| 1. |
- Abdel-Khalik, Jonas, et al.
(author)
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Bile acid biosynthesis in Smith-Lemli-Opitz syndrome bypassing cholesterol: Potential importance of pathway intermediates.
- 2021
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In: The Journal of steroid biochemistry and molecular biology. - : Elsevier BV. - 1879-1220 .- 0960-0760. ; 206
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Journal article (peer-reviewed)abstract
- Bile acids are the end products of cholesterol metabolism secreted into bile. They are essential for the absorption of lipids and lipid soluble compounds from the intestine. Here we have identified a series of unusual Δ5-unsaturated bile acids in plasma and urine of patients with Smith-Lemli-Opitz syndrome (SLOS), a defect in cholesterol biosynthesis resulting in elevated levels of 7-dehydrocholesterol (7-DHC), an immediate precursor of cholesterol. Using liquid chromatography - mass spectrometry (LC-MS) we have uncovered a pathway of bile acid biosynthesis in SLOS avoiding cholesterol starting with 7-DHC and proceeding through 7-oxo and 7β-hydroxy intermediates. This pathway also occurs to a minor extent in healthy humans, but elevated levels of pathway intermediates could be responsible for some of the features SLOS. The pathway is also active in SLOS affected pregnancies as revealed by analysis of amniotic fluid. Importantly, intermediates in the pathway, 25-hydroxy-7-oxocholesterol, (25R)26-hydroxy-7-oxocholesterol, 3β-hydroxy-7-oxocholest-5-en-(25R)26-oic acid and the analogous 7β-hydroxysterols are modulators of the activity of Smoothened (Smo), an oncoprotein that mediates Hedgehog (Hh) signalling across membranes during embryogenesis and in the regeneration of postembryonic tissue. Computational docking of the 7-oxo and 7β-hydroxy compounds to the extracellular cysteine rich domain of Smo reveals that they bind in the same groove as both 20S-hydroxycholesterol and cholesterol, known activators of the Hh pathway.
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| 2. |
- Cui, Peng, et al.
(author)
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Long-term androgen excess induces insulin resistance and non-alcoholic fatty liver disease in PCOS-like rats.
- 2021
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In: The Journal of steroid biochemistry and molecular biology. - : Elsevier BV. - 1879-1220 .- 0960-0760. ; 208
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Journal article (peer-reviewed)abstract
- Women with polycystic ovary syndrome (PCOS) are at higher risk for metabolic disorders compared to healthy women, and about 51 % of women with PCOS suffer from non-alcoholic fatty liver disease (NAFLD). Investigation into the pathological mechanism behind this association will provide insights for the prevention and treatment of this complication.Dihydrotestosterone (DHT), a nonaromatic androgen, was used to mimic the pathological conditions of hyperandrogenism and insulin resistance. Hematoxylin and eosin staining, Oil Red O staining, immunofluorescent staining, Western blots, and qRT-PCR were used to verify the hepatic steatosis and inflammation, and the latter two methods were also used for energy and mitochondrion-related assays. ELISA was used to measure the level of reactive oxygen species.Twelve weeks of DHT exposure led to obesity and insulin resistance as well as hepatic steatosis, lipid deposition, and different degrees of inflammation. The expression of molecules involved in respiratory chain and aerobic respiration processes, such as electron transfer complex II, pyruvate dehydrogenase, and succinate dehydrogenase complex subunit A, was inhibited. In addition, molecules associated with apoptosis and autophagy were also abnormally expressed, such as increased Bak mRNA, an increased activated caspase-3 to caspase-3 ratio, and increased Atg12 protein expression. All of these changes are associated with the mitochondria and lead to lipid deposition and inflammation in the liver.Long-term androgen excess contributes to insulin resistance and hepatic steatosis by affecting mitochondrial function and causing an imbalance in apoptosis and autophagy, thus suggesting the pathogenesis of NAFLD in women with PCOS.
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| 3. |
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| 4. |
- Kermpatsou, Despoina, et al.
(author)
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Cellular responses to silencing of PDIA3 (protein disulphide-isomerase A3) : Effects on proliferation, migration, and genes in control of active vitamin D
- 2024
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In: Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier. - 0960-0760 .- 1879-1220. ; 240
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Journal article (peer-reviewed)abstract
- The active form of vitamin D, 1,25-dihydroxyvitamin D3, is known to act via VDR (vitamin D receptor), affecting several physiological processes. In addition, PDIA3 (protein disulphide-isomerase A3) has been associated with some of the functions of 1,25-dihydroxyvitamin D3. In the present study we used siRNA-mediated silencing of PDIA3 in osteosarcoma and prostate carcinoma cell lines to examine the role(s) of PDIA3 for 1,25-dihydroxyvitamin D3-dependent responses. PDIA3 silencing affected VDR target genes and significantly altered the 1,25-dihydroxyvitamin D3-dependent induction of CYP24A1, essential for elimination of excess 1,25-dihydroxyvitamin D3. Also, PDIA3 silencing significantly altered migration and proliferation in prostate PC3 cells, independently of 1,25-dihydroxyvitamin D3. 1,25-Dihydroxyvitamin D3 increased thermostability of PDIA3 in cellular thermal shift assay, supporting functional interaction between PDIA3 and 1,25-dihydroxyvitamin D3-dependent pathways. In summary, our data link PDIA3 to 1,25-dihydroxyvitamin D3-mediated signalling, underline and extend its role in proliferation and reveal a novel function in maintenance of 1,25-dihydroxyvitamin D3 levels.
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| 5. |
- Monteiro, Fátima Liliana, et al.
(author)
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Estrogen receptor beta expression and role in cancers
- 2024
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In: Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier BV. - 0960-0760 .- 1879-1220. ; 242
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Journal article (peer-reviewed)abstract
- Estrogen drives the growth of some cancers, such as breast cancer, via estrogen receptor alpha (ERα). Estrogen also activates ERβ, but whether ERβ is expressed and has a role in different cancers is debated. The use of nonspecific antibodies has contributed to the confusion, and this review delves into ERβ's controversial role in cancer and focuses on tumor expression that can be supported by non-antibody-dependent assays. We discuss its expression at the transcript level and focus on its potential role in lymphoma, granulosa cell tumors, testicular, and adrenal cancers, emphasizing recent findings and the complexities that necessitate further research.
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| 6. |
- Piec, I., et al.
(author)
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Gestational hypercalcemia: Prevalence and biochemical profile
- 2020
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In: Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier BV. - 0960-0760 .- 1879-1220. ; 199
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Journal article (peer-reviewed)abstract
- © 2020 Elsevier Ltd Gestational hypercalcemia is associated with an increased risk of maternal, fetal and neonatal morbidity and mortality. Hypercalcemia may develop during pregnancy in individuals who were previously asymptomatic. The increased sensitivity during pregnancy may be related to physiological, gestational alterations in vitamin D and calcium metabolism and may be influenced by gene variants. The prevalence is unknown. We investigated the prevalence of hypercalcemia in trimester 3 (T3) in a population representative prospective cohort study (n = 1832) in South-West Sweden. Women with serum albumin (Alb) adjusted calcium (CaAlb) ≥ 2.65 mmol/L in T3 (n = 30) were matched to normo-calcemic controls, and markers of calcium and vitamin D metabolism were investigated in trimester 1 (T1) and T3. Serum concentrations of Ca, phosphate (P), Magnesium (Mg), Alb and creatinine (Cr), parathyroid hormone (PTH; T3 only), vitamin D metabolites (total 25(OH)D, 1,25(OH)2D, 24,25(OH)2D, and free 25(OH)D) were analysed in T1 and T3. CaAlb (Payne; inter-laboratory difference: UEA = 0.15 + 0.9*UGOT; UEA 2.54 = UGOT 2.65) and estimated glomerular filtration rate (eGFR; modified 4-variable MDRD) and vitamin D metabolites ratios (VMR) were calculated. Normally and non-normally distributed data were presented as mean (SD) or median (95 %CI). Group differences in relationships between vitamin D metabolites and with PTH were investigated with multiple regression analyses. Hypercalcemia in T3 was found in 1.7 % of women. PTH concentrations suggestive of primary hyperparathyroidism was found in 1 woman and none had 25(OH)D or 24,25(OH)2D concentrations in the toxicity range or suggestive of mutations in the CYP24A1 gene. CaAlb was significantly higher in hypercalcemic cases compared to controls in T1 (2.44 (2.30–2.80) vs 2.37 (2.25–2.49) mmol/L) and T3 (2.63 (2.52–2.78) vs 2.46 (2.31–2.58) mmol/L). Serum P was higher among cases than controls in T3 (1.12 (0.16) vs 1.07 (0.18) mmol/L) but not in T1 (1.12 (0.18) and 1.12 (0.16) mmol/L). PTH in T3 was lower in cases (1.6 (1.6–2.8) vs 2.3 (2.1–2.8) pmol/L) but 1,25(OH)2D concentrations were similar. There were no significant group differences in serum 25(OH)D, free 25(OH)D, 24,25(OH)2D, Mg, Alb, Cr and eGFR. Regression analyses did not show significant differences between cases and controls in relationships between vitamin D metabolites and with PTH, except for the free 25(OH)D-PTH relationship and a higher free:total 25(OH)D ratio in cases at T1. In conclusion, most common causes of hypercalcemia were excluded in the majority of women. Hypercalcemic women had a relatively high serum 1,25(OH)2D concentration despite an appropriately suppressed PTH, suggestive of abnormal gestational adaptions.
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| 7. |
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| 8. |
- Siekkeri Vandikas, Maria, 1980, et al.
(author)
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High levels of serum vitamin D-binding protein in patients with psoriasis: A case-control study and effects of ultraviolet B phototherapy.
- 2021
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In: The Journal of steroid biochemistry and molecular biology. - : Elsevier BV. - 1879-1220 .- 0960-0760. ; 211
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Journal article (peer-reviewed)abstract
- The role of vitamin D in psoriasis remains contradictory despite the fact that vitamin D analogues constitute an established treatment for psoriasis. It has been proposed that the ability of vitamin D to exert anti-inflammatory effects might not depend solely on the concentration of serum 25(OH)D but also on the concentration of vitamin D-binding protein (DBP). High concentrations of DBP might diminish vitamin D's biologic action. The aims of this study were (i) to analyze the serum levels of DBP, total and calculated free 25(OH)D in patients with psoriasis and compare the results with healthy controls and (ii) to study the effect of ultraviolet B (UVB) phototherapy on DBP levels. Caucasian subjects (n = 68) with active plaque psoriasis were compared with a population-based sample of men and women (n = 105), matched for age and sex. Season of enrollment was taken into consideration. The patients were also studied before and after UVB phototherapy. The severity of the disease was calculated as Psoriasis Area Severity Index (PASI). DBP, free 25(OH)D index and total 25(OH)D were higher in patients with psoriasis compared with controls (P= 0.004, P = 0.045 and P < 0.0001, respectively). DBP did not change after phototherapy, whereas 25(OH)D increased and intact parathyroid hormone (iPTH) decreased (P < 0.001 for both). Psoriasis improved and PASI decreased after phototherapy (P < 0.001). There was no correlation between DBP and 25(OH)D or between DBP and PASI. Measurement of DBP is recommended when evaluating vitamin D status in patients with psoriasis. High DBP levels in psoriasis imply a disturbed vitamin D pathway that warrants further investigation. Direct measurement of free 25(OH)D, instead of total 25(OH)D that circumvents abnormally high levels of DBP, could be considered.
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| 9. |
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| 10. |
- Zelleroth, Sofia, 1990-, et al.
(author)
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Structurally different anabolic androgenic steroids reduce neurite outgrowth and neuronal viability in primary rat cortical cell cultures
- 2021
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In: Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier BV. - 0960-0760 .- 1879-1220. ; 210
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Journal article (peer-reviewed)abstract
- The illicit use of anabolic androgenic steroids (AAS) among adolescents and young adults is a major concern due to the unknown and unpredictable impact of AAS on the developing brain and the consequences of this on mental health, cognitive function and behaviour. The present study aimed to investigate the effects of supra-physiological doses of four structurally different AAS (testosterone, nandrolone, stanozolol and trenbolone) on neurite development and cell viability using an in vitro model of immature primary rat cortical cell cultures. A high-throughput screening image-based approach, measuring the neurite length and number of neurons, was used for the analysis of neurite outgrowth. In addition, cell viability and expression of the Tubb3 gene (encoding the protein beta-III tubulin) were investigated. Testosterone, nandrolone, and trenbolone elicited adverse effects on neurite outgrowth as deduced from an observed reduced neurite length per neuron. Trenbolone was the only AAS that reduced the cell viability as indicated by a decreased number of neurons and declined mitochondrial function. Moreover, trenbolone downregulated the Tubb3 mRNA expression. The adverse impact on neurite development was neither inhibited nor supressed by the selective androgen receptor (AR) antagonist, flutamide, suggesting that the observed effects result from another mechanism or mechanisms of action that are operating apart from AR activation. The results demonstrate a possible AAS-induced detrimental effect on neuronal development and regenerative functions. An impact on these events, that are essential mechanisms for maintaining normal brain function, could possibly contribute to behavioural alterations seen in AAS users.
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