Browsing by Subject "GLUCOCORTICOIDS"

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  • Czamara, Darina; Dieckmann, Linda; Roeh, Simone; Kraemer, Sarah; Rancourt, Rebecca C.; Sammallahti, Sara; Kajantie, Eero; Laivuori, Hannele; Eriksson, Johan G.; Räikkönen, Katri; Henrich, Wolfgang; Plagemann, Andreas; Binder, Elisabeth B.; Braun, Thorsten; Entringer, Sonja (2021)
    Background Glucocorticoids (GCs) play a pivotal role in fetal programming. Antenatal treatment with synthetic GCs (sGCs) in individuals in danger of preterm labor is common practice. Adverse short- and long-term effects of antenatal sGCs have been reported, but their effects on placental epigenetic characteristics have never been systematically studied in humans. Results We tested the association between exposure to the sGC betamethasone (BET) and placental DNA methylation (DNAm) in 52 exposed cases and 84 gestational-age-matched controls. We fine-mapped associated loci using targeted bisulfite sequencing. The association of placental DNAm with gene expression and co-expression analysis on implicated genes was performed in an independent cohort including 494 placentas. Exposure to BET was significantly associated with lower placenta DNAm at an enhancer of FKBP5. FKBP5 (FK506-binding protein 51) is a co-chaperone that modulates glucocorticoid receptor activity. Lower DNAm at this enhancer site was associated with higher expression of FKBP5 and a co-expressed gene module. This module is enriched for genes associated with preeclampsia and involved in inflammation and immune response. Conclusions Our findings suggest that BET exposure during pregnancy associates with few but lasting changes in placental DNAm and may promote a gene expression profile associated with placental dysfunction and increased inflammation. This may represent a pathway mediating GC-associated negative long-term consequences and health outcomes in offspring.
  • Keski-Nisula, Juho; Pesonen, Eero; Olkkola, Klaus T.; Ahlroth, Terri; Puntila, Juha; Andersson, Sture; Neuvonen, Pertti J.; Suominen, Pertti K. (2016)
    Background. The optimal dose of methylprednisolone during pediatric open heart surgical procedures is unknown. This study compared the antiinflammatory and cardioprotective effects of high and lower doses of methylprednisolone in children undergoing cardiac operations. Methods. Thirty children, between 1 and 18 months old and undergoing total correction of tetralogy of Fallot, were randomized in double-blind fashion to receive either 5 or 30 mg/kg of intravenous methylprednisolone after anesthesia induction. Plasma concentrations of methylprednisolone, interleukin-6 (IL-6), IL-8, and IL-10, troponin T, and glucose were measured at anesthesia induction before administration of the study drug, at 30 minutes on cardiopulmonary bypass (CPB), just after weaning from CPB, and at 6 hours after CPB. Troponin T and blood glucose were also measured on the first postoperative morning. Results. Significantly higher methylprednisolone concentrations were measured in patients receiving 30 mg/kg of methylprednisolone at 30 minutes on CBP, after weaning from CPB and at 6 hours after CPB (p <0.001). No differences were detected in IL-6, IL-8, IL-10, or troponin concentrations at any time point. Blood glucose levels were significantly higher in patients receiving 30 mg/kg of methylprednisolone at 6 hours after CPB (p = 0.04) and on the first postoperative morning (p = 0.02). Conclusions. Based on the measured concentrations of interleukins or troponin T, a 30 mg/kg dose of methylprednisolone during pediatric open heart operations does not offer any additional antiinflammatory or cardioprotective benefit over a 5 mg/kg dose. Higher dose of methylprednisolone exposes patients more frequently to hyperglycemia. (C) 2016 by The Society of Thoracic Surgeons
  • Nam, Jinhan; Koppinen, Tapani K.; Voutilainen, Merja H. (2021)
    Multiple sclerosis (MS) is a progressive autoimmune disease characterized by T-cell mediated demyelination in central nervous system (CNS). Experimental autoimmune encephalomyelitis (EAE) is a widely used in vivo disease model of MS. Glucocorticoids such as dexamethasone (dex) function as immunosuppressants and are commonly used to treat acute exacerbations of MS. Dex is also often used as a positive control in EAE studies, as it has been shown to promote motor behavior, inhibit immune cell infiltration into the CNS and regulate the activation of glial cell in EAE. This study further validated the effects of intravenously administrated dex by time-dependent fashion in EAE. Dex postponed clinical signs and motor defects in early stages of EAE. Histological analysis revealed that the degeneration of myelin and axons, as well as the infiltration of peripheral immune cells into the white matter of spinal cord was inhibited by dex in early stages of EAE. Additionally, dex-treatment delayed the neuroinflammatory activation of microglia and astrocytes. Furthermore, this study analyzed the expression of the neurotrophic factor mesencephalic astrocyte-derived neurotrophic factor (MANF) in EAE, and the effect of treatment with dex on MANF-expression. We show that in dex-treated EAE mice expression MANF increased within myelinated areas of spinal cord white matter. We also show that intravenous administration with hMANF in EAE mice improved clinical signs and motor behavior in the early stage of EAE. Our report gives insight to the progression of EAE by providing a time-dependent analysis. Moreover, this study investigates the link between MANF and the EAE model, and shows that MANF is a potential drug candidate for MS.
  • Utge, Siddheshwar; Räikkönen, Katri; Kajantie, Eero; Lipsanen, Jari; Andersson, Sture; Strandberg, Timo; Reynolds, Rebecca M.; Eriksson, Johan G.; Lahti, Jari (2018)
    Purpose: Corticosteroid-binding globulin (CBG) transports glucocorticoids in blood. Variation in genes SERPINA6 encoding for CBG, SERPINA2 and SERPINAI (serpin family A member 6, 2, and 1) have been shown to influence morning plasma cortisol and CBG in adults. However, association of this genetic variation with diurnal and stress-induced salivary cortisol remain unknown. This study aims to investigate the effect of genetic variation in SERPINA6/2/1 loci on diurnal and stress-induced salivary cortisol in children. Methods: We studied 186, 8-year-old children with genome-wide genotyping. We generated weighted polygenic risk score (PRS) based on 6 genome-wide significant SNPs (rs11621961, rs11629171, rs7161521, rs2749527, rs3762132, rs4900229) derived from the CORNET meta-analyses. Salivary cortisol was measured across one day and in response to the Trier Social Stress Test for Children (TSST-C). Results: Mixed models, adjusted for covariates, showed that the PRS x sampling time interactions associated with diurnal (P <0.001) and stress-induced (P = 0.009) salivary cortisol. In the high PRS group (dichotomized at median) the diurnal salivary cortisol pattern decreased less from awakening to bedtime than in the low PRS group (standardized estimates of sampling time -0.64 vs. -0.73, P <0.0001 for both estimates). In response to stress, salivary cortisol increased in the high PRS group while it remained unchanged in the low PRS group (standardized estimates of sampling time 0.12, P = 0.015 vs. -0.06, P = 0.16). These results were mainly driven by minor alleles of rs7161521 (SERPINA6) and rs4900229 (SERPINAI). Conclusions: Genetic variation in SERPINA6/2/1loci may underpin higher hypothalamic-pituitary-adrenocortical axis activity in children.
  • Parri, E; Kuusanmaki, H; Bulanova, D; Mustjoki, S; Wennerberg, K (2021)
    Mature natural killer (NK) cell neoplasms are rare but very aggressive types of cancers. With 3 currently available treatments, they have a very poor prognosis and, as such, are an example of group of cancers in which the development of effective precision therapies is needed. Using both short- and long-term drug sensitivity testing, we explored novel ways to target NK-cell neoplasms by combining the clinically approved JAK inhibitor ruxolitinib with other targeted agents. We profiled 7 malignant NK-cell lines in drug sensitivity screens and identified that these exhibit differential drug sensitivities based on their genetic background. In short-term assays, various classes of drugs combined with ruxolitinib seemed highly potent. Strikingly, resistance to most of these combinations emerged rapidly when explored in long-term assays. However, 4 combinations were identified that selectively eradicated the cancer cells and did not allow for development of resistance: ruxolitinib combined with the mouse double-minute 2 homolog (MDM2) inhibitor idasanutlin in STAT3-mutant, TPS3 wild-type cell lines; ruxolitinib combined with the farnesyltransferase inhibitor tipifarnib in TP53-mutant cell lines; and ruxolitinib combined with either the glucocorticoid dexamethasone or the myeloid cell leukemia-1 (MCL-1) inhibitor S63845 but both without a clear link to underlying genetic features. In conclusion, using a new drug sensitivity screening approach, we identified drug combinations that selectively target mature NK-cell neoplasms and do not allow for development of resistance, some of which can be applied in a genetically stratified manner.
  • Linko, Rita Teresa; Hedger, Mark P.; Pettila, Ville; Ruokonen, Esko; Ala-Kokko, Tero; Ludlow, Helen; de Kretser, David M. (2014)