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- Emanuelsson, Ida, et al.
(författare)
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Expression and regulation of CYP17A1 and 3β-hydroxysteroid dehydrogenase in cells of the nervous system : potential effects of vitamin D on brain steroidogenesis
- 2018
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Ingår i: Neurochemistry International. - : Elsevier BV. - 0197-0186 .- 1872-9754. ; 113, s. 46-55
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Tidskriftsartikel (refereegranskat)abstract
- Steroids are reported to have diverse functions in the nervous system. Enzymatic production of steroid hormones has been reported in different cell types, including astrocytes and neurons. However, the information on some of the steroidogenic enzymes involved is insufficient in many respects. Contradictory results have been reported concerning the relative importance of different cell types in the nervous system for expression of CYP17A1 and 3b-hydroxysteroid dehydrogenase (3b-HSD). 3b-HSD is important in all basic steroidogenic pathways and CYP17A1 is required to form sex hormones. In the current investigation we studied the expression of these enzymes in cultured primary rat astrocytes, in neuron-enriched cells from rat cerebral cortex and in human neuroblastoma SH-SY5Y cells, a cell line often used as an in vitro model of neuronal function and differentiation. As part of this study we also examined potential effects on CYP17A1 and 3b-HSD by vitamin D, a compound previously shown to have regulatory effects in steroid hormone-producing cells outside the brain. The results of our study indicate that astrocytes are a major site for expression of 3b-HSD whereas expression of CYP17A1 is found in both astrocytes and neurons. The current data suggest that neurons, contrary to some previous reports, are not involved in 3b-HSD reactions. Previous studies have shown that vitamin D can influence gene expression and hormone production by steroidogenic enzymes in some cells. We found that vitamin D suppressed CYP17A1-mediated activity by 20% in SH-SY5Ycells and astrocytes. Suppression of CYP17A1 mRNA levels was considerably stronger, about 50% in SH-SY5Y cells and 75% in astrocytes. In astrocytes 3b-HSD was also suppressed by vitamin D, about 20% at the enzyme activity level and 60% at the mRNA level. These data suggest that vitamin D-mediated regulation of CYP17A1 and 3b-HSD, particularly on the transcriptional level, may play a role in the nervous system.
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- Emanuelsson, Ida, et al.
(författare)
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Protective effects of 27-and 24-hydroxycholesterol against staurosporine-induced cell death in undifferentiated neuroblastoma SH-SY5Y cells
- 2012
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Ingår i: Neuroscience Letters. - : Elsevier BV. - 0304-3940 .- 1872-7972. ; 525:1, s. 44-48
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Tidskriftsartikel (refereegranskat)abstract
- Alterations in cholesterol metabolism have been linked to several neurodegenerative disorders, including Alzheimer's disease, multiple sclerosis and Parkinson's disease. Brain cholesterol is metabolized to the oxysterols 24-hydroxycholesterol and 27-hydroxycholesterol. Disturbed levels of these oxysterols are found in neurodegenerative conditions. In the current study we examined the effects of 27- and 24-hydroxycholesterol on viability of human neuroblastoma SH-SY5Y cells treated with staurosporine, a toxic substance that induces apoptosis. Analyses using MTT assay and measurement of lactate dehydrogenase release showed that presence of 27-hydroxycholesterol counteracted the toxic effects of staurosporine on these cells. Also, 27-hydroxycholesterol significantly decreased the staurosporine-mediated induction of caspase-3 and -7, known to be important in apoptotic events. 24-Hydroxycholesterol had similar effects on viability as 27-hydroxycholesterol in low concentrations, although in higher concentrations this oxysterol exacerbated the toxic effects of staurosporine. From these findings it may be concluded that effects of oxysterols on cellular viability are strongly dependent on the concentration and on the type of oxysterol. Previous studies on oxysterols have reported that these compounds are pro-apoptotic or trigger pathological changes that result in neurodegeneration. The present data indicate that, during some conditions, oxysterols may have neuroprotective effects.
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- Emanuelsson, Ida, 1983-
(författare)
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Steroids and steroid-metabolizing enzymes in the nervous system : Special focus on cell survival and sex hormone synthesis
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Some steroids in the brain and peripheral nervous system have been shown to have neuroprotective effects but the knowledge is limited. The present study examines the effects of steroids including oxysterols, vitamin D and vitamin D analogs on cell viability/growth and steroidogenesis in the nervous system.Both 24- and 27-hydroxycholesterol reduced staurosporine-induced toxicity in human neuroblastoma SH-SY5Y cells. In addition, 27-hydroxycholesterol decreased the staurosporine-mediated induction of caspases, known to be important in apoptotic events. From the findings it may be concluded that effects of oxysterols on cellular viability are dependent on the concentration and on the type of oxysterol. 24-Hydroxycholesterol was also found to attenuate oxidative stress both in SH-SY5Y cells and astrocytes. The results indicate that during some conditions, oxysterols may have neuroprotective effects.The vitamin D analogs tacalcitol and calcipotriol strongly reduced proliferation, cell viability and migration of human glioblastoma T98G cells, similarly as 1,25(OH)2D3 , the physiological form of vitamin D. Glioblastoma is the most lethal type of primary tumors in the CNS. These findings suggest that vitamin D analogs are potential candidates in treatment of brain tumors, most likely in combination with other therapies.Astrocytes were found to be a major site for expression of 3β-hydroxysteroid dehydrogenase (3β-HSD) whereas expression of CYP17A1 was found in both astrocytes and neurons. 3β-HSD and CYP17A1 are important steroidogenic enzymes. Vitamin D inhibited both CYP17A1- and 3β-HSD -mediated activity and mRNA levels, with a stronger effect on mRNA expression than on enzyme activity. This indicates that 1,25(OH)2D3 could affect the production of sex hormones in the brain.In summary, results from this thesis contribute to the knowledge on the effects of oxysterols on cell viability and oxidative stress in cells from the CNS. Also the results provide data on the effects of vitamin D in the brain and suggest that vitamin D analogs may be promising candidates for treatment of certain brain tumors.
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- Emanuelsson, Ida, et al.
(författare)
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Vitamin D Analogues Tacalcitol and Calcipotriol Inhibit Proliferation and Migration of T98G Human Glioblastoma Cells
- 2018
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Ingår i: Neuroscience. - : John Wiley & Sons. - 0306-4522 .- 1873-7544.
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Tidskriftsartikel (refereegranskat)abstract
- The active form of vitamin D (1,25-dihydroxyvitamin D) acts as a steroid hormone and binds to the vitamin D receptor. This receptor is expressed in most cell types including cells in the central nervous system (CNS). Vitamin D has several functions in the body including effects on brain development, neuroprotection and immunological regulation. It has been shown that vitamin D has antiproliferative activities in different cancer cell lines. Tacalcitol and calcipotriol are synthetic analogues of 1,25-dihydroxyvitamin D with reduced effect on calcium metabolism. The aim of this study was to analyse the effects of tacalcitol and calcipotriol on cell viability, proliferation and migration in the human glioblastoma cell line T98G. Glioblastoma is the most lethal type of primary tumours in the CNS. Both analogues decreased cell viability and/or growth, dose-dependently, in concentrations between 1 nM and 10 M. Manual counting indicated suppressive effects by the vitamin D analogues on proliferation. Treatment with tacalcitol strongly suppressed thymidine incorporation, indicating that the vitamin D analogues mainly inhibit proliferation. Also, effects on cell migration were measured with wound-healing assay. Both calcipotriol and tacalcitol reduced the migration rate of T98G cells compared to vehicle-treated cells. However, they had no effect on caspase-3 and -7 activities, suggesting that their mechanism of action does not involve induction of apoptosis. The current results indicate that the vitamin D analogues tacalcitol and calcipotriol strongly reduce proliferation and migration of human glioblastoma T98G cells, suggesting a potential role for this type of compounds in treatment of brain cancer.
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