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BMC Anesthesiology Sep 2023Dexamethasone (Dexa) has been recently found to exert an analgesic effect, whose action is closely related to IL-8. However, whether dexamethasone induces...
BACKGROUND
Dexamethasone (Dexa) has been recently found to exert an analgesic effect, whose action is closely related to IL-8. However, whether dexamethasone induces antinociception via glycolysis and mitochondria-related pathways is still unclear.
METHODS
Right hind paw inflammatory pain in mice was induced by intraplantar injection of Freund's Complete Adjuvant (FCA). Von Frey test was then used to measure the paw withdrawal threshold. The detection of glycolysis and mitochondrial pathway-related proteins and IL-8 were determined by Western blot and ELISA. The potential interaction between Dexa and fructose-1,6-bisphosphate (FBP, a PKM2 activator) was examined by simulation predictions using molecular docking.
RESULTS
Intrathecal administration of Dexa (20 µg/20 µL) had an obvious analgesic effect in FCA-treated mice, which was counteracted by the glycolysis inhibitor 2-deoxyglucose (2-DG, 5 mg/20 µL) or the mitochondria-related pathway inhibitor oligomycin complex (Oligo, 5 µg/20 µL). In the glycolysis pathway, Dexa decreased GLUT3 and had no impact on HIF-1α expression during FCA-induced inflammation. Additionally, Dexa further increased the PKM2 level, accompanied by the formation of hydrogen bonds between Dexa and the PKM2 activator fructose-1,6-bisphosphate (FBP). In the mitochondrial pathway, Dexa downregulated the expression of Mfn2 protein but not the PGC-1α and SIRT-1 levels in the spinal cord. Moreover, both 2-DG and Oligo decreased Mfn2 expression. Finally, IL-8 level was reduced by the single or combined administration of Dexa, 2-DG, and Oligo.
CONCLUSION
Dexa attenuated IL-8 expression via glycolysis and mitochondrial pathway-related proteins, thus mediating the analgesic effect during inflammatory pain.
Topics: Animals; Mice; Interleukin-8; Molecular Docking Simulation; Fructose; Glycolysis; Mitochondria; Dexamethasone; Analgesics
PubMed: 37723417
DOI: 10.1186/s12871-023-02277-9 -
Dental Materials : Official Publication... Jun 2023To evaluate the effect of doxycycline and dexamethasone doped nanoparticles covering titanium surfaces, on osteoblasts proliferation and differentiation.
OBJECTIVES
To evaluate the effect of doxycycline and dexamethasone doped nanoparticles covering titanium surfaces, on osteoblasts proliferation and differentiation.
METHODS
Doxycycline and dexamethasone doped polymeric nanoparticles were applied on titanium discs (Ti-DoxNPs and Ti-DexNPs). Undoped NPs and uncovered Ti discs were used as control. Human MG-63 osteoblast-like cells were cultured. Osteoblasts proliferation was tested by MTT assay. Alkaline phosphatase activity was analyzed. Differentiation gene expression was assessed by real-time quantitative polymerase chain reaction. Scanning Electron Microscopy was performed to assess osteoblasts morphology. Mean comparisons were conducted by ANOVA and Wilcoxon or Tukey tests (p < 0.05).
RESULTS
No differences in osteoblasts proliferation were found. Osteoblasts grown on Ti-DoxNPs significantly increased alkaline phosphatase activity. Doxycycline and dexamethasone nanoparticles produced an over-expression of the main osteogenic proliferative genes (TGF-β1, TGF-βR1 and TGF-βR2). The expression of Runx-2 was up-regulated. The osteogenic proteins (AP, OSX and OPG) were also overexpressed on osteoblasts cultured on Ti-DoxNPs and Ti-DexNPs. The OPG/RANKL ratio was the highest when DoxNPs were present (75-fold increase with respect to the control group). DexNPs also produced a significantly higher OPG/RANKL ratio with respect to the control (20 times higher). Osteoblasts grown on titanium discs were mainly flat and polygonal in shape, with inter-cellular connections. In contrast, osteoblasts cultured on Ti-DoxNPs or Ti-DexNPs were found to be spindle-shaped and had abundant secretions on their surfaces.
SIGNIFICANCE
DoxNPs and DexNPs were able to stimulate osteoblasts differentiation when applied on titanium surfaces, being considered potential inducers of osteogenic environment when performing regenerative procedures around titanium dental implants.
Topics: Humans; Titanium; Doxycycline; Alkaline Phosphatase; Cell Differentiation; Osteogenesis; Nanoparticles; Dexamethasone; Osteoblasts; Surface Properties; Cell Proliferation
PubMed: 37173196
DOI: 10.1016/j.dental.2023.05.004 -
BioMed Research International 2018To conduct a meta-analysis, assessing the efficacy and safety of the combination treatment of dexamethasone and rituximab for adults with ITP (primary immune... (Meta-Analysis)
Meta-Analysis Review
To conduct a meta-analysis, assessing the efficacy and safety of the combination treatment of dexamethasone and rituximab for adults with ITP (primary immune thrombocytopenia). Randomized controlled trials that compared rituximab and dexamethasone combination treatment to dexamethasone monotherapy in the treatment of adults with ITP were collected by searching Pubmed, Embase, Cochrane, China National Knowledge (CNKI), Wanfang database, and Sino Med. We conducted pooled analyses on OR (overall response) rate, CR (complete response) rate, PR (partial response) rate, SR (sustained response) rate, R (relapse) rate, change in Treg cell count (mean [SD]), and AE (adverse event). GRADE pro scale was used to assess the quality of the evidence. Publication bias was assessed with Egger's test method. A total of 11 randomized controlled trials were eligible for inclusion. The overall efficacy estimates favored combination arm in terms of OR rate at month 3, CR rate at week 4 and month 3, SR rate, and Treg cell count at week 2. Subgroup analysis showed that females obtained a higher OR rate than males did at week 4. No significant difference was found in pooled analysis of relapse rate between combination arm and monotherapy arm. The comparison of serious AE and other AEs showed no significant difference either. A total of 19 outcomes were assessed by GRADE pro software, of which 79% (15/19) was scaled as moderate-to-high level. Publication bias existed in studies on OR at week 4 (=0.025), CR at week 4 (=0.017), infection (=0.006), and rash (=0.028) of the AEs. Dexamethasone combined with rituximab can provide a better long-term response in the treatment of adults with ITP and will not increase the risk of adverse effects.
Topics: Animals; Combined Modality Therapy; Dexamethasone; Humans; Purpura, Thrombocytopenic, Idiopathic; Randomized Controlled Trials as Topic; Rituximab
PubMed: 30648105
DOI: 10.1155/2018/1316096 -
Dexamethasone suppresses the proliferation and migration of VSMCs by FAK in high glucose conditions.BMC Pharmacology & Toxicology Aug 2022High glucose conditions cause some changes in the vessels of diabetes through the signal transduction pathways. Dexamethasone and other corticosteroids have a wide range...
BACKGROUND
High glucose conditions cause some changes in the vessels of diabetes through the signal transduction pathways. Dexamethasone and other corticosteroids have a wide range of biological effects in immunological events. In the present study, the effects of dexamethasone were investigated on the VSMC (vascular smooth muscle cell) proliferation, and migration based on the FAK gene and protein changes in high glucose conditions.
METHODS AND MATERIALS
The vascular smooth muscle cells were cultured in DMEM and were treated with dexamethasone (10 M, 10 M, and 10 M) for 24, and 48 h in high glucose conditions. The cell viability was estimated by MTT method. The FAK gene expression levels and pFAK protein values were determined by RT-qPCR and western blotting techniques, respectively. A scratch assay was used to evaluate cellular migration.
RESULTS
The FAK gene expression levels decreased significantly dependent on dexamethasone doses at 24 and 48 h. The pFAK protein values decreased significantly with a time lag at 24- and 48-h periods as compared with gene expression levels.
CONCLUSION
The results showed that the inhibition of VSMC proliferation and migration by dexamethasone in the high glucose conditions may be related to the changes of FAK.
Topics: Cell Proliferation; Cells, Cultured; Dexamethasone; Glucose; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle
PubMed: 35978346
DOI: 10.1186/s40360-022-00604-3 -
Biomedicine & Pharmacotherapy =... Sep 2022Acute respiratory distress syndrome (ARDS) is a lethal clinical entity that has become an emergency event with the outbreak of COVID-19. However, to date, there are no...
Acute respiratory distress syndrome (ARDS) is a lethal clinical entity that has become an emergency event with the outbreak of COVID-19. However, to date, there are no well-proven pharmacotherapies except dexamethasone. This study is aimed to evaluate IRAK4 inhibitors as a potential treatment for ARDS-cytokine release syndrome (CRS). We applied two IRAK4 inhibitors, BAY-1834845 and PF-06650833 to an inhaled lipopolysaccharide (LPS)-induced ARDS mouse model with control of high dose dexamethasone (10 mg/kg). Unexpectedly, although both compounds had excellent IC on IRAK4 kinase activity, only BAY-1834845 but not PF-06650833 or high dose dexamethasone could significantly prevent lung injury according to a blinded pathology scoring. Further, only BAY-1834845 and BAY-1834845 combined with dexamethasone could effectively improve the injury score of pre-existed ARDS. Compared with PF-06650833 and high dose dexamethasone, BAY-1834845 remarkably decreased inflammatory cells infiltrating lung tissue and neutrophil count in BALF. BAY-1834845, DEX, and the combination of the two agents could decrease BALF total T cells, monocyte, and macrophages. In further cell type enrichment analysis based on lung tissue RNA-seq, both BAY-1834845 and dexamethasone decreased signatures of inflammatory cells and effector lymphocytes. Interestingly, unlike the dexamethasone group, BAY-1834845 largely preserved the signatures of naïve lymphocytes and stromal cells such as endothelial cells, chondrocytes, and smooth muscle cells. Differential gene enrichment suggested that BAY-1834845 downregulated genes more efficiently than dexamethasone, especially TNF, IL-17, interferon, and Toll-like receptor signaling.
Topics: Animals; Mice; COVID-19 Drug Treatment; Dexamethasone; Endothelial Cells; Interleukin-1 Receptor-Associated Kinases; Isoquinolines; Lactams; Lipopolysaccharides; Lung; Protein Kinase Inhibitors; Respiratory Distress Syndrome
PubMed: 36076574
DOI: 10.1016/j.biopha.2022.113459 -
Frontiers in Immunology 2023Severe COVID-19 is characterized by cytokine storm, an excessive production of proinflammatory cytokines that contributes to acute lung damage and death. Dexamethasone...
INTRODUCTION
Severe COVID-19 is characterized by cytokine storm, an excessive production of proinflammatory cytokines that contributes to acute lung damage and death. Dexamethasone is routinely used to treat severe COVID-19 and has been shown to reduce patient mortality. However, the mechanisms underlying the beneficial effects of dexamethasone are poorly understood.
METHODS
We conducted transcriptomic analysis of peripheral blood mononuclear cells (PBMCs) from COVID-19 patients with mild disease, and patients with severe COVID-19 with and without dexamethasone treatment. We then treated healthy donor PBMCs in vitro with dexamethasone and investigated the effects of dexamethasone treatment ion channel abundance (by RT-qPCR and flow cytometry) and function (by electrophysiology, Ca2+ influx measurements and cytokine release) in T cells.
RESULTS
We observed that dexamethasone treatment in severe COVID-19 inhibited pro-inflammatory and immune exhaustion pathways, circulating cytotoxic and Th1 cells, interferon (IFN) signaling, genes involved in cytokine storm, and Ca signaling. Ca influx is regulated by Kv1.3 potassium channels, but their role in COVID-19 pathogenesis remains elusive. Kv1.3 mRNA was increased in PBMCs of severe COVID-19 patients, and was significantly reduced in the dexamethasone-treated group. In agreement with these findings, in vitro treatment of healthy donor PBMCs with dexamethasone reduced Kv1.3 abundance in T cells and CD56dimNK cells. Furthermore, functional studies showed that dexamethasone treatment significantly reduced Kv1.3 activity, Ca2+ influx and IFN-g production in T cells.
CONCLUSION
Our findings suggest that dexamethasone attenuates inflammatory cytokine release via Kv1.3 suppression, and this mechanism contributes to dexamethasone-mediated immunosuppression in severe COVID-19.
Topics: Humans; COVID-19; Leukocytes, Mononuclear; Calcium; Cytokine Release Syndrome; COVID-19 Drug Treatment; Cytokines; Dexamethasone
PubMed: 37033961
DOI: 10.3389/fimmu.2023.1143350 -
Allergy Mar 2021
Topics: COVID-19; Dexamethasone; Docosahexaenoic Acids; Fatty Acids, Unsaturated; Humans; Inflammation; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 32956495
DOI: 10.1111/all.14595 -
Anesthesiology Nov 2021
Review
Topics: Antiemetics; Dexamethasone; Humans; Postoperative Complications; Risk Assessment; Risk Factors; Surgical Procedures, Operative
PubMed: 34370818
DOI: 10.1097/ALN.0000000000003898 -
Redox Report : Communications in Free... Dec 2023Primary hepatocytes are widely used as a tool for studying metabolic function and regulation in the liver. However, the metabolic properties of primary hepatocytes are...
Primary hepatocytes are widely used as a tool for studying metabolic function and regulation in the liver. However, the metabolic properties of primary hepatocytes are gradually lost after isolation. Here, we illustrated that fatty acid metabolism is the major compromised metabolic process in isolated primary hepatocytes, along with drastically decreased GSH and ROS content, while lipid peroxidation is increased. Gain- and loss-of-function studies revealed that Slc7a11 expression is critical in maintaining fatty acid metabolism and facilitating hormone-induced fatty acid metabolic events, which is synergistic with dexamethasone treatment. Intriguingly, Slc7a11 expression and dexamethasone treatment cooperatively upregulated AKT and AMPK signaling and mitochondrial complex expression in primary hepatocytes. Furthermore, direct treatment with reduced GSH or inhibition of ferroptosis is sufficient to drive protective effects on fatty acid metabolism in primary hepatocytes. Our results demonstrate that Slc7a11 expression in isolated primary hepatocytes induces GSH production, which protects against ferroptosis, to increase fatty acid metabolic gene expression, AKT and AMPK signaling and mitochondrial function in synergy with dexamethasone treatment, thereby efficiently preserving primary hepatocyte metabolic signatures, thus providing a promising approach to better reserve primary hepatocyte metabolic activities after isolation to potentially improve the understanding of liver biological functions from studies using primary hepatocytes.
Topics: AMP-Activated Protein Kinases; Proto-Oncogene Proteins c-akt; Hepatocytes; Fatty Acids; Dexamethasone; Glutathione
PubMed: 37750478
DOI: 10.1080/13510002.2023.2260646 -
PLoS Computational Biology Jan 2022Chimeric antigen receptor (CAR) T-cell therapy is potentially an effective targeted immunotherapy for glioblastoma, yet there is presently little known about the...
Chimeric antigen receptor (CAR) T-cell therapy is potentially an effective targeted immunotherapy for glioblastoma, yet there is presently little known about the efficacy of CAR T-cell treatment when combined with the widely used anti-inflammatory and immunosuppressant glucocorticoid, dexamethasone. Here we present a mathematical model-based analysis of three patient-derived glioblastoma cell lines treated in vitro with CAR T-cells and dexamethasone. Advanced in vitro experimental cell killing assay technologies allow for highly resolved temporal dynamics of tumor cells treated with CAR T-cells and dexamethasone, making this a valuable model system for studying the rich dynamics of nonlinear biological processes with translational applications. We model the system as a nonautonomous, two-species predator-prey interaction of tumor cells and CAR T-cells, with explicit time-dependence in the clearance rate of dexamethasone. Using time as a bifurcation parameter, we show that (1) dexamethasone destabilizes coexistence equilibria between CAR T-cells and tumor cells in a dose-dependent manner and (2) as dexamethasone is cleared from the system, a stable coexistence equilibrium returns in the form of a Hopf bifurcation. With the model fit to experimental data, we demonstrate that high concentrations of dexamethasone antagonizes CAR T-cell efficacy by exhausting, or reducing the activity of CAR T-cells, and by promoting tumor cell growth. Finally, we identify a critical threshold in the ratio of CAR T-cell death to CAR T-cell proliferation rates that predicts eventual treatment success or failure that may be used to guide the dose and timing of CAR T-cell therapy in the presence of dexamethasone in patients.
Topics: Adult; Cell Line, Tumor; Dexamethasone; Glioblastoma; Humans; Immunotherapy, Adoptive; Male; Middle Aged; Receptors, Chimeric Antigen
PubMed: 35081104
DOI: 10.1371/journal.pcbi.1009504