The extent of documentation varied among the elements assessed-e.g. 24 (1.9%) records documented advice at discharge, 171 (13.8%) documented postnatal blood pressure, 437 (353%) documented fetal heart rate, and 1220 (98.5%) documented admission date. The extent of documentation was better at higher level facilities.Conclusion: The quality of clinical documentation in the JSY program was found to be unacceptably poor in Madhya Pradesh. Improving staff skills and practices in clinical documentation and record keeping will be required to enable clinical processes to be assessed and quality of care to be improved. (C) 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd.
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| 28. |
- Wuopio, Jonas, et al.
(författare)
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Cathepsin B and S as markers for cardiovascular risk and all-cause mortality in patients with stable coronary heart disease during 10 years : a CLARICOR trial sub-study.
- 2018
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Ingår i: Atherosclerosis. - : Elsevier BV. - 0021-9150 .- 1879-1484. ; 278, s. 97-102
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: The lysosomal cysteine proteases cathepsin B and S have been implicated in the atherosclerotic process. The present paper investigates the association between serum levels of cathepsin B and S and cardiovascular events and mortality in patients with stable coronary heart disease.METHODS: The CLARICOR trial is a randomised, placebo-controlled trial investigating the effect of clarithromycin versus placebo in patients with stable coronary heart disease. The outcome was time to either a cardiovascular event or all-cause mortality. The placebo group was used as discovery sample and the clarithromycin group as replication sample: n = 1998, n = 1979; mean age (years) 65, 65; 31%, 30% women; follow-up for 10 years; number of composite outcomes n = 1204, n = 1220; respectively. We used a pre-defined multivariable Cox regression model adjusting for inflammation, established cardiovascular risk factors, kidney function, and use of cardiovascular drugs.RESULTS: Cathepsin B was associated with an increased risk of the composite outcome in both samples after multivariable adjustment (discovery: multivariable ratio (HR) per standard deviation increase 1.12, 95% confidence interval (CI) 1.05-1.19, p < 0.001, replication; HR 1.14, 95% CI 1.07-1.21, p < 0.001). There was no significant association between cathepsin S and the composite outcome in either the discovery or replication sample after multivariable adjustment (p>0.45). Secondary analyses suggest that cathepsin B was predominantly associated with mortality rather than specific cardiovascular events.CONCLUSIONS: Cathepsin B, but not serum cathepsin S, was associated with an increased risk of cardiovascular events in patients with stable coronary heart disease. The clinical implications of our findings remain to be established.
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| 29. |
- Ruge, Toralph, et al.
(författare)
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Circulating endostatin as a risk factor for cardiovascular events in patients with stable coronary heart disease : A CLARICOR trial sub-study
- 2019
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Ingår i: Atherosclerosis. - : Elsevier BV. - 0021-9150 .- 1879-1484. ; 284, s. 202-208
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: Raised levels of serum endostatin, a biologically active fragment of collagen XVIII, have been observed in patients with ischemic heart disease but association with incident cardiovascular events in patients with stable coronary heart disease is uncertain.METHODS: The CLARICOR-trial is a randomized, placebo-controlled trial of stable coronary heart disease patients evaluating 14-day treatment with clarithromycin. The primary outcome was a composite of acute myocardial infarction, unstable angina pectoris, cerebrovascular disease or all-cause mortality. In the present sub-study using 10-year follow-up data, we investigated associations between serum endostatin at entry (randomization) and the composite outcome and its components during follow-up. The placebo group was used as discovery sample (1204 events, n = 1998) and the clarithromycin-treated group as replication sample (1220 events, n = 1979).RESULTS: In Cox regression models adjusting for cardiovascular risk factors, glomerular filtration rate, and current pharmacological treatment, higher serum endostatin was associated with an increased risk of the composite outcome in the discovery sample (hazard ratio per standard deviation increase 1.11, 95% CI 1.03-1.19, p = 0.004), but slightly weaker and not statistically significant in the replication sample (hazard ratio 1.06, 95% CI 1.00-1.14, p = 0.06). In contrast, strong and consistent associations were found between endostatin and cardiovascular and all-cause mortality in all multivariable models and sub-samples. Addition of endostatin to a model with established cardiovascular risk factors provided no substantial improvement of risk prediction (<1%).CONCLUSIONS: Raised levels of serum endostatin might be associated with cardiovascular events in patients with stable coronary heart disease. The clinical utility of endostatin measurements remains to be established.
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