Browsing by Subject "Dexamethasone"

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  • Manjur, A. B. M. Kaiser; Lempiainen, Joanna K.; Malinen, Marjo; Varjosalo, Markku; Palvimo, Jorma J.; Niskanen, Einari A. (2021)
    Glucocorticoid (GC) receptor (GR) is a key transcription factor (TF) that regulates vital metabolic and antiinflammatory processes. We have identified BCL6 corepressor (BCOR) as a dexamethasone-stimulated interaction partner of GR. BCOR is a component of non-canonical polycomb repressor complex 1.1 (ncPCR1.1) and linked to different developmental disorders and cancers, but the role of BCOR in GC signaling is poorly characterized. Here, using ChIP-seq we show that, GC induces genome-wide redistribution of BCOR chromatin binding towards GR-occupied enhancers in HEK293 cells. As assessed by RNA-seq, depletion of BCOR altered the expression of hundreds of GC-regulated genes, especially the ones linked to TNF signaling, GR signaling and cell migration pathways. Biotinylation-based proximity mapping revealed that GR and BCOR share several interacting partners, including nuclear receptor corepressor NCOR1. ChIP-seq showed that the NCOR1 co-occurs with both BCOR and GR on a subset of enhancers upon GC treatment. Simultaneous depletion of BCOR and NCOR1 influenced GR target gene expression in a combinatorial and gene-specific manner. Finally, we show using live cell imaging that the depletion of BCOR together with NCOR1 markedly enhances cell migration. Collectively, our data suggest BCOR as an important gene and pathway selective coregulator of GR transcriptional activity.
  • Snäll, Johanna; Törnwall, Jyrki; Suominen, Anna Liisa; Thoren, Hanna (2018)
    To clarify pre- and postoperative C-reactive protein (CRP) levels in patients with facial fractures and to investigate the influence of perioperatively administered dexamethasone on postoperative CRP levels. Facial fracture patients were randomized to receive perioperatively a total dose of 30 mg of dexamethasone (OradexonA (R)), whereas patients in the control group received no glucocorticoid. The analysis included patients who had CRP measured pre- and postoperatively. A total of 73 adult patients with facial fractures were included in the final analysis. Mean CRP level was elevated preoperatively and the level increased further after surgery. However, postoperative CRP rise was significantly impeded by dexamethasone (p <0.001), regardless of gender, age, treatment delay, site of fracture, surgical approach, and duration of surgery. CRP rise halved on the 1st postoperative day when dexamethasone was used. In addition, dexamethasone resulted in a CRP decrease on the 2nd postoperative day, whereas the CRP rise continued in the control group. CRP rise is a normal body response after facial fracture and surgery that can be markedly reduced with dexamethasone. CRP changes should be considered with caution if perioperative dexamethasone is used.
  • Kainulainen, S.; Tornwall, J.; Koivusalo, A. M.; Suominen, A. L.; Lassus, Patrik (2017)
    Objectives: Glucocorticoids are widely used in association with major surgery of the head and neck to improve postoperative rehabilitation, shorten intensive care unit and hospital stay, and reduce neck swelling. This study aimed to clarify whether peri-and postoperative use of dexamethasone in reconstructive head and neck cancer surgery is associated with any advantages or disadvantages. Materials and methods: This prospective double-blind randomized controlled trial comprised 93 patients. A total dose of 60 mg of dexamethasone was administered to 51 patients over three days peri-and post-operatively. The remaining 42 patients served as controls. The main primary outcome variables were neck swelling, length of intensive care unit and hospital stay, duration of intubation or tracheostomy, and delay to start of possible radiotherapy. Complications were also recorded. Results: No statistical differences emerged between the two groups in any of the main primary outcome variables. However, there were more major complications, especially infections, needing secondary surgery within three weeks of the operation in patients receiving dexamethasone than in control patients (27% vs. 7%, p = 0.012). Conclusions: The use of dexamethasone in oral cancer patients with microvascular reconstruction did not provide a benefit. More major complications, especially infections, occurred in patients receiving dexamethasone. Our data thus do not support the use of peri-and postoperative dexamethasone in oropharyngeal cancer patients undergoing microvascular reconstruction. (C) 2016 Elsevier Ltd. All rights reserved.
  • Bhattacharya, Madhushree; Sadeghi, Amir; Sarkhel, Sanjay; Hagström, Marja; Bahrpeyma, Sina; Toropainen, Elisa; Auriola, Seppo; Urtti, Arto (2020)
    Tissue barriers limit drug delivery in the eye. Therefore, retinal diseases are treated with intravitreal injections. Delivery systems with reduced dosing frequency and/or cellular drug delivery properties are needed. We present here a modular peptide-based delivery system for cell targeted release of dexamethasone in the retinal pigment epithelial cells. The peptide–dexamethasone conjugates consist of cell penetrating peptide, enzyme cleavable linker and dexamethasone that is conjugated with hydrazone bond. The conjugates are chemically stable in the vitreous, internalize into the retinal pigment epithelial cells and release dexamethasone intracellularly by en- zymatic action of cathepsin D. In vitro binding assay and molecular docking confirm binding of the released dexamethasone fragment to the human glucocorticoid receptor. In vivo rabbit studies show increased vitreal retention of dexamethasone with a peptide conjugate. Modular peptide conjugates are a promising approach for drug delivery into the retinal cells.
  • Balla, Anusha; Ruponen, Marika; Valtari, Annika; Toropainen, Elisa; Tuomainen, Marjo; Alvarez-Lorenzo, Carmen; del Amo, Eva M.; Urtti, Arto; Vellonen, Kati-Sisko (2022)
    Rapid precorneal loss of topically applied eye drops limits ocular drug absorption. Controlling release and precorneal residence properties of topical formulations may improve ocular drug bioavailability and duration of action. In this study, we evaluated in vivo ocular pharmacokinetics of dexamethasone in rabbits after application of a drug solution (0.01%), suspension (Maxidex (R) 0.1%), and hydrogels of 2-hydroxyethyl methacrylate (HEMA) and acrylic acid (AAc) copolymers. The rabbits received a single eyedrop (solution or suspension) or dexamethasone-loaded hydrogel topically. Dexamethasone in tear fluid was sampled with glass capillaries and quantitated by LC-MS/MS. Higher dexamethasone exposure (AUC) in the tear fluid was observed with the suspension (approximate to 3.6-fold) and hydrogel (12.8-fold) as compared to the solution. During initial 15 min postapplication, the highest AUC of dissolved dexamethasone was seen after hydrogel application (368 min*mu g/ mL) followed by suspension (109.9 min*mu g/mL) and solution (28.7 min*mu g/mL. Based on kinetic simulations, dexamethasone release from hydrogels in vivo and in vitro is comparable. Our data indicate that prolonged exposure of absorbable dexamethasone in tear fluid is reached with hydrogels and suspensions. Pharmacokinetic understanding of formulation behavior in the lacrimal fluid helps in the design of dexamethasone delivery systems with improved ocular absorption and prolonged duration of action.