Browsing by Subject "Glucocorticoids"

Now showing 1 - 8 of 8
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    Acute Biventricular Heart Failure After COVID-19 Infection in an Orthotropic Heart Transplant Patient: A Case Report
    (Elsevier, 2021-05) Berg, Nicholas; Ilonze, Onyedika; Bajpai, Vatsal; Guglin, Maya; Rao, Roopa; Medicine, School of Medicine
    The cardiac effects of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) include myocarditis, takotsubo cardiomyopathy, pericardial effusion, and cardioembolic events in the general population. The effects of SARS-CoV-2 in heart transplant patients are unclear. We describe a case of myocarditis in the transplanted heart that responded to methylprednisolone.
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    A Case Series of Severe Hospitalized COVID-19 Patients Treated with Tocilizumab and Glucocorticoids: A Report from Saudi Arabian Hospital
    (Atlantis Press, 2021-01-22) Al Bahrani, Salma Yassin; Al-Tawfiq, Jaffar A.; Alshaer, Abdulaziz R.; Shilash, Amal; Alswefy, Khalid; Al-Zayer, Razan Salamah; Abouelela, Amr Mohamed; Medicine, School of Medicine
    Background: The clinical spectrum of COVID-19 is variable and ranges from asymptomatic, mildly symptomatic, moderately severe and severe disease. A small proportion might develop severe disease and may have cytokine storm. One of the therapeutic options to treat such cases is Tocilizumab (TCZ). In this study, we present cases of severe COVID-19 treated with TCZ and glucocorticoids and discuss the treatment responses. Methods: This is a retrospective observational study of severe COVID-19 cases treated with TCZ and glucocorticoids. The case series examined the characteristics and outcome of those patients. Results: This study included 40 Severe Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) confirmed patients who received TCZ and glucocorticoids. The mean age of the included patients was 57.55 (±Standard deviation 12.86) years. There were 34 (85%) males, 19 (47.5%) were obese (BMI >30), 13 (32.5%) over weight, and five (12.5%) normal weight. The mean days from positive SARS-CoV-2 polymerase chain reaction (PCR) test to admission was 1.641 (±3.2) days. Of the patients, 18 (45%) had diabetes mellitus, 14 (35%) had hypertension. The mean days from hospital admission to ICU was 1.8 (±2.6), 20 (50%) required mechanical ventilation, 39 (97.5%) had received prone position, seven (17.5%) had renal replacement therapy, 13 (32.5%) required inotropes, four (10%) had plasmapheresis, one (2.5%) had intravenous immunoglobulin, all patients received steroid therapy, and the majority 31 (77.5%) did not receive any anti-viral therapy. Of all the patients, six (15%) died, 28 (70%) were discharged and six (15%) were still in hospital. Conclusion: The overall mortality rate was lower than those cited in meta-analysis. As our understanding of the COVID-19 continues, the approach and therapeutics are also evolving.
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    Glucocorticoid Excess in Bone and Muscle
    (Springer, 2018-03) Sato, Amy Y.; Peacock, Munro; Bellido, Teresita; Anatomy and Cell Biology, School of Medicine
    Glucocorticoids (GC), produced and released by the adrenal glands, regulate numerous physiological processes in a wide range of tissues. Because of their profound immunosuppressive and anti-inflammatory actions, GC are extensively used for the treatment of immune and inflammatory conditions, the management of organ transplantation, and as a component of chemotherapy regimens for cancers. However, both pathologic endogenous elevation and long-term use of exogenous GC are associated with severe adverse effects. In particular, excess GC has devastating effects on the musculoskeletal system. GC increase bone resorption and decrease formation leading to bone loss, microarchitectural deterioration and fracture. GC also induce loss of muscle mass and strength leading to an increased incidence of falls. The combined effects on bone and muscle account for the increased fracture risk with GC. This review summarizes the advance in knowledge in the last two decades about the mechanisms of action of GC in bone and muscle and the attempts to interfere with the damaging actions of GC in these tissues with the goal of developing more effective therapeutic strategies.
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    Glucocorticoid hormone-induced chromatin remodeling enhances human hematopoietic stem cell homing and engraftment
    (Nature Publishing Group, 2017-04) Guo, Bin; Huang, Xinxin; Cooper, Scott; Broxmeyer, Hal E.; Microbiology and Immunology, School of Medicine
    Efficient hematopoietic stem cell (HSC) homing is important for hematopoietic cell transplantation (HCT), especially when HSC numbers are limited, as in the use of cord blood (CB). In a screen of small-molecule compounds, we identified glucocorticoid (GC) hormone signaling as an activator of CXCR4 expression in human CB HSCs and hematopoietic progenitor cells (HPCs). Short-term GC pretreatment of human CB HSCs and HPCs promoted SDF-1-CXCR4-axis-mediated chemotaxis, homing, and long-term engraftment when these cells were transplanted into primary- and secondary-recipient NSG mice. Mechanistically, activated glucocorticoid receptor binds directly to a glucocorticoid response element in the CXCR4 promoter and recruits the SRC-1-p300 complex to promote H4K5 and H4K16 histone acetylation, facilitating transcription of CXCR4. These results suggest a new and readily available means to enhance the clinical efficacy of CB HCT.
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    Glucocorticoid Induced Leucine Zipper in Lipopolysaccharide Induced Neuroinflammation
    (Frontiers, 2019) Witek, Emily; Hickman, Debra; Lahiri, Debomoy K.; Srinivasan, Mythily; Oral Pathology, Medicine and Radiology, School of Dentistry
    Glucocorticoids (GC) are steroid hormones secreted as the end-product of the neuroendocrine stress cascade. Both absence and elevated GC mediate neurotoxic responses, suggesting that a narrow window ranging from physiological to slightly high GC mediate protective responses. The beneficial effects of GC are attributed to the transactivation of regulatory proteins and inhibition mediated by glucocorticoid receptor interactions with other co-factors. The glucocorticoid induced leucine zipper (GILZ) is a gene strongly upregulated by GC and mediates many of the anti-inflammatory and anti-proliferative effects of GC. Although GILZ is constitutively expressed in many tissues including the brain, the expression has been shown to occur with varying dynamics suggesting that the local milieu modulates its expression with consequent effects on cellular responses. Here we investigated the expression profile of GILZ in lipopolysaccharide mediated neuroinflammation model of Alzheimer’s disease. Our data suggest that the GILZ expression is downregulated in neuroinflammation correlating inversely with the pro-inflammatory cytokines and innate immune responses.
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    HSD3B1 genotype identifies glucocorticoid responsiveness in severe asthma
    (National Academy of Sciences, 2020-01-28) Zein, Joe; Gaston, Benjamin; Bazeley, Peter; DeBoer, Mark D.; Igo, Robert P., Jr; Bleecker, Eugene R.; Meyers, Deborah; Comhair, Suzy; Marozkina, Nadzeya V.; Cotton, Calvin; Patel, Mona; Alyamani, Mohammad; Xu, Weiling; Busse, William W.; Calhoun, William J.; Ortega, Victor; Hawkins, Gregory A.; Castro, Mario; Chung, Kian Fan; Fahy, John V.; Fitzpatrick, Anne M.; Israel, Elliot; Jarjour, Nizar N.; Levy, Bruce; Mauger, David T.; Moore, Wendy C.; Noel, Patricia; Peters, Stephen P.; Teague, W. Gerald; Wenzel, Sally E.; Erzurum, Serpil C.; Sharifi, Nima; Medicine, School of Medicine
    Asthma resistance to glucocorticoid treatment is a major health problem with unclear etiology. Glucocorticoids inhibit adrenal androgen production. However, androgens have potential benefits in asthma. HSD3B1 encodes for 3β-hydroxysteroid dehydrogenase-1 (3β-HSD1), which catalyzes peripheral conversion from adrenal dehydroepiandrosterone (DHEA) to potent androgens and has a germline missense-encoding polymorphism. The adrenal restrictive HSD3B1(1245A) allele limits conversion, whereas the adrenal permissive HSD3B1(1245C) allele increases DHEA metabolism to potent androgens. In the Severe Asthma Research Program (SARP) III cohort, we determined the association between DHEA-sulfate and percentage predicted forced expiratory volume in 1 s (FEV1PP). HSD3B1(1245) genotypes were assessed, and association between adrenal restrictive and adrenal permissive alleles and FEV1PP in patients with (GC) and without (noGC) daily oral glucocorticoid treatment was determined (n = 318). Validation was performed in a second cohort (SARP I&II; n = 184). DHEA-sulfate is associated with FEV1PP and is suppressed with GC treatment. GC patients homozygous for the adrenal restrictive genotype have lower FEV1PP compared with noGC patients (54.3% vs. 75.1%; P < 0.001). In patients with the homozygous adrenal permissive genotype, there was no FEV1PP difference in GC vs. noGC patients (73.4% vs. 78.9%; P = 0.39). Results were independently confirmed: FEV1PP for homozygous adrenal restrictive genotype in GC vs. noGC is 49.8 vs. 63.4 (P < 0.001), and for homozygous adrenal permissive genotype, it is 66.7 vs. 67.7 (P = 0.92). The adrenal restrictive HSD3B1(1245) genotype is associated with GC resistance. This effect appears to be driven by GC suppression of 3β-HSD1 substrate. Our results suggest opportunities for prediction of GC resistance and pharmacologic intervention.
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    Prevention of glucocorticoid induced-apoptosis of osteoblasts and osteocytes by protecting against endoplasmic reticulum (ER) stress in vitro and in vivo in female mice
    (Elsevier, 2015-04) Sato, Amy Y.; Tu, Xiaolin; McAndrews, Kevin A.; Plotkin, Lilian I.; Bellido, Teresita; Department of Anatomy & Cell Biology, IU School of Medicine
    Endoplasmic reticulum (ER) stress is associated with increased reactive oxygen species (ROS), results from accumulation of misfolded/unfolded proteins, and can trigger apoptosis. ER stress is alleviated by phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), which inhibits protein translation allowing the ER to recover, thus promoting cell viability. We investigated whether osteoblastic cell apoptosis induced by glucocorticoids (GCs) is due to induction of ROS/ER stress and whether inhibition of eIF2α dephosphorylation promotes survival opposing the deleterious effects of GC in vitro and in vivo. Apoptosis of osteocytic MLO-Y4 and osteoblastic OB-6 cells induced by dexamethasone was abolished by ROS inhibitors. Like GC, the ER stress inducing agents brefeldin A and tunicamycin induced osteoblastic cell apoptosis. Salubrinal or guanabenz, specific inhibitors of eIF2α dephosphorylation, blocked apoptosis induced by either GC or ER stress inducers. Moreover, GC markedly decreased mineralization in OB-6 cells or primary osteoblasts; and salubrinal or guanabenz increased mineralization and prevented the inhibitory effect of GC. Furthermore, salubrinal (1 mg/kg/day) abolished osteoblast and osteocyte apoptosis in cancellous and cortical bone and partially prevented the loss of BMD at all sites and the decreased vertebral cancellous bone formation induced by treatment with prednisolone for 28 days (1.4 mg/kg/day). We conclude that part of the pro-apoptotic actions of GC on osteoblastic cells is mediated through ER stress, and that inhibition of eIF2α dephosphorylation protects from GC-induced apoptosis of osteoblasts and osteocytes in vitro and in vivo and from the deleterious effects of GC on the skeleton.
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    Timing of postnatal steroids for bronchopulmonary dysplasia: association with pulmonary and neurodevelopmental outcomes
    (Nature Publishing Group, 2020-02-04) Harmon, Heidi M.; Jensen, Erik A.; Tan, Sylvia; Chaudhary, Aasma S.; Slaughter, Jonathan L.; Bell, Edward F.; Wyckoff, Myra H.; Hensman, Angelita M.; Sokol, Gregory M.; DeMauro, Sara B.; Pediatrics, School of Medicine
    Objective: To determine the associations between age at first postnatal corticosteroids (PNS) exposure and risk for severe bronchopulmonary dysplasia (BPD) and neurodevelopmental impairment (NDI). Study Design: Cohort study of 951 infants born <27 weeks gestational age at NICHD Neonatal Research Network sites who received PNS between 8 days of life (DOL) and 36 weeks’ postmenstrual age was used to produce adjusted odds ratios (aOR). Results: Compared to infants in the reference group (22–28 DOL-lowest rate), aOR for severe BPD was similar for children given PNS between DOL 8–49 but higher among infants treated at DOL 50–63 (aOR 1.77, 95% CI 1.03–3.06), and at DOL ≥64 (aOR 3.06, 95% CI 1.44–6.48). The aOR for NDI did not vary significantly by age of PNS exposure. Conclusion: For infants at high risk of BPD, initial PNS should be considered prior to 50 DOL for the lowest associated odds of severe BPD.