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Ramírez-Valle F, Maranville JC, Roy S, Plenge RM. Sequential immunotherapy: towards cures for autoimmunity. Nat Rev Drug Discov 2024; 23:501-524. [PMID: 38839912 DOI: 10.1038/s41573-024-00959-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/24/2024] [Indexed: 06/07/2024]
Abstract
Despite major progress in the treatment of autoimmune diseases in the past two decades, most therapies do not cure disease and can be associated with increased risk of infection through broad suppression of the immune system. However, advances in understanding the causes of autoimmune disease and clinical data from novel therapeutic modalities such as chimeric antigen receptor T cell therapies provide evidence that it may be possible to re-establish immune homeostasis and, potentially, prolong remission or even cure autoimmune diseases. Here, we propose a 'sequential immunotherapy' framework for immune system modulation to help achieve this ambitious goal. This framework encompasses three steps: controlling inflammation; resetting the immune system through elimination of pathogenic immune memory cells; and promoting and maintaining immune homeostasis via immune regulatory agents and tissue repair. We discuss existing drugs and those in development for each of the three steps. We also highlight the importance of causal human biology in identifying and prioritizing novel immunotherapeutic strategies as well as informing their application in specific patient subsets, enabling precision medicine approaches that have the potential to transform clinical care.
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O’Neil JD, Bolimowska OO, Clayton SA, Tang T, Daley KK, Lara-Reyna S, Warner J, Martin CS, Mahida RY, Hardy RS, Arthur JSC, Clark AR. Dexamethasone impairs the expression of antimicrobial mediators in lipopolysaccharide-activated primary macrophages by inhibiting both expression and function of interferon β. Front Immunol 2023; 14:1190261. [PMID: 37942320 PMCID: PMC10628473 DOI: 10.3389/fimmu.2023.1190261] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 10/11/2023] [Indexed: 11/10/2023] Open
Abstract
Glucocorticoids potently inhibit expression of many inflammatory mediators, and have been widely used to treat both acute and chronic inflammatory diseases for more than seventy years. However, they can have several unwanted effects, amongst which immunosuppression is one of the most common. Here we used microarrays and proteomic approaches to characterise the effect of dexamethasone (a synthetic glucocorticoid) on the responses of primary mouse macrophages to a potent pro-inflammatory agonist, lipopolysaccharide (LPS). Gene ontology analysis revealed that dexamethasone strongly impaired the lipopolysaccharide-induced antimicrobial response, which is thought to be driven by an autocrine feedback loop involving the type I interferon IFNβ. Indeed, dexamethasone strongly and dose-dependently inhibited the expression of IFNβ by LPS-activated macrophages. Unbiased proteomic data also revealed an inhibitory effect of dexamethasone on the IFNβ-dependent program of gene expression, with strong down-regulation of several interferon-induced antimicrobial factors. Surprisingly, dexamethasone also inhibited the expression of several antimicrobial genes in response to direct stimulation of macrophages with IFNβ. We tested a number of hypotheses based on previous publications, but found that no single mechanism could account for more than a small fraction of the broad suppressive impact of dexamethasone on macrophage type I interferon signaling, underlining the complexity of this pathway. Preliminary experiments indicated that dexamethasone exerted similar inhibitory effects on primary human monocyte-derived or alveolar macrophages.
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Affiliation(s)
- John D. O’Neil
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | - Oliwia O. Bolimowska
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | - Sally A. Clayton
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | - Tina Tang
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | - Kalbinder K. Daley
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | - Samuel Lara-Reyna
- Institute of Microbiology and Infection, University of Birmingham, Birmingham, United Kingdom
| | - Jordan Warner
- School of Life Sciences, University of Dundee, Dundee, United Kingdom
| | - Claire S. Martin
- School of Biomedical Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Rahul Y. Mahida
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | - Rowan S. Hardy
- School of Biomedical Sciences, University of Birmingham, Birmingham, United Kingdom
| | | | - Andrew R. Clark
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
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Abstract
Bile acids wear many hats, including those of an emulsifier to facilitate nutrient absorption, a cholesterol metabolite, and a signaling molecule in various tissues modulating itching to metabolism and cellular functions. Bile acids are synthesized in the liver but exhibit wide-ranging effects indicating their ability to mediate organ-organ crosstalk. So, how does a steroid metabolite orchestrate such diverse functions? Despite the inherent chemical similarity, the side chain decorations alter the chemistry and biology of the different bile acid species and their preferences to bind downstream receptors distinctly. Identification of new modifications in bile acids is burgeoning, and some of it is associated with the microbiota within the intestine. Here, we provide a brief overview of the history and the various receptors that mediate bile acid signaling in addition to its crosstalk with the gut microbiota.
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Affiliation(s)
| | | | - Sayeepriyadarshini Anakk
- Correspondence: Sayeepriyadarshini Anakk, PhD, Department of Molecular & Integrative Physiology, University of Illinois at Urbana-Champaign, 506 S Mathews Ave, 453 Medical Sciences Bldg, Urbana, IL 61801, USA.
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Pang JP, Hu XP, Wang YX, Liao JN, Chai X, Wang XW, Shen C, Wang JJ, Zhang LL, Wang XY, Zhu F, Weng QJ, Xu L, Hou TJ, Li D. Discovery of a novel nonsteroidal selective glucocorticoid receptor modulator by virtual screening and bioassays. Acta Pharmacol Sin 2022; 43:2429-2438. [PMID: 35110698 PMCID: PMC8809242 DOI: 10.1038/s41401-021-00855-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 12/27/2021] [Indexed: 12/31/2022]
Abstract
Synthetic glucocorticoids (GCs) have been widely used in the treatment of a broad range of inflammatory diseases, but their clinic use is limited by undesired side effects such as metabolic disorders, osteoporosis, skin and muscle atrophies, mood disorders and hypothalamic-pituitary-adrenal (HPA) axis suppression. Selective glucocorticoid receptor modulators (SGRMs) are expected to have promising anti-inflammatory efficacy but with fewer side effects caused by GCs. Here, we reported HT-15, a prospective SGRM discovered by structure-based virtual screening (VS) and bioassays. HT-15 can selectively act on the NF-κB/AP1-mediated transrepression function of glucocorticoid receptor (GR) and repress the expression of pro-inflammation cytokines (i.e., IL-1β, IL-6, COX-2, and CCL-2) as effectively as dexamethasone (Dex). Compared with Dex, HT-15 shows less transactivation potency that is associated with the main adverse effects of synthetic GCs, and no cross activities with other nuclear receptors. Furthermore, HT-15 exhibits very weak inhibition on the ratio of OPG/RANKL. Therefore, it may reduce the side effects induced by normal GCs. The bioactive compound HT-15 can serve as a starting point for the development of novel therapeutics for high dose or long-term anti-inflammatory treatment.
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Affiliation(s)
- Jin-Ping Pang
- Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Xue-Ping Hu
- Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Yun-Xia Wang
- Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Jia-Ning Liao
- Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Xin Chai
- Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Xu-Wen Wang
- Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Chao Shen
- Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Jia-Jia Wang
- State Key Lab of CAD&CG, Zhejiang University, Hangzhou, 310058, China
| | - Lu-Lu Zhang
- State Key Lab of CAD&CG, Zhejiang University, Hangzhou, 310058, China
| | - Xin-Yue Wang
- Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Feng Zhu
- Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Qin-Jie Weng
- State Key Lab of CAD&CG, Zhejiang University, Hangzhou, 310058, China
| | - Lei Xu
- Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou, 213001, China
| | - Ting-Jun Hou
- Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
- Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Dan Li
- Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
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The anti-inflammatory effect of myrrh ethanolic extract in comparison with prednisolone on an autoimmune disease rat model induced by silicate. Inflammopharmacology 2022; 30:2537-2546. [PMID: 35930173 DOI: 10.1007/s10787-022-01042-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Accepted: 07/16/2022] [Indexed: 11/05/2022]
Abstract
Autoimmune disease is a complex chronic disease that triggers immune activation against autoantigens resulting in tissue damage. Epidemiological data showed that autoimmune diseases are increasing worldwide over the last decades owing to increased environmental pollution. This study investigates the therapeutic effect of myrrh as a natural medicine compared to prednisolone in the treatment of immune-mediated glomerulonephritis induced by silicate. The autoimmune disease model in rats was induced by injecting 5 mg crystalline sodium silicate suspension subcutaneously once weekly for 20 weeks, and then the rats were treated either with myrrh extract or prednisolone or with both for 6 weeks. Liver and kidney function tests, histopathology, and immunohistochemistry of TNF-α expression in kidney tissue were performed. The creatinine significantly elevated in silica-treated group and decreased in other treated groups. Histopathology of the kidney revealed improvement of glomerular and tubular basement thickness in all treated groups, but the inflammatory cell count slightly decreased in the group treated with myrrh than the other treated groups which showed a marked decrease. TNF-α expression was significantly decreased in all treated groups. Interestingly, the myrrh did not produce hepatic lesions and improve the side effect of prednisolone in the liver when taken in combination. Therefore, myrrh extract possessed anti-inflammatory properties and counteracted the side effect of prednisolone on the liver. Myrrh extract can serve as a conjunctive therapy with prednisolone to treat autoimmune diseases.
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Pelechas E, Drosos AA. State-of-the-art glucocorticoid-targeted drug therapies for the treatment of rheumatoid arthritis. Expert Opin Pharmacother 2022; 23:703-711. [PMID: 35313795 DOI: 10.1080/14656566.2022.2049238] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Glucocorticoids are steroid hormones broadly used for the treatment of several inflammatory and autoimmune diseases among other numerous indications, including rheumatoid arthritis. AREAS COVERED For the purposes of this article, the authors have performed an extensive review of the literature to present the latest studies on glucocorticoid use in rheumatoid arthritis. They also provide the reader with their expert perspectives on future developments. EXPERT OPINION The authors do not anticipate that glucocorticoids with be replaced in the near future by newer drugs. As such, rheumatologists should be fully aware of the possible side-effects and educate appropriately their patients to recognize and report them. Newer formulations, such as the liposomal/nanoparticle-based treatments, will result in less pronounced adverse effects, but the input of clinical experience along with the current recommendations for the glucocorticoid use will benefit both clinicians and patients with rheumatoid arthritis.
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Affiliation(s)
- Eleftherios Pelechas
- Rheumatology Clinic, Department of Internal Medicine, Medical School, University of Ioannina, Ioannina, Greece
| | - Alexandros A Drosos
- Rheumatology Clinic, Department of Internal Medicine, Medical School, University of Ioannina, Ioannina, Greece
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Kyle CJ, Nixon M, Homer NZM, Morgan RA, Andrew R, Stimson RH, Walker BR. ABCC1 modulates negative feedback control of the hypothalamic-pituitary-adrenal axis in vivo in humans. Metabolism 2022; 128:155118. [PMID: 34990712 PMCID: PMC8861854 DOI: 10.1016/j.metabol.2021.155118] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 12/24/2021] [Accepted: 12/27/2021] [Indexed: 11/23/2022]
Abstract
BACKGROUND Cortisol and corticosterone both circulate in human plasma and, due to differing export by ATP-binding cassette (ABC) transporters, may exert differential cellular effects. ABCB1 (expressed in brain) exports cortisol not corticosterone while ABCC1 (expressed in adipose and skeletal muscle) exports corticosterone not cortisol. We hypothesised that ABCC1 inhibition increases corticosteroid receptor occupancy by corticosterone but not cortisol in humans. METHODS A randomised double-blind crossover study was conducted in 14 healthy men comparing placebo and ABCC1 inhibitor probenecid. Blood sampling, including from veins draining adipose and muscle, was undertaken before and after administration of mineralocorticoid receptor antagonist potassium canrenoate and glucocorticoid receptor antagonist mifepristone (RU486). RESULTS During placebo, systemic plasma cortisol and corticosterone concentrations increased promptly after canrenoate. Cortisol uptake was detected from adipose but not muscle following canrenoate + RU486. Probenecid significantly increased systemic cortisol concentrations, and tended to increase corticosterone and ACTH concentrations, after combined receptor antagonism but had no effects on net glucocorticoid balance in either adipose or muscle. Using quantitative PCR in brain bank tissue, ABCC1 expression was 5-fold higher in human pituitary than hypothalamus and hippocampus. ABCB1 was more highly expressed in hypothalamus compared to pituitary. CONCLUSIONS Although displacement of corticosterone and/or cortisol from receptors in adipose and skeletal muscle could not be measured with sufficient precision to detect effects of probenecid, ABCC1 inhibition induced a greater incremental activation of the hypothalamic-pituitary-adrenal axis after combined receptor blockade, consistent with ABCC1 exporting corticosterone from the pituitary and adding to the evidence that ABC transporters modulate tissue glucocorticoid sensitivity.
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Affiliation(s)
- Catriona J Kyle
- BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, UK
| | - Mark Nixon
- BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, UK
| | - Natalie Z M Homer
- BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, UK; Mass Spectrometry Core, Edinburgh Clinical Research Facility, Queen's Medical Research Institute, University of Edinburgh, UK
| | - Ruth A Morgan
- BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, UK
| | - Ruth Andrew
- BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, UK
| | - Roland H Stimson
- BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, UK
| | - Brian R Walker
- BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, UK; Translational & Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
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8
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Alemany M. Estrogens and the regulation of glucose metabolism. World J Diabetes 2021; 12:1622-1654. [PMID: 34754368 PMCID: PMC8554369 DOI: 10.4239/wjd.v12.i10.1622] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 03/10/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
The main estrogens: estradiol, estrone, and their acyl-esters have been studied essentially related to their classical estrogenic and pharmacologic functions. However, their main effect in the body is probably the sustained control of core energy metabolism. Estrogen nuclear and membrane receptors show an extraordinary flexibility in the modulation of metabolic responses, and largely explain gender and age differences in energy metabolism: part of these mechanisms is already sufficiently known to justify both. With regard to energy, the estrogen molecular species act essentially through four key functions: (1) Facilitation of insulin secretion and control of glucose availability; (2) Modulation of energy partition, favoring the use of lipid as the main energy substrate when more available than carbohydrates; (3) Functional protection through antioxidant mechanisms; and (4) Central effects (largely through neural modulation) on whole body energy management. Analyzing the different actions of estrone, estradiol and their acyl esters, a tentative classification based on structure/effects has been postulated. Either separately or as a group, estrogens provide a comprehensive explanation that not all their quite diverse actions are related solely to specific molecules. As a group, they constitute a powerful synergic action complex. In consequence, estrogens may be considered wardens of energy homeostasis.
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Affiliation(s)
- Marià Alemany
- Faculty of Biology, University of Barcelona, Barcelona 08028, Catalonia, Spain
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Robin F, Lescoat A, Jego P, Guggenbuhl P. [Is it (really) necessary to treat all postmenopausal women receiving corticosteroid therapy with bone preventive therapy?]. Rev Med Interne 2021; 42:597-599. [PMID: 34353612 DOI: 10.1016/j.revmed.2021.07.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 07/17/2021] [Accepted: 07/18/2021] [Indexed: 10/20/2022]
Affiliation(s)
- F Robin
- Department of Rheumatology, CHU Rennes, France; Inserm, Univ Rennes, INRA, CHU Rennes, Institut NUMECAN (Nutrition Metabolisms and Cancer), 35033 Rennes, France.
| | - A Lescoat
- Department of Internal Medicine and Clinical Immunology, CHU Rennes, University of Rennes 1, Rennes, France; University of Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, 35000 Rennes, France
| | - P Jego
- Department of Internal Medicine and Clinical Immunology, CHU Rennes, University of Rennes 1, Rennes, France; University of Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, 35000 Rennes, France
| | - P Guggenbuhl
- Department of Rheumatology, CHU Rennes, France; Inserm, Univ Rennes, INRA, CHU Rennes, Institut NUMECAN (Nutrition Metabolisms and Cancer), 35033 Rennes, France
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Gong W, Song J, Liang J, Ma H, Wu W, Zhang Y, Yang L, Huang S, Jia Z, Zhang A. Reduced Lon protease 1 expression in podocytes contributes to the pathogenesis of podocytopathy. Kidney Int 2020; 99:854-869. [PMID: 33181155 DOI: 10.1016/j.kint.2020.10.025] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 09/26/2020] [Accepted: 10/09/2020] [Indexed: 12/16/2022]
Abstract
Emerging evidence has shown that mitochondrial dysfunction is closely related to the pathogenesis of podocytopathy, but the molecular mechanisms mediating mitochondrial dysfunction in podocytes remain unclear. Lon protease 1 is an important soluble protease localized in the mitochondrial matrix, although its exact role in podocyte injury has yet to be determined. Here we investigated the specific role of this protease in podocyte in glomerular injury and the progression of podocytopathy using podocyte-specific Lon protease 1 knockout mice, murine podocytes in culture and kidney biopsy samples from patients with focal segmental glomerular sclerosis and minimal change disease. Downregulated expression of Lon protease 1 was observed in glomeruli of kidney biopsy samples demonstrating a negative correlation with urinary protein levels and glomerular pathology of patients with focal segmental glomerular sclerosis and minimal change disease. Podocyte-specific deletion of Lon protease 1 caused severe proteinuria, impaired kidney function, severe kidney injury and even mortality in mice. Mechanistically, we found that continuous podocyte Lon protease 1 ablation induced mitochondrial homeostasis imbalance and dysfunction, which then led to podocyte injury and glomerular sclerosis. In vitro experiments implicated the kidney protective effect of Lon protease 1, which inhibited mitochondrial dysfunction and podocyte apoptosis. Thus, our findings suggest that the regulation of Lon protease 1 in podocytes may provide a novel therapeutic approach for the podocytopathy.
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Affiliation(s)
- Wei Gong
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; Department of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Jiayu Song
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; Department of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Jing Liang
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; Department of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Haoyang Ma
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; Department of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Wenxiao Wu
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; Department of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Yue Zhang
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; Department of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Li Yang
- Renal Division, Peking University First Hospital, Beijing, China
| | - Songming Huang
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; Department of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Zhanjun Jia
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; Department of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical University, Nanjing, China.
| | - Aihua Zhang
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; Department of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical University, Nanjing, China.
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11
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Wang S, Panush RS. Certain perspectives about the use of corticosteroids for managing hospitalized patients with rheumatic diseases. Clin Rheumatol 2020; 39:3131-3136. [DOI: 10.1007/s10067-020-05349-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 08/04/2020] [Accepted: 08/12/2020] [Indexed: 11/24/2022]
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12
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Petta I, Peene I, Elewaut D, Vereecke L, De Bosscher K. Risks and benefits of corticosteroids in arthritic diseases in the clinic. Biochem Pharmacol 2019; 165:112-125. [PMID: 30978323 DOI: 10.1016/j.bcp.2019.04.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 04/08/2019] [Indexed: 02/06/2023]
Abstract
Glucocorticoids (GCs) constitute a first line treatment for many autoimmune and inflammatory diseases. Due to their potent anti-inflammatory and immunosuppressive actions, GCs are added frequently to disease modifying antirheumatic drugs (DMARDs) in various arthritic diseases, such as rheumatoid arthritis. However, their prolonged administration or administration at high doses is associated with adverse effects that may be (quality of) life-threatening, including osteoporosis, metabolic, gastrointestinal and cardiovascular side effects. In this review, we summarize the clinical and pharmacological effects of GCs in different arthritic diseases, while documenting the current research efforts towards the identification of novel and more efficient GCs with reduced side effects.
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Affiliation(s)
- Ioanna Petta
- Department of Rheumatology, Faculty of Medicine and Health Sciences, Host-Microbiota Interaction Lab (HMI) and Laboratory for Molecular Immunology and Inflammation, Ghent University, Corneel Heymanslaan 10, 9000 Ghent, Belgium; VIB Center for Inflammation Research (IRC), Ghent University, Technologiepark 71 - Zwijnaarde, 9052 Ghent, Belgium; Ghent Gut Inflammation Group (GGIG), Ghent University, Ghent, Belgium
| | - Isabelle Peene
- Department of Rheumatology, Faculty of Medicine and Health Sciences, Host-Microbiota Interaction Lab (HMI) and Laboratory for Molecular Immunology and Inflammation, Ghent University, Corneel Heymanslaan 10, 9000 Ghent, Belgium; VIB Center for Inflammation Research (IRC), Ghent University, Technologiepark 71 - Zwijnaarde, 9052 Ghent, Belgium; Department of Rheumatology, AZ SintJan, Ruddershove 10, 8000 Brugge, Belgium
| | - Dirk Elewaut
- Department of Rheumatology, Faculty of Medicine and Health Sciences, Host-Microbiota Interaction Lab (HMI) and Laboratory for Molecular Immunology and Inflammation, Ghent University, Corneel Heymanslaan 10, 9000 Ghent, Belgium; VIB Center for Inflammation Research (IRC), Ghent University, Technologiepark 71 - Zwijnaarde, 9052 Ghent, Belgium; Ghent Gut Inflammation Group (GGIG), Ghent University, Ghent, Belgium
| | - Lars Vereecke
- Department of Rheumatology, Faculty of Medicine and Health Sciences, Host-Microbiota Interaction Lab (HMI) and Laboratory for Molecular Immunology and Inflammation, Ghent University, Corneel Heymanslaan 10, 9000 Ghent, Belgium; VIB Center for Inflammation Research (IRC), Ghent University, Technologiepark 71 - Zwijnaarde, 9052 Ghent, Belgium; Ghent Gut Inflammation Group (GGIG), Ghent University, Ghent, Belgium
| | - Karolien De Bosscher
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium; Translational Nuclear Receptor Research, VIB Center for Medical Biotechnology, Albert Baertsoenkaai 3, 9000, Ghent, Belgium.
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13
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Pott A, Just S. Metabolic Profiling of Glucocorticoid Deficiency: A "Fishing" Expedition. EBioMedicine 2018; 37:27-28. [PMID: 30389507 PMCID: PMC6286254 DOI: 10.1016/j.ebiom.2018.10.058] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Accepted: 10/23/2018] [Indexed: 11/28/2022] Open
Affiliation(s)
- Alexander Pott
- Molecular Cardiology, Department of Internal Medicine II, University of Ulm, Ulm, Germany; Department of Internal Medicine II, University of Ulm, Ulm, Germany
| | - Steffen Just
- Molecular Cardiology, Department of Internal Medicine II, University of Ulm, Ulm, Germany.
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14
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Cataldi MP, Lu P, Blaeser A, Lu QL. Ribitol restores functionally glycosylated α-dystroglycan and improves muscle function in dystrophic FKRP-mutant mice. Nat Commun 2018; 9:3448. [PMID: 30150693 PMCID: PMC6110760 DOI: 10.1038/s41467-018-05990-z] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Accepted: 08/09/2018] [Indexed: 02/07/2023] Open
Abstract
O-mannosylated α-dystroglycan (α-DG) serves as receptors for cell-cell and cell-extracellular matrix adhesion and signaling. Hypoglycosylation of α-DG is involved in cancer progression and underlies dystroglycanopathy with aberrant neuronal development. Here we report that ribitol, a pentose alcohol with previously unknown function in mammalian cells, partially restores functional O-mannosylation of α-DG (F-α-DG) in the dystroglycanopathy model containing a P448L mutation in fukutin-related protein (FKRP) gene, which is clinically associated with severe congenital muscular dystrophy. Oral administration of ribitol increases levels of ribitol-5-phosphate and CDP-ribitol and restores therapeutic levels of F-α-DG in skeletal and cardiac muscles. Furthermore, ribitol, given before and after the onset of disease phenotype, reduces skeletal muscle pathology, significantly decreases cardiac fibrosis and improves skeletal and respiratory functions in the FKRP mutant mice. Ribitol treatment presents a new class, low risk, and easy to administer experimental therapy to restore F-α-DG in FKRP-related muscular dystrophy.
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Affiliation(s)
- Marcela P Cataldi
- McColl-Lockwood Laboratory for Muscular Dystrophy Research, Cannon Research Center, Carolinas Medical Center, Carolinas Healthcare System, Charlotte, NC, 28203, USA
| | - Peijuan Lu
- McColl-Lockwood Laboratory for Muscular Dystrophy Research, Cannon Research Center, Carolinas Medical Center, Carolinas Healthcare System, Charlotte, NC, 28203, USA
| | - Anthony Blaeser
- McColl-Lockwood Laboratory for Muscular Dystrophy Research, Cannon Research Center, Carolinas Medical Center, Carolinas Healthcare System, Charlotte, NC, 28203, USA
| | - Qi Long Lu
- McColl-Lockwood Laboratory for Muscular Dystrophy Research, Cannon Research Center, Carolinas Medical Center, Carolinas Healthcare System, Charlotte, NC, 28203, USA.
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15
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Vassiliadi DA, Tsagarakis S. Multiple benefits from dual release hydrocortisone: a "hard" view from bones. Endocrine 2018; 61:177-179. [PMID: 29774503 DOI: 10.1007/s12020-018-1628-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Accepted: 05/05/2018] [Indexed: 10/16/2022]
Affiliation(s)
- D A Vassiliadi
- Department of Endocrinology, Diabetes and Metabolism, Evangelismos Hospital, Athens, Greece
| | - S Tsagarakis
- Department of Endocrinology, Diabetes and Metabolism, Evangelismos Hospital, Athens, Greece.
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16
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Godoy LD, Rossignoli MT, Delfino-Pereira P, Garcia-Cairasco N, de Lima Umeoka EH. A Comprehensive Overview on Stress Neurobiology: Basic Concepts and Clinical Implications. Front Behav Neurosci 2018; 12:127. [PMID: 30034327 PMCID: PMC6043787 DOI: 10.3389/fnbeh.2018.00127] [Citation(s) in RCA: 418] [Impact Index Per Article: 59.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Accepted: 06/06/2018] [Indexed: 12/20/2022] Open
Abstract
Stress is recognized as an important issue in basic and clinical neuroscience research, based upon the founding historical studies by Walter Canon and Hans Selye in the past century, when the concept of stress emerged in a biological and adaptive perspective. A lot of research after that period has expanded the knowledge in the stress field. Since then, it was discovered that the response to stressful stimuli is elaborated and triggered by the, now known, stress system, which integrates a wide diversity of brain structures that, collectively, are able to detect events and interpret them as real or potential threats. However, different types of stressors engage different brain networks, requiring a fine-tuned functional neuroanatomical processing. This integration of information from the stressor itself may result in a rapid activation of the Sympathetic-Adreno-Medullar (SAM) axis and the Hypothalamus-Pituitary-Adrenal (HPA) axis, the two major components involved in the stress response. The complexity of the stress response is not restricted to neuroanatomy or to SAM and HPA axes mediators, but also diverge according to timing and duration of stressor exposure, as well as its short- and/or long-term consequences. The identification of neuronal circuits of stress, as well as their interaction with mediator molecules over time is critical, not only for understanding the physiological stress responses, but also to understand their implications on mental health.
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Affiliation(s)
- Lívea Dornela Godoy
- Physiology Department, Ribeirão Preto School of Medicine, University of São Paulo, São Paulo, Brazil
| | - Matheus Teixeira Rossignoli
- Department of Neuroscience and Behavioral Sciences, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
| | - Polianna Delfino-Pereira
- Department of Neuroscience and Behavioral Sciences, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
| | - Norberto Garcia-Cairasco
- Physiology Department, Ribeirão Preto School of Medicine, University of São Paulo, São Paulo, Brazil
- Department of Neuroscience and Behavioral Sciences, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
| | - Eduardo Henrique de Lima Umeoka
- Department of Neuroscience and Behavioral Sciences, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
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17
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Palmowski Y, Buttgereit T, Buttgereit F. The 70th anniversary of glucocorticoids in rheumatic diseases: the second youth of an old friend. Rheumatology (Oxford) 2018; 58:580-587. [DOI: 10.1093/rheumatology/key169] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Revised: 05/09/2018] [Indexed: 12/20/2022] Open
Abstract
Abstract
Seventy years ago, the first administration of cortisone in a patient with RA marked a milestone in the treatment of inflammatory diseases. However, the initial enthusiasm rapidly vanished as the administration of high doses for lengthy periods revealed worrisome adverse effects. It has taken several decades to overcome the (sometimes excessive) mistrust and to achieve a more differentiated evaluation of the benefit–risk profile and the adequate usage of glucocorticoids (GCs). Today, GCs remain indispensable for the treatment of many inflammatory conditions and their usefulness in RA as a disease-modifying low-dose co-medication is widely acknowledged. Recent studies show promising results concerning both traditional GCs and new formulations. Still, decades of relatively little scientific attention have resulted in a continuing lack of detailed evidence. Hence there is an ongoing need for further research regarding mechanisms of GC actions, the further optimization of treatment parameters for traditional GCs and new formulations.
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Affiliation(s)
- Yannick Palmowski
- Center for Musculoskeletal Surgery, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Thomas Buttgereit
- Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany
- Department of Dermatology, Venereology and Allergology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Frank Buttgereit
- Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany
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18
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Allijn IE, Oldenkamp R, Storm G, Ragas AMJ, Schiffelers RM. Environmental impact of switching from the synthetic glucocorticoid prednisolone to the natural alkaloid berberine. PLoS One 2018; 13:e0199095. [PMID: 29902284 PMCID: PMC6002123 DOI: 10.1371/journal.pone.0199095] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Accepted: 05/31/2018] [Indexed: 11/18/2022] Open
Abstract
Low amounts of human pharmaceuticals in the aquatic environment can affect bacteria, animals and ultimately humans. Here, the environmental consequences of a shift in prescription behavior from prednisolone to berberine was modeled using an environmental decision support system based on four consecutive steps: emission, fate, exposure and effect. This model estimates the relative aquatic and human health impacts of alternative pharmaceutical prescriptions throughout Europe. Since a Defined Daily Dose (DDD) of berberine has yet to be formulated, the environmental impacts of berberine and prednisolone were compared under the assumption of equal DDDs. Subsequently, the relative impact ratio indicates the extent to which the actual DDD of berberine might be higher to still be environmentally preferable over prednisolone. In fact, berberine can be administered at a six times higher dose throughout Europe before its impact on the aquatic environment exceeds that of one prescription of prednisolone. On average, the results for impacts on human health are similar, with the median impact ratio ranging between 5.87 and 22.8 depending on the level of drinking water purification. However, for some regions in Spain, Austria, Baltic States and Finland, berberine can only be considered an environmentally better alternative if it is administered at a lower dose than prednisolone. We conclude that for most regions in Europe it is, up until a certain dose of berberine, beneficial for the aquatic environment and therefore human health to prefer prescription of berberine over prednisolone.
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Affiliation(s)
- Iris E. Allijn
- Department of Biomaterials Science and Technology, TechMed Centre, University of Twente, Enschede, The Netherlands
- * E-mail:
| | - Rik Oldenkamp
- Department of Environmental Science, Institute for Water and Wetland Research, Radboud University, Nijmegen, The Netherlands
- Environment Department, University of York, York, United Kingdom
| | - Gert Storm
- Department of Biomaterials Science and Technology, TechMed Centre, University of Twente, Enschede, The Netherlands
- Department of Pharmaceutics, Utrecht University, Utrecht, The Netherlands
| | - Ad M. J. Ragas
- Department of Environmental Science, Institute for Water and Wetland Research, Radboud University, Nijmegen, The Netherlands
- Department of Science, Open Universiteit, Heerlen, The Netherlands
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19
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Ripa L, Edman K, Dearman M, Edenro G, Hendrickx R, Ullah V, Chang HF, Lepistö M, Chapman D, Geschwindner S, Wissler L, Svanberg P, Lawitz K, Malmberg J, Nikitidis A, Olsson RI, Bird J, Llinas A, Hegelund-Myrbäck T, Berger M, Thorne P, Harrison R, Köhler C, Drmota T. Discovery of a Novel Oral Glucocorticoid Receptor Modulator (AZD9567) with Improved Side Effect Profile. J Med Chem 2018; 61:1785-1799. [PMID: 29424542 DOI: 10.1021/acs.jmedchem.7b01690] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Synthetic glucocorticoids (GC) are essential for the treatment of a broad range of inflammatory diseases. However, their use is limited by target related adverse effects on, e.g., glucose homeostasis and bone metabolism. Starting from a nonsteroidal GR ligand (4) that is a full agonist in reporter gene assays, we exploited key functional triggers within the receptor, generating a range of structurally diverse partial agonists. Of these, only a narrow subset exhibited full anti-inflammatory efficacy and a significantly reduced impact on adverse effect markers in human cell assays compared to prednisolone. This led to the discovery of AZD9567 (15) with excellent in vivo efficacy when dosed orally in a rat model of joint inflammation. Compound 15 is currently being evaluated in clinical trials comparing the efficacy and side effect markers with those of prednisolone.
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Affiliation(s)
- Lena Ripa
- Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 43183 , Sweden
| | - Karl Edman
- Discovery Sciences, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 431 83 , Sweden
| | - Matthew Dearman
- Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 43183 , Sweden
| | - Goran Edenro
- Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 43183 , Sweden
| | - Ramon Hendrickx
- Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 43183 , Sweden
| | - Victoria Ullah
- Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 43183 , Sweden
| | - Hui-Fang Chang
- Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 43183 , Sweden
| | - Matti Lepistö
- Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 43183 , Sweden
| | - Dave Chapman
- Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 43183 , Sweden
| | - Stefan Geschwindner
- Discovery Sciences, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 431 83 , Sweden
| | - Lisa Wissler
- Discovery Sciences, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 431 83 , Sweden
| | - Petter Svanberg
- Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 43183 , Sweden
| | | | - Jesper Malmberg
- Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 43183 , Sweden
| | - Antonios Nikitidis
- Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 43183 , Sweden
| | - Roine I Olsson
- Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 43183 , Sweden
| | - James Bird
- Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 43183 , Sweden
| | - Antoni Llinas
- Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 43183 , Sweden
| | - Tove Hegelund-Myrbäck
- Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 43183 , Sweden
| | - Markus Berger
- Medicinal Chemistry Berlin, Drug Discovery, Pharmaceuticals , Bayer AG , Berlin 13353 , Germany
| | - Philip Thorne
- AstraZeneca R&D Charnwood , Bakewell Road , Loughborough , Leicestershire LE11 5RH , U.K
| | - Richard Harrison
- AstraZeneca R&D Charnwood , Bakewell Road , Loughborough , Leicestershire LE11 5RH , U.K
| | - Christian Köhler
- Discovery Sciences, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 431 83 , Sweden
| | - Tomas Drmota
- Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit , AstraZeneca Gothenburg , Pepparedsleden 1 , Mölndal 43183 , Sweden
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20
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Patil RH, Naveen Kumar M, Kiran Kumar KM, Nagesh R, Kavya K, Babu RL, Ramesh GT, Chidananda Sharma S. Dexamethasone inhibits inflammatory response via down regulation of AP-1 transcription factor in human lung epithelial cells. Gene 2017; 645:85-94. [PMID: 29248584 DOI: 10.1016/j.gene.2017.12.024] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Revised: 12/12/2017] [Accepted: 12/13/2017] [Indexed: 01/22/2023]
Abstract
The production of inflammatory mediators by epithelial cells in inflammatory lung diseases may represent an important target for the anti-inflammatory effects of glucocorticoids. Activator protein-1 is a major activator of inflammatory genes and has been proposed as a target for inhibition by glucocorticoids. We have used human pulmonary type-II A549 cells to examine the effect of dexamethasone on the phorbol ester (PMA)/Lipopolysaccharide (LPS) induced pro-inflammatory cytokines and AP-1 factors. A549 cells were treated with and without PMA or LPS or dexamethasone and the cell viability and nitric oxide production was measured by MTT assay and Griess reagent respectively. Expression of pro-inflammatory cytokines and AP-1 factors mRNA were measured using semi quantitative RT-PCR. The PMA/LPS treated cells show significant 2-3 fold increase in the mRNA levels of pro-inflammatory cytokines (IL-1β, IL-2, IL-6, IL-8 and TNF-α), cyclo‑oxygenase-2 (COX-2) and specific AP-1 factors (c-Jun, c-Fos and Jun-D). Whereas, pretreatment of cells with dexamethasone significantly inhibited the LPS induced nitric oxide production and PMA/LPS induced mRNAs expression of above pro-inflammatory cytokines, COX-2 and AP-1 factors. Cells treated with dexamethasone alone at both the concentrations inhibit the mRNAs expression of IL-1β, IL-6 and TNF-α compared to control. Our study reveals that dexamethasone decreased the mRNAs expression of c-Jun and c-Fos available for AP-1 formation suggested that AP-1 is the probable key transcription factor involved in the anti-inflammatory activity of dexamethasone. This may be an important molecular mechanism of steroid action in asthma and other chronic inflammatory lung diseases which may be useful for treatment of lung inflammatory diseases.
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Affiliation(s)
- Rajeshwari H Patil
- Department of Microbiology and Biotechnology, Bangalore University, Jnana Bharathi, Bengaluru 560 056, Karnataka, India; Department of Biotechnology, The Oxford College of Science, HSR Layout, Bengaluru 560102, Karnataka, India.
| | - M Naveen Kumar
- Department of Microbiology and Biotechnology, Bangalore University, Jnana Bharathi, Bengaluru 560 056, Karnataka, India
| | - K M Kiran Kumar
- Department of Microbiology and Biotechnology, Bangalore University, Jnana Bharathi, Bengaluru 560 056, Karnataka, India
| | - Rashmi Nagesh
- Department of Microbiology and Biotechnology, Bangalore University, Jnana Bharathi, Bengaluru 560 056, Karnataka, India
| | - K Kavya
- Department of Microbiology and Biotechnology, Bangalore University, Jnana Bharathi, Bengaluru 560 056, Karnataka, India
| | - R L Babu
- Department of Bioinformatics and Biotechnology, Karnataka State Women's University, Jnana Shakthi Campus, Vijayapura 586 108, Karnataka, India; Department of Biology and Center for Biotechnology and Biomedical Sciences, Norfolk State University, Norfolk, VA, USA
| | - Govindarajan T Ramesh
- Department of Biology and Center for Biotechnology and Biomedical Sciences, Norfolk State University, Norfolk, VA, USA
| | - S Chidananda Sharma
- Department of Microbiology and Biotechnology, Bangalore University, Jnana Bharathi, Bengaluru 560 056, Karnataka, India
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21
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Mazziotti G, Formenti AM, Frara S, Roca E, Mortini P, Berruti A, Giustina A. MANAGEMENT OF ENDOCRINE DISEASE: Risk of overtreatment in patients with adrenal insufficiency: current and emerging aspects. Eur J Endocrinol 2017; 177:R231-R248. [PMID: 28583942 DOI: 10.1530/eje-17-0154] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Revised: 05/31/2017] [Accepted: 06/05/2017] [Indexed: 01/17/2023]
Abstract
The effects of long-term replacement therapy of adrenal insufficiency (AI) are still a matter of controversy. In fact, the established glucocorticoid replacement regimens do not completely reproduce the endogenous hormonal production and the monitoring of AI treatment may be a challenge for the lack of reliable clinical and biochemical markers. Consequently, several AI patients are frequently exposed to relative glucocorticoid excess potentially leading to develop chronic complications, such as diabetes mellitus, dyslipidemia, hypertension and fragility fractures with consequent impaired QoL and increased mortality risk. This review deals with the pathophysiological and clinical aspects concerning the over-replacement therapy of primary and secondary AI.
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Affiliation(s)
- G Mazziotti
- Endocrinology Unit, ASST, Carlo Poma, Mantua, Italy
| | - A M Formenti
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - S Frara
- Chair of Endocrinology, San Raffaele Vita-Salute University, Milan, Italy
| | - E Roca
- Chair of Medical Oncology, University of Brescia, Brescia, Italy
| | - P Mortini
- Chair of Neurosurgery, San Raffaele Vita-Salute University, Milan, Italy
| | - A Berruti
- Chair of Medical Oncology, University of Brescia, Brescia, Italy
| | - A Giustina
- Chair of Endocrinology, San Raffaele Vita-Salute University, Milan, Italy
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22
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Ng HP, Jennings S, Wang J, Molina PE, Nelson S, Wang G. Non-canonical Glucocorticoid Receptor Transactivation of gilz by Alcohol Suppresses Cell Inflammatory Response. Front Immunol 2017. [PMID: 28638383 PMCID: PMC5461336 DOI: 10.3389/fimmu.2017.00661] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Acute alcohol exposure suppresses cell inflammatory response. The underlying mechanism has not been fully defined. Here we report that alcohol was able to activate glucocorticoid receptor (GR) signaling in the absence of glucocorticoids (GCs) and upregulated glucocorticoid-induced leucine zipper (gilz), a prominent GC-responsive gene. Such a non-canonical activation of GR was not blocked by mifepristone, a potent GC competitor. The proximal promoter of gilz, encompassing five GC-responsive elements (GREs), was incorporated and tested in a luciferase reporter system. Deletion and/or mutation of the GREs abrogated the promoter responsiveness to alcohol. Thus, the GR–GRE interaction transduced the alcohol action on gilz. Alcohol induced GR nuclear translocation, which was enhanced by the alcohol dehydrogenase inhibitor fomepizole, suggesting that it was alcohol, not its metabolites, that engendered the effect. Gel mobility shift assay showed that unliganded GR was able to bind GREs and such interaction withstood clinically relevant levels of alcohol. GR knockout via CRISPR/Cas9 gene targeting or GILZ depletion via small RNA interference diminished alcohol suppression of cell inflammatory response to LPS. Thus, a previously unrecognized, non-canonical GR activation of gilz is involved in alcohol modulation of cell immune response.
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Affiliation(s)
- Hang Pong Ng
- Alcohol and Drug Abuse Center, Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA, United States
| | - Scott Jennings
- Alcohol and Drug Abuse Center, Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA, United States
| | - Jack Wang
- Alcohol and Drug Abuse Center, Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA, United States
| | - Patricia E Molina
- Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA, United States
| | - Steve Nelson
- Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, United States
| | - Guoshun Wang
- Alcohol and Drug Abuse Center, Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA, United States
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23
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Abstract
The first sex steroid to be crystallized was the vertebrate ovarian hormone, estrone - a less potent metabolite of 17β-estradiol, which in mammals stimulates the female urge to mate (estrus). The gadfly (Greek oistros) lent its name to the process of estrus, as an insect that bites and torments in classical Greek mythology. With the purification and crystallization of a moult-inducing steroid (ecdysone) from insects, an interesting parallel emerged between mating and moulting in lower mammals and arthropods. Ecdysterone (potent ecdysone metabolite) has anabolic effects in mammalian muscle cells that can be blocked by selective estrogen receptor antagonists. Insects utilize ecdysteroids in similar ways that vertebrates use estrogens, including stimulation of oocyte growth and maturation. Ecdysteroids also modify precopulatory insect mating behaviour, further reinforcing the gonad-gadfly/mate-moult analogy.
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Affiliation(s)
- Stephen G Hillier
- Medical Research Council Centre for Reproductive HealthUniversity of Edinburgh, Queen's Medical Research Institute, Edinburgh, United Kingdom
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24
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Lee YY, Cho NH, Lee JW, Kim NK, Kim HS, Kim MK. Clinical Characteristics of Patients with Adrenal Insufficiency in a General Hospital. Endocrinol Metab (Seoul) 2017; 32:83-89. [PMID: 28256113 PMCID: PMC5368127 DOI: 10.3803/enm.2017.32.1.83] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2016] [Revised: 01/05/2017] [Accepted: 02/28/2017] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Adrenal insufficiency (AI) is a life-threatening disorder caused by the deficiency of adrenal steroid hormones. This retrospective cross-sectional study investigated the characteristics of patients with AI in Korea. METHODS All consecutive patients with suspected AI who received care at a tertiary referral center in Korea in 2014 and underwent adrenocorticotropic hormone stimulation or insulin-tolerance testing were identified through a review of medical charts. Patients diagnosed with AI were enrolled. Their demographic, clinical, and treatment details were extracted. RESULTS Of 771 patients with suspected AI, 183 (23.7%) received a definitive diagnosis. The most common reason for testing was the presence of suspicious AI-related symptoms (30.0%), followed by a history of steroid medications (23.5%). Their mean age was 66.7 years, and females predominated (67.8%). The most common symptoms were general weakness, anorexia, arthralgia, and fever. Approximately half (53.6%) had a history of steroid use. Hydrocortisone was the most common treatment (71.6%), with most patients taking a 30 mg dose (44.2%). The most common dose frequency was twice a day (78.6%). Fourteen patients were treated for adrenal crisis (n=10, 5.5%) or an intercurrent illness (n=4, 2.2%). CONCLUSION AI may have been caused by steroid medication use in many of the patients included in this study. The detection of AI can be improved by careful history-taking and being alert to the possibility that a patient has used steroids.
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Affiliation(s)
- Ye Yeon Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Nan Hee Cho
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Jong Won Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Nam Kyung Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Hye Soon Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Mi Kyung Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea.
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25
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Hathout Y, Conklin LS, Seol H, Gordish-Dressman H, Brown KJ, Morgenroth LP, Nagaraju K, Heier CR, Damsker JM, van den Anker JN, Henricson E, Clemens PR, Mah JK, McDonald C, Hoffman EP. Serum pharmacodynamic biomarkers for chronic corticosteroid treatment of children. Sci Rep 2016; 6:31727. [PMID: 27530235 PMCID: PMC4987691 DOI: 10.1038/srep31727] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Accepted: 07/25/2016] [Indexed: 12/13/2022] Open
Abstract
Corticosteroids are extensively used in pediatrics, yet the burden of side effects is significant. Availability of a simple, fast, and reliable biochemical read out of steroidal drug pharmacodynamics could enable a rapid and objective assessment of safety and efficacy of corticosteroids and aid development of corticosteroid replacement drugs. To identify potential corticosteroid responsive biomarkers we performed proteome profiling of serum samples from DMD and IBD patients with and without corticosteroid treatment using SOMAscan aptamer panel testing 1,129 proteins in <0.1 cc of sera. Ten pro-inflammatory proteins were elevated in untreated patients and suppressed by corticosteroids (MMP12, IL22RA2, CCL22, IGFBP2, FCER2, LY9, ITGa1/b1, LTa1/b2, ANGPT2 and FGG). These are candidate biomarkers for anti-inflammatory efficacy of corticosteroids. Known safety concerns were validated, including elevated non-fasting insulin (insulin resistance), and elevated angiotensinogen (salt retention). These were extended by new candidates for metabolism disturbances (leptin, afamin), stunting of growth (growth hormone binding protein), and connective tissue remodeling (MMP3). Significant suppression of multiple adrenal steroid hormones was also seen in treated children (reductions of 17-hydroxyprogesterone, corticosterone, 11-deoxycortisol and testosterone). A panel of new pharmacodynamic biomarkers for corticosteroids in children was defined. Future studies will need to bridge specific biomarkers to mechanism of drug action, and specific clinical outcomes.
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Affiliation(s)
- Yetrib Hathout
- Research Center for Genetic Medicine, Children's National Health Systems, Washington, DC 20010, USA
| | - Laurie S Conklin
- Research Center for Genetic Medicine, Children's National Health Systems, Washington, DC 20010, USA
| | - Haeri Seol
- Research Center for Genetic Medicine, Children's National Health Systems, Washington, DC 20010, USA
| | - Heather Gordish-Dressman
- Research Center for Genetic Medicine, Children's National Health Systems, Washington, DC 20010, USA
| | - Kristy J Brown
- Research Center for Genetic Medicine, Children's National Health Systems, Washington, DC 20010, USA
| | - Lauren P Morgenroth
- Research Center for Genetic Medicine, Children's National Health Systems, Washington, DC 20010, USA
| | - Kanneboyina Nagaraju
- Research Center for Genetic Medicine, Children's National Health Systems, Washington, DC 20010, USA
| | - Christopher R Heier
- Research Center for Genetic Medicine, Children's National Health Systems, Washington, DC 20010, USA
| | - Jesse M Damsker
- Research Center for Genetic Medicine, Children's National Health Systems, Washington, DC 20010, USA
| | - John N van den Anker
- Research Center for Genetic Medicine, Children's National Health Systems, Washington, DC 20010, USA
| | - Erik Henricson
- Department of Physical Medicine &Rehabilitation, University of California, Davis School of Medicine, Davis, CA 95618, USA
| | - Paula R Clemens
- Neurology Service, Department of Veterans Affairs Medical Center, Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Jean K Mah
- Department of Pediatrics, Alberta Children's Hospital, Calgary, AB, T3B 6A8 Canada
| | - Craig McDonald
- Department of Physical Medicine &Rehabilitation, University of California, Davis School of Medicine, Davis, CA 95618, USA
| | - Eric P Hoffman
- Research Center for Genetic Medicine, Children's National Health Systems, Washington, DC 20010, USA
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Uçar A, Baş F, Saka N. Diagnosis and management of pediatric adrenal insufficiency. World J Pediatr 2016; 12:261-274. [PMID: 27059746 DOI: 10.1007/s12519-016-0018-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Accepted: 02/24/2015] [Indexed: 10/22/2022]
Abstract
BACKGROUND Adrenal insufficiency (AI) is a wellknown cause of potentially life-threatening disorders. Defects at each level of the hypothalamic-pituitary-adrenal axis can impair adrenal function, leading to varying degrees of glucocorticoid (GC) deficiency. Iatrogenic AI induced by exogenous GCs is the most common cause of AI. The criteria for the diagnosis and management of iatrogenic AI, neonatal AI, and critical illness-related corticosteroid insufficiency (CIRCI) are not clear. DATA SOURCES We reviewed the recent original publications and classical data from the literature, as well as the clinical, diagnostic and management strategies of pediatric AI. RESULTS Practical points in the diagnosis and management of AI with an emphasis on iatrogenic AI, neonatal AI, and CIRCI are provided. Given the lack of sensitive and practical biochemical tests for diagnosis of subtle AI, GC treatment has to be tailored to highly suggestive clinical symptoms and signs. Treatment of adrenal crisis is well standardized and patients almost invariably respond well to therapy. It is mainly the delay in treatment that is responsible for mortality in adrenal crisis. CONCLUSIONS Education of patients and health care professionals is mandatory for timely interventions for patients with adrenal crisis.
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Affiliation(s)
- Ahmet Uçar
- Growth-Development and Pediatric Endocrine Unit, Istanbul School of Medicine, Istanbul University, Istanbul, Turkey.
| | - Firdevs Baş
- Growth-Development and Pediatric Endocrine Unit, Istanbul School of Medicine, Istanbul University, Istanbul, Turkey
| | - Nurçin Saka
- Growth-Development and Pediatric Endocrine Unit, Istanbul School of Medicine, Istanbul University, Istanbul, Turkey
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Glucocorticoid Steroid and Alendronate Treatment Alleviates Dystrophic Phenotype with Enhanced Functional Glycosylation of α-Dystroglycan in Mouse Model of Limb-Girdle Muscular Dystrophy with FKRPP448L Mutation. THE AMERICAN JOURNAL OF PATHOLOGY 2016; 186:1635-48. [DOI: 10.1016/j.ajpath.2016.02.015] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Revised: 02/02/2016] [Accepted: 02/19/2016] [Indexed: 12/13/2022]
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In Vitro and In Vivo Correlation of Colon-Targeted Compression-Coated Tablets. JOURNAL OF PHARMACEUTICS 2016; 2016:5742967. [PMID: 26989562 PMCID: PMC4773564 DOI: 10.1155/2016/5742967] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Accepted: 01/17/2016] [Indexed: 11/29/2022]
Abstract
This study was performed to assess and correlate in vitro drug release with in vivo absorption of prednisolone (PDL) from a colon-targeted tablet prepared by compression coating of core tablet. In vivo drug absorption study was conducted using a high performance liquid chromatographic (HPLC) method, which was developed and validated for the estimation of PDL in rabbit plasma. The calibration curve showed linearity in the concentration range of 0.05 to 50 μg/mL with the correlation coefficient (r) of 0.999. The method was specific and sensitive with the limit of detection (LOD) and lower limit of quantification (LLOQ) of 31.89 ± 1.10 ng/mL and 96.63 ± 3.32 ng/mL, respectively. The extraction recovery (ER) of PDL from three different levels of quality control (QC) samples ranged from 98.18% to 103.54%. In vitro drug release study revealed that less than 10% drug was released in 6.34 h and almost complete (98.64%) drug release was achieved in the following 6 h. In vivo drug absorption study demonstrated lower values of Cmax, AUCtotal, and protracted Tmax from compression-coated tablet. The results confirmed the maximum release of drug in the colon while minimizing release in the upper gastrointestinal tract (GIT). An excellent in vitro and in vivo correlation (IVIVC) was also achieved after considering the lag time.
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Manning DM. The Human Person at the Heart of Medicine: Reflections of a Physician with Lymphoma. Linacre Q 2016; 83:15-19. [DOI: 10.1080/00243639.2016.1143169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Abstract
The author, a physician living with lymphoma for five years, relates the details of the lived experience. He reflects on the impact of his illness on aspects of his life: personal health, professional work as a physician, and his journey in faith.
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Affiliation(s)
- Sarah A Jones
- Monash University Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, 246 Clayton Road, Clayton, Melbourne, Victoria 3168, Australia
| | - Eric F Morand
- Monash University Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, 246 Clayton Road, Clayton, Melbourne, Victoria 3168, Australia
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Cazzola M, Coppola A, Rogliani P, Matera MG. Novel glucocorticoid receptor agonists in the treatment of asthma. Expert Opin Investig Drugs 2015; 24:1473-82. [PMID: 26293110 DOI: 10.1517/13543784.2015.1078310] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Inhaled corticosteroids are the only drugs that effectively suppress the airway inflammation, but they can induce considerable systemic and adverse effects when they are administered chronically at high doses. Consequently, the pharmaceutical industry is still searching for newer entities with an improved therapeutic index. AREAS COVERED Herein, the authors review the research in the glucocorticoid field to identify ligands of the glucocorticoid receptor (GR). These ligands preferentially induce transrepression with little or no transactivating activity, in order to have a potent anti-inflammatory action and a low side-effects profile. EXPERT OPINION Several agents have been synthesized, but few have been tested in experimental models of asthma. Furthermore, only three (BI-54903, GW870086X and AZD5423) have entered clinical development, although the development of at least one of them (BI-54903) was discontinued. The reason for the limited success so far obtained is that the model of transactivation versus transrepression is a too simplistic representation of GR activity. It is difficult to uncouple the therapeutic and harmful effects mediated by GR, but some useful information that might change the current perspective is appearing in the literature. The generation of gene expression 'fingerprints' produced by different GR agonists in target and off-target human tissues could be useful in identifying drug candidates with an improved therapeutic ratio.
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Affiliation(s)
- Mario Cazzola
- a 1 University of Rome Tor Vergata, Department of Systems Medicine , Rome, Italy.,b 2 University of Rome Tor Vergata, Respiratory Pharmacology Research Unit, Department of Systems Medicine , Rome, Italy .,c 3 University Hospital Tor Vergata, Division of Respiratory Medicine , Rome, Italy
| | - Angelo Coppola
- a 1 University of Rome Tor Vergata, Department of Systems Medicine , Rome, Italy.,c 3 University Hospital Tor Vergata, Division of Respiratory Medicine , Rome, Italy
| | - Paola Rogliani
- a 1 University of Rome Tor Vergata, Department of Systems Medicine , Rome, Italy.,c 3 University Hospital Tor Vergata, Division of Respiratory Medicine , Rome, Italy
| | - Maria Gabriella Matera
- d 4 Second University of Naples, Unit of Pharmacology, Department of Experimental Medicine , Naples, Italy
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Dillingham BC, Knoblach SM, Many GM, Harmon BT, Mullen AM, Heier CR, Bello L, McCall JM, Hoffman EP, Connor EM, Nagaraju K, Reeves EKM, Damsker JM. VBP15, a novel anti-inflammatory, is effective at reducing the severity of murine experimental autoimmune encephalomyelitis. Cell Mol Neurobiol 2015; 35:377-387. [PMID: 25392236 PMCID: PMC11486228 DOI: 10.1007/s10571-014-0133-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2014] [Accepted: 10/27/2014] [Indexed: 12/26/2022]
Abstract
Multiple sclerosis is a chronic disease of the central nervous system characterized by an autoimmune inflammatory reaction that leads to axonal demyelination and tissue damage. Glucocorticoids, such as prednisolone, are effective in the treatment of multiple sclerosis in large part due to their ability to inhibit pro-inflammatory pathways (e.g., NFκB). However, despite their effectiveness, long-term treatment is limited by adverse side effects. VBP15 is a recently described compound synthesized based on the lazeroid steroidal backbone that shows activity in acute and chronic inflammatory conditions, yet displays a much-reduced side effect profile compared to traditional glucocorticoids. The purpose of this study was to determine the effectiveness of VBP15 in inhibiting inflammation and disease progression in experimental autoimmune encephalomyelitis (EAE), a widely used mouse model of multiple sclerosis. Our data show that VBP15 is effective at reducing both disease onset and severity. In parallel studies, we observed that VBP15 was able to inhibit the production of NFκB-regulated pro-inflammatory transcripts in human macrophages. Furthermore, treatment with prednisolone-but not VBP15-increased expression of genes associated with bone loss and muscle atrophy, suggesting lack of side effects of VBP15. These findings suggest that VBP15 may represent a potentially safer alternative to traditional glucocorticoids in the treatment of multiple sclerosis and other inflammatory diseases.
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Affiliation(s)
- Blythe C Dillingham
- Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC, 20010, USA
| | - Susan M Knoblach
- Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC, 20010, USA
- Department of Integrative Systems Biology, Children's National Medical Center and George Washington University School of Medicine and Health Sciences, Washington, DC, 20010, USA
| | - Gina M Many
- Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC, 20010, USA
| | - Brennan T Harmon
- Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC, 20010, USA
| | - Amanda M Mullen
- Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC, 20010, USA
| | - Christopher R Heier
- Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC, 20010, USA
| | - Luca Bello
- Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC, 20010, USA
| | - John M McCall
- PharMac LLC, Boca Grande, FL, 33921, USA
- ReveraGen BioPharma, Silver Spring, MD, 20910, USA
| | - Eric P Hoffman
- Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC, 20010, USA
- Department of Integrative Systems Biology, Children's National Medical Center and George Washington University School of Medicine and Health Sciences, Washington, DC, 20010, USA
- ReveraGen BioPharma, Silver Spring, MD, 20910, USA
| | | | - Kanneboyina Nagaraju
- Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC, 20010, USA
- Department of Integrative Systems Biology, Children's National Medical Center and George Washington University School of Medicine and Health Sciences, Washington, DC, 20010, USA
- ReveraGen BioPharma, Silver Spring, MD, 20910, USA
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Romão JS, Hamdy MS, Mul G, Baltrusaitis J. Photocatalytic decomposition of cortisone acetate in aqueous solution. JOURNAL OF HAZARDOUS MATERIALS 2015; 282:208-215. [PMID: 24953705 DOI: 10.1016/j.jhazmat.2014.05.087] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2014] [Revised: 05/02/2014] [Accepted: 05/29/2014] [Indexed: 06/03/2023]
Abstract
The photocatalytic decomposition of cortisone 21-acetate (CA), a model compound for the commonly used steroid, cortisone, was studied. CA was photocatalytically decomposed in a slurry reactor with the initial rates between 0.11 and 0.46 mg L(-1)min(-1) at 10 mg L(-1) concentration, using the following heterogeneous photocatalysts in decreasing order of their catalytic activity: ZnO>Evonik TiO2 P25>Hombikat TiO2>WO3. Due to the lack of ZnO stability in aqueous solutions, TiO2 P25 was chosen for further experiments. The decomposition reaction was found to be pseudo-first order and the rate constant decreased as a function of increasing initial CA concentration. Changing the initial pH of the CA solution did not affect the reaction rate significantly. The decomposition reaction in the presence of the oxidizing sacrificial agent sodium persulfate showed an observed decomposition rate constant of 0.004 min(-1), lower than that obtained for TiO2 P25 (0.040 min(-1)). The highest photocatalytic degradation rate constant was obtained combining both TiO2 P25 and S2O8(2-) (0.071 min(-1)) showing a synergistic effect. No reactive intermediates were detected using LC-MS showing fast photocatalytic decomposition kinetics of CA.
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Affiliation(s)
- Joana Sobral Romão
- PhotoCatalytic Synthesis Group, MESA+Institute for Nanotechnology, Faculty of Science and Technology, University of Twente, Meander 229, PO Box 217, 7500 AE Enschede, The Netherlands
| | - Mohamed S Hamdy
- PhotoCatalytic Synthesis Group, MESA+Institute for Nanotechnology, Faculty of Science and Technology, University of Twente, Meander 229, PO Box 217, 7500 AE Enschede, The Netherlands
| | - Guido Mul
- PhotoCatalytic Synthesis Group, MESA+Institute for Nanotechnology, Faculty of Science and Technology, University of Twente, Meander 229, PO Box 217, 7500 AE Enschede, The Netherlands.
| | - Jonas Baltrusaitis
- PhotoCatalytic Synthesis Group, MESA+Institute for Nanotechnology, Faculty of Science and Technology, University of Twente, Meander 229, PO Box 217, 7500 AE Enschede, The Netherlands.
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Schmidt M, Straub RH. 11β-hydroxysteroid dehydrogenase enzymes modulate effects of glucocorticoids in rheumatoid arthritis synovial cells. Neuroimmunomodulation 2015; 22:40-5. [PMID: 25227721 DOI: 10.1159/000362725] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
The tissue availability of active glucocorticoids (cortisol in humans) depends on their rate of synthesis from cholesterol, downstream metabolism, excretion and interconversion. The latter is mediated by the 11β-hydroxysteroid dehydrogenases (11βHSDs). In this review, we summarize the features of the two isoenzymes, 11βHSD1 and 11βHSD2, and current available experimental data related to 11βHSDs, which are relevant in the context of synovial cells in rheumatoid arthritis (RA). We conclude that due to complex feedback mechanisms inherent to the hypothalamic-pituitary-adrenal axis, currently available transgenic animal models cannot display the full potential otherwise inherent to the techniques. Studies with tissue explants, mixed synovial cell preparations, cell lines derived from synovial cells, and related primary cells or established cell lines indicate that there are relatively clear differences between the two isoenzymes. 11βHSD1 is expressed primarily in fibroblasts and osteoblasts, and may be responsible for fibroblast survival and aid in the resolution of inflammation, but it is also involved in bone damage. 11βHSD2 is expressed primarily in macrophages and lymphocytes, and may be responsible for their survival, suggesting that it is critical in chronic inflammation. The situation in synovial tissue would allow 11βHSD2-expressing cells to tap the energy resources of 11βHSD1-expressing cells. The overall properties of this local glucocorticoid interconversion system might limit therapeutic use of glucocorticoids in RA. © 2014 S. Karger AG, Basel.
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Affiliation(s)
- Martin Schmidt
- Institute of Biochemistry II, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany
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Johannsson G, Falorni A, Skrtic S, Lennernäs H, Quinkler M, Monson JP, Stewart PM. Adrenal insufficiency: review of clinical outcomes with current glucocorticoid replacement therapy. Clin Endocrinol (Oxf) 2015; 82:2-11. [PMID: 25187037 DOI: 10.1111/cen.12603] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2014] [Revised: 06/25/2014] [Accepted: 08/27/2014] [Indexed: 11/28/2022]
Abstract
Glucocorticoid replacement therapy in patients with adrenal insufficiency (AI), whether primary (Addison's disease) or secondary (due to hypopituitarism), has been established for some 50 years. The current standard treatment regimen involves twice- or thrice-daily dosing with a glucocorticoid, most commonly oral hydrocortisone. Based on previous small-scale studies and clinical perception, life expectancy with conventional glucocorticoid replacement therapy has been considered normal, with a low incidence of adverse events. Data from the past 10-15 years, however, have shown that morbidity remains high and life expectancy is reduced. The increased morbidity and decreased life expectancy appear to be due to both increased exposure to cortisol and insufficient cortisol coverage during infections and other stress-related events. This is thought to reflect a failure of treatment to replicate the natural circadian rhythm of cortisol release, together with a failure to identify and deliver individualized cortisol exposure and to manage patients adequately when increased doses are required. The resulting over- or under-treatment may result in Cushing-like symptoms or adrenal crisis, respectively. This review summarizes the morbidity and mortality seen in patients receiving the current standard of care for AI and suggests areas for improvement in glucocorticoid replacement therapy.
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Affiliation(s)
- Gudmundur Johannsson
- Department of Endocrinology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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Ellero-Simatos S, Fleuren WWM, Bauerschmidt S, Dokter WHA, Toonen EJM. Identification of gene signatures for prednisolone-induced metabolic dysfunction in collagen-induced arthritic mice. Pharmacogenomics 2014; 15:629-41. [PMID: 24798720 DOI: 10.2217/pgs.14.3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND Prednisolone is a potent anti-inflammatory glucocorticoid (GC) but chronic use is hampered by metabolic side effects. Little is known about the long-term effects of GCs on gene-expression in vivo during inflammation. AIM Identify gene signatures underlying prednisolone-induced metabolic side effects in a complex in vivo inflammatory setting after long-term treatment. MATERIALS & METHODS We performed whole-genome expression profiling in liver and muscle from arthritic and nonarthritic mice treated with several doses of prednisolone for 3 weeks and used text-mining to link gene signatures to metabolic pathways. RESULTS Prednisolone-induced gene signatures were highly tissue specific. We identified a short-list of genes significantly affected by both prednisolone and inflammation in liver and involved in glucose and fatty acid metabolism. For several of these genes the association with GCs is novel. CONCLUSION The identified gene signatures may provide useful starting points for the development of GCs with a better safety profile.
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Affiliation(s)
- Sandrine Ellero-Simatos
- Division Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden, The Netherlands
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Abstract
Glucocorticoids (GC) are steroid hormones with important implications in the treatment of various inflammatory and autoimmune diseases. At the same time GC are known to have numerous side-effects. Endogenous GC are predominantly produced by the adrenal glands, and adrenal-derived GC serve important functions in the regulation of development, metabolism, and immune regulation. The last two decades of research have led to the identification of numerous alternative sources of extra-adrenal GC synthesis. Among other tissues the intestine and lung are capable of locally producing considerable amounts of immunoregulatory GC. This local steroidogenesis in these mucosal tissues appears to be regulated by transcription factors and mediators different from those in the adrenals, likely reflecting an adaptation to the local requirements and conditions. Here we summarize the current knowledge about the extra-adrenal GC synthesis in the mucosal tissues, with special emphasis on the intestinal epithelium, and its implication on the regulation of immune homeostasis and inflammatory processes.
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Affiliation(s)
- Feodora Kostadinova
- Biochemical Pharmacology, Department of Biology, University of Konstanz , Germany
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Makol A, Davis JM, Crowson CS, Therneau TM, Gabriel SE, Matteson EL. Time trends in glucocorticoid use in rheumatoid arthritis: results from a population-based inception cohort, 1980-1994 versus 1995-2007. Arthritis Care Res (Hoboken) 2014; 66:1482-8. [PMID: 24821680 PMCID: PMC4177279 DOI: 10.1002/acr.22365] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2013] [Accepted: 04/29/2014] [Indexed: 01/16/2023]
Abstract
OBJECTIVE To examine trends in glucocorticoid (GC) use and dosing among patients diagnosed with rheumatoid arthritis (RA) over time. METHODS A population-based inception cohort of RA patients diagnosed during 1980-2007 was followed longitudinally through their medical records until death, migration, or December 31, 2008. GC start and stop dates were collected, along with doses in prednisone equivalents. RESULTS The study population comprised 349 patients (68% women) diagnosed in 1980-1994 and 464 (69% women) diagnosed in 1995-2007, with a median followup of 15.3 and 5.7 years, respectively. A higher proportion of patients started GCs in their first year of disease in 1995-2007 (68% versus 36%; P < 0.001), but the starting dose (mean 8.7 versus 10.3 mg; P = 0.08) and cumulative dose in the first year of use (mean 1.8g [mean daily dose 4.9 mg] versus 2.1 gm [mean daily dose 5.8 mg]; P = 0.48) were not different. A higher proportion also discontinued GCs in their first year of disease in the 1995-2007 cohort (P < 0.001). These differences in GC initiation and discontinuation persisted throughout followup. Prevalence of GC use was higher in the 1995-2007 cohort for the first 3 years of disease. CONCLUSION More patients are starting GCs early in their disease course now compared to previously, which is consistent with established treatment guidelines. A higher proportion are also discontinuing GCs, but the proportion of patients taking GCs at any given point of disease during the first 4 years is higher now than previously. Despite early addition of a disease-modifying antirheumatic drug, some patients may not be able to discontinue GCs over the long term.
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Affiliation(s)
- Ashima Makol
- Division of Rheumatology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - John M. Davis
- Division of Rheumatology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Cynthia S. Crowson
- Division of Rheumatology, Mayo Clinic College of Medicine, Rochester, MN, USA
- Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Terry M. Therneau
- Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Sherine E. Gabriel
- Division of Rheumatology, Mayo Clinic College of Medicine, Rochester, MN, USA
- Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Eric L. Matteson
- Division of Rheumatology, Mayo Clinic College of Medicine, Rochester, MN, USA
- Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, USA
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Fan H, Kao W, Yang YH, Gu R, Harris J, Fingerle-Rowson G, Bucala R, Ngo D, Beaulieu E, Morand EF. Macrophage migration inhibitory factor inhibits the antiinflammatory effects of glucocorticoids via glucocorticoid-induced leucine zipper. Arthritis Rheumatol 2014; 66:2059-70. [PMID: 24782327 DOI: 10.1002/art.38689] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2013] [Accepted: 04/25/2014] [Indexed: 12/28/2022]
Abstract
OBJECTIVE Glucocorticoids remain a mainstay in the treatment of rheumatoid arthritis (RA). Dose-dependent adverse effects highlight the need for therapies that regulate glucocorticoid sensitivity to enable dosage reduction. Macrophage migration inhibitory factor (MIF) is a proinflammatory protein that has been implicated in the pathogenesis of RA; it impairs glucocorticoid sensitivity via MAPK phosphatase 1 (MKP-1) inhibition. The intracellular protein glucocorticoid-induced leucine zipper (GILZ) mimics the effects of glucocorticoids in models of RA, but whether it represents a target for the modulation of glucocorticoid sensitivity remains unknown. We undertook this study to investigate whether GILZ is involved in the regulation of glucocorticoid sensitivity by MIF. METHODS GILZ expression was studied in the presence and absence of MIF, and the role of GILZ in the MIF-dependent regulation of the glucocorticoid sensitivity mediator MKP-1 was studied at the level of expression and function. RESULTS GILZ expression was significantly inhibited by endogenous MIF, both basally and during responses to glucocorticoid treatment. The effects of MIF on GILZ were dependent on the expression and Akt-induced nuclear translocation of the transcription factor FoxO3A. GILZ was shown to regulate the expression of MKP-1 and consequent MAPK phosphorylation and cytokine release. CONCLUSION MIF exerts its effects on MKP-1 expression and MAPK activity through inhibitory effects on GILZ. These findings suggest a previously unsuspected interaction between MIF and GILZ and identify GILZ as a potential target for the therapeutic regulation of glucocorticoid sensitivity.
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Affiliation(s)
- Huapeng Fan
- Monash University, Clayton, Victoria, Australia
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Boardman C, Chachi L, Gavrila A, Keenan CR, Perry MM, Xia YC, Meurs H, Sharma P. Mechanisms of glucocorticoid action and insensitivity in airways disease. Pulm Pharmacol Ther 2014; 29:129-43. [PMID: 25218650 DOI: 10.1016/j.pupt.2014.08.008] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2014] [Revised: 08/18/2014] [Accepted: 08/25/2014] [Indexed: 01/04/2023]
Abstract
Glucocorticoids are the mainstay for the treatment of chronic inflammatory diseases including asthma and chronic obstructive pulmonary disease (COPD). However, it has been recognized that glucocorticoids do not work well in certain patient populations suggesting reduced sensitivity. The ultimate biologic responses to glucocorticoids are determined by not only the concentration of glucocorticoids but also the differences between individuals in glucocorticoid sensitivity, which is influenced by multiple factors. Studies are emerging to understand these mechanisms in detail, which would help in increasing glucocorticoid sensitivity in patients with chronic airways disease. This review aims to highlight both classical and emerging concepts of the anti-inflammatory mechanisms of glucocorticoids and also review some novel strategies to overcome steroid insensitivity in airways disease.
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Affiliation(s)
- C Boardman
- Airway Disease, National Heart and Lung Institute, Imperial College, London, United Kingdom
| | - L Chachi
- Institute for Lung Health, Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, United Kingdom
| | - A Gavrila
- Institute for Lung Health, Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, United Kingdom
| | - C R Keenan
- Department of Pharmacology, University of Melbourne, Parkville, Victoria, Australia
| | - M M Perry
- Airway Disease, National Heart and Lung Institute, Imperial College, London, United Kingdom
| | - Y C Xia
- Department of Pharmacology, University of Melbourne, Parkville, Victoria, Australia
| | - H Meurs
- Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands
| | - P Sharma
- Department of Physiology and Pharmacology, Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, University of Calgary, 4C46 HRIC, 3280 Hospital Dr NW, Calgary, AB, Canada T2N 4N1.
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41
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Toonen EJM, Laskewitz AJ, van Dijk TH, Bleeker A, Grefhorst A, Schouten AE, Bastiaanssen EAJ, Ballak DB, Koenders MI, van Doorn C, van der Vleuten MAJ, van Lierop MJC, Groen AK, Dokter WHA. Glucose kinetics in the collagen-induced arthritis model: an all-in-one model to assess both efficacy and metabolic side effects of glucocorticoids. PLoS One 2014; 9:e98684. [PMID: 25181348 PMCID: PMC4151983 DOI: 10.1371/journal.pone.0098684] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2012] [Accepted: 05/07/2014] [Indexed: 01/02/2023] Open
Abstract
Prednisolone and other glucocorticoids (GCs) are potent anti-inflammatory drugs, but chronic use is hampered by metabolic side effects. Therefore, there is an urgent medical need for improved GCs that are as effective as classical GCs but have a better safety profile. A well-established model to assess anti-inflammatory efficacy is the chronic collagen-induced arthritis (CIA) model in mice, a model with features resembling rheumatoid arthritis. Models to quantify undesired effects of glucocorticoids on glucose kinetics are less well-established. Recently, we have described a model to quantify basal blood glucose kinetics using stably-labeled glucose. In the present study, we have integrated this blood glucose kinetic model in the CIA model to enable quantification of both efficacy and adverse effects in one animal model. Arthritis scores were decreased after treatment with prednisolone, confirming the anti-inflammatory properties of GCs. Both inflammation and prednisolone induced insulin resistance as insulin secretion was strongly increased whereas blood glucose concentrations and hepatic glucose production were only slightly decreased. This insulin resistance did not directly resulted in hyperglycemia, indicating a highly adaptive compensatory mechanism in these mice. In conclusion, this 'all-in-one' model allows for studying effects of (novel) GC compounds on the development of arthritis and glucose kinetics in a single animal. This integrative model provides a valuable tool for investigating (drug-induced) metabolic dysregulation in an inflammatory setting.
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Affiliation(s)
- Erik J. M. Toonen
- Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
- * E-mail:
| | - Anke J. Laskewitz
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Theo H. van Dijk
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Aycha Bleeker
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Aldo Grefhorst
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Annelies E. Schouten
- Department of Immune Therapeutics, MSD Research Laboratories, Oss, The Netherlands
| | | | - Dov B. Ballak
- Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Marije I. Koenders
- Department of Experimental Rheumatology, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Cindy van Doorn
- Department of Immune Therapeutics, MSD Research Laboratories, Oss, The Netherlands
| | | | | | - Albert K. Groen
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Wim H. A. Dokter
- Department of Immune Therapeutics, MSD Research Laboratories, Oss, The Netherlands
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Abstract
Adrenal insufficiency is the clinical manifestation of deficient production or action of glucocorticoids, with or without deficiency also in mineralocorticoids and adrenal androgens. It is a life-threatening disorder that can result from primary adrenal failure or secondary adrenal disease due to impairment of the hypothalamic-pituitary axis. Prompt diagnosis and management are essential. The clinical manifestations of primary adrenal insufficiency result from deficiency of all adrenocortical hormones, but they can also include signs of other concurrent autoimmune conditions. In secondary or tertiary adrenal insufficiency, the clinical picture results from glucocorticoid deficiency only, but manifestations of the primary pathological disorder can also be present. The diagnostic investigation, although well established, can be challenging, especially in patients with secondary or tertiary adrenal insufficiency. We summarise knowledge at this time on the epidemiology, causal mechanisms, pathophysiology, clinical manifestations, diagnosis, and management of this disorder.
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Affiliation(s)
- Evangelia Charmandari
- Division of Endocrinology, Metabolism, and Diabetes, First Department of Pediatrics, University of Athens Medical School, Aghia Sophia Children's Hospital, Athens, Greece; Division of Endocrinology and Metabolism, Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
| | - Nicolas C Nicolaides
- Division of Endocrinology, Metabolism, and Diabetes, First Department of Pediatrics, University of Athens Medical School, Aghia Sophia Children's Hospital, Athens, Greece; Division of Endocrinology and Metabolism, Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - George P Chrousos
- Division of Endocrinology, Metabolism, and Diabetes, First Department of Pediatrics, University of Athens Medical School, Aghia Sophia Children's Hospital, Athens, Greece; Division of Endocrinology and Metabolism, Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
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43
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Hofmann AF, Hagey LR. Key discoveries in bile acid chemistry and biology and their clinical applications: history of the last eight decades. J Lipid Res 2014; 55:1553-95. [PMID: 24838141 DOI: 10.1194/jlr.r049437] [Citation(s) in RCA: 243] [Impact Index Per Article: 22.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2014] [Indexed: 12/12/2022] Open
Abstract
During the last 80 years there have been extraordinary advances in our knowledge of the chemistry and biology of bile acids. We present here a brief history of the major achievements as we perceive them. Bernal, a physicist, determined the X-ray structure of cholesterol crystals, and his data together with the vast chemical studies of Wieland and Windaus enabled the correct structure of the steroid nucleus to be deduced. Today, C24 and C27 bile acids together with C27 bile alcohols constitute most of the bile acid "family". Patterns of bile acid hydroxylation and conjugation are summarized. Bile acid measurement encompasses the techniques of GC, HPLC, and MS, as well as enzymatic, bioluminescent, and competitive binding methods. The enterohepatic circulation of bile acids results from vectorial transport of bile acids by the ileal enterocyte and hepatocyte; the key transporters have been cloned. Bile acids are amphipathic, self-associate in solution, and form mixed micelles with polar lipids, phosphatidylcholine in bile, and fatty acids in intestinal content during triglyceride digestion. The rise and decline of dissolution of cholesterol gallstones by the ingestion of 3,7-dihydroxy bile acids is chronicled. Scientists from throughout the world have contributed to these achievements.
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Affiliation(s)
- Alan F Hofmann
- Department of Medicine, University of California, San Diego, San Diego, CA
| | - Lee R Hagey
- Department of Medicine, University of California, San Diego, San Diego, CA
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44
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Imrich R, Vlcek M, Kerlik J, Vogeser M, Kirchhoff F, Penesova A, Radikova Z, Lukac J, Rovensky J. Determinants of adrenal androgen hypofunction in premenopausal females with rheumatoid arthritis. Physiol Res 2014; 63:321-9. [PMID: 24564598 DOI: 10.33549/physiolres.932663] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
The aim of our study was to investigate adrenocortical function in the context of disease activity and inflammatory status in premenopausal RA females. Adrenal glucocorticoid and androgen responses to the 1 microg ACTH 1-24 test were investigated in 23 premenopausal RA and in 15 age- and BMI-matched healthy females. Twelve RA patients were on low-dose prednisone (<8.5 mg/day). Patients with DAS28>3.2 had lower (p<0.05) total plasma cortisol, 17-hydroxyprogesterone, dehydroepiandrosterone and androstenedione responses in the ACTH test compared to healthy controls. Patients with DAS28>3.2 had lower (p<0.05) dehydroepiandrosterone response in the ACTH test compared to patients with DAS28</=3.2. C-reactive protein (CRP), DAS28, and interleukin (IL)-6 negatively correlated with androstenedione response to ACTH 1-24. Responses of all measured adrenal steroids were lower (p<0.05) in patients on low-dose glucocorticoids compared to healthy controls. RA patients not treated with glucocorticoids had lower total cortisol response (p=0.038) but did not differ in free plasma cortisol in the ACTH test. The results indicate an association of increased disease activity with a decrease in adrenal androgen production in RA and normal cortisol bioavailability in patients not treated with glucocorticoids.
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Affiliation(s)
- R Imrich
- Center for Molecular Medicine, Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovak Republic.
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45
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Stuijver DJF, Majoor CJ, van Zaane B, Souverein PC, de Boer A, Dekkers OM, Büller HR, Gerdes VEA. Use of oral glucocorticoids and the risk of pulmonary embolism: a population-based case-control study. Chest 2013; 143:1337-1342. [PMID: 23258429 DOI: 10.1378/chest.12-1446] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
Abstract
BACKGROUND Recently, endogenous glucocorticoid excess has been identified as a risk factor for VTE. Whether exogenous use of glucocorticoids is associated with an increased risk of VTE is unclear. We aimed to quantify the risk of symptomatic pulmonary embolism (PE) in patients using corticosteroids. METHODS A case-control study using the PHARMO Record Linkage System, a Dutch population-based pharmacy registry, was conducted. Cases were 4,495 patients with a first hospital admission for PE between 1998 and 2008. Control subjects were 16,802 sex- and age-matched subjects without a history of PE. International Classification of Diseases codes for hospitalization were used to retrieve information on underlying conditions. RESULTS The risk of PE was highest in the first 30 days of glucocorticoid exposure (adjusted OR, 5.9; 95% CI, 2.3-3.9) and gradually decreased with increasing duration of use (OR, 1.9; 95% CI, 1.3-2.9) for long-term users (> 1 year). Low-dose glucocorticoid use (prednisolone daily dose equivalent < 5 mg) carried a twofold increased risk of PE (OR, 1.8; 95% CI, 1.3-2.4), whereas a 10-fold increased risk was observed for the highest dose of glucocorticoids (prednisolone > 30 mg) (OR, 9.6; 95% CI, 4.3-20.5). Stratification for both duration and dose of glucocorticoid showed the highest risk of PE in recently started users compared with long-term users at the time of PE, irrespective of the dose. CONCLUSION Patients treated with oral glucocorticoids may be at an increased risk of PE, especially during the first month of exposure. This hypothesis requires confirmation in future studies.
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Affiliation(s)
- Danka J F Stuijver
- Department of Internal Medicine, Slotervaart Hospital, Amsterdam; Department of Vascular Medicine, Academic Medical Center, Amsterdam.
| | - Christof J Majoor
- Department of Pulmonary Medicine, Academic Medical Center, Amsterdam
| | - Bregje van Zaane
- Department of Internal Medicine, Slotervaart Hospital, Amsterdam; Department of Vascular Medicine, Academic Medical Center, Amsterdam
| | - Patrick C Souverein
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht
| | - Anthonius de Boer
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht
| | - Olaf M Dekkers
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands; Department of Endocrinology and Metabolism, Leiden University Medical Center, Leiden, The Netherlands
| | - Harry R Büller
- Department of Vascular Medicine, Academic Medical Center, Amsterdam
| | - Victor E A Gerdes
- Department of Internal Medicine, Slotervaart Hospital, Amsterdam; Department of Vascular Medicine, Academic Medical Center, Amsterdam
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46
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Georgakopoulou EA, Scully C. Systemic use of non-biologic corticosteroids in orofacial diseases. Oral Dis 2013; 20:127-35. [PMID: 23746234 DOI: 10.1111/odi.12132] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2013] [Revised: 05/01/2013] [Accepted: 05/01/2013] [Indexed: 12/26/2022]
Abstract
Systemic non-biologic agents have long been in clinical use in medicine - often with considerable efficacy, albeit with some adverse effects--as with all medications. With the advent of biologic agents, all of which currently are restricted to systemic use, there is a growing need to ensure which agents have the better therapeutic ratio. The non-biologic agents (NBAs) include a range of agents, most especially the corticosteroids (corticosteroids). This study reviews the corticosteroids in systemic use in management of orofacial mucocutaneous diseases; subsequent studies discuss corticosteroid-sparing agents used in the management of orofacial diseases, such as calcineurin inhibitors used to produce immunosuppression; purine synthetase inhibitors; and cytotoxic and other immunomodulatory agents.
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47
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Damsker JM, Dillingham BC, Rose MC, Balsley MA, Heier CR, Watson AM, Stemmy EJ, Jurjus RA, Huynh T, Tatem K, Uaesoontrachoon K, Berry DM, Benton AS, Freishtat RJ, Hoffman EP, McCall JM, Gordish-Dressman H, Constant SL, Reeves EKM, Nagaraju K. VBP15, a glucocorticoid analogue, is effective at reducing allergic lung inflammation in mice. PLoS One 2013; 8:e63871. [PMID: 23667681 PMCID: PMC3646769 DOI: 10.1371/journal.pone.0063871] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2013] [Accepted: 04/11/2013] [Indexed: 01/22/2023] Open
Abstract
Asthma is a chronic inflammatory condition of the lower respiratory tract associated with airway hyperreactivity and mucus obstruction in which a majority of cases are due to an allergic response to environmental allergens. Glucocorticoids such as prednisone have been standard treatment for many inflammatory diseases for the past 60 years. However, despite their effectiveness, long-term treatment is often limited by adverse side effects believed to be caused by glucocorticoid receptor-mediated gene transcription. This has led to the pursuit of compounds that retain the anti-inflammatory properties yet lack the adverse side effects associated with traditional glucocorticoids. We have developed a novel series of steroidal analogues (VBP compounds) that have been previously shown to maintain anti-inflammatory properties such as NFκB-inhibition without inducing glucocorticoid receptor-mediated gene transcription. This study was undertaken to determine the effectiveness of the lead compound, VBP15, in a mouse model of allergic lung inflammation. We show that VBP15 is as effective as the traditional glucocorticoid, prednisolone, at reducing three major hallmarks of lung inflammation—NFκB activity, leukocyte degranulation, and pro-inflammatory cytokine release from human bronchial epithelial cells obtained from patients with asthma. Moreover, we found that VBP15 is capable of reducing inflammation of the lung in vivo to an extent similar to that of prednisone. We found that prednisolone–but not VBP15 shortens the tibia in mice upon a 5 week treatment regimen suggesting effective dissociation of side effects from efficacy. These findings suggest that VBP15 may represent a potent and safer alternative to traditional glucocorticoids in the treatment of asthma and other inflammatory diseases.
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Affiliation(s)
- Jesse M Damsker
- ReveraGen BioPharma, Rockville, Maryland, United States of America.
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48
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Fleuren WWM, Linssen MML, Toonen EJM, van der Zon GCM, Guigas B, de Vlieg J, Dokter WHA, Ouwens DM, Alkema W. Prednisolone induces the Wnt signalling pathway in 3T3-L1 adipocytes. Arch Physiol Biochem 2013; 119:52-64. [PMID: 23506355 PMCID: PMC3665230 DOI: 10.3109/13813455.2013.774022] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Synthetic glucocorticoids are potent anti-inflammatory drugs but show dose-dependent metabolic side effects such as the development of insulin resistance and obesity. The precise mechanisms involved in these glucocorticoid-induced side effects, and especially the participation of adipose tissue in this are not completely understood. We used a combination of transcriptomics, antibody arrays and bioinformatics approaches to characterize prednisolone-induced alterations in gene expression and adipokine secretion, which could underlie metabolic dysfunction in 3T3-L1 adipocytes. Several pathways, including cytokine signalling, Akt signalling, and Wnt signalling were found to be regulated at multiple levels, showing that these processes are targeted by prednisolone. These results suggest that mechanisms by which prednisolone induce insulin resistance include dysregulation of wnt signalling and immune response processes. These pathways may provide interesting targets for the development of improved glucocorticoids.
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Affiliation(s)
- Wilco W. M. Fleuren
- CDD, CMBI, NCMLS, Radboud University Medical CentreNijmegenThe Netherlands
- Netherlands Bioinformatics Centre (NBIC)NijmegenThe Netherlands
| | - Margot M. L. Linssen
- Department of Molecular Cell Biology, Leiden University Medical CenterLeidenThe Netherlands
| | - Erik J. M. Toonen
- Department of Medicine, Radboud University Medical CentreNijmegenThe Netherlands
| | | | - Bruno Guigas
- Department of Molecular Cell Biology, Leiden University Medical CenterLeidenThe Netherlands
- Department of Parasitology, Leiden University Medical CenterLeidenThe Netherlands
| | - Jacob de Vlieg
- CDD, CMBI, NCMLS, Radboud University Medical CentreNijmegenThe Netherlands
- Netherlands eScience CenterAmsterdamThe Netherlands
| | | | - D. Margriet Ouwens
- Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes CenterDüsseldorfGermany
- Department of Endocrinology, Ghent University HospitalGhentBelgium
| | - Wynand Alkema
- CDD, CMBI, NCMLS, Radboud University Medical CentreNijmegenThe Netherlands
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McCandless EE, Rai SK, Mwangi D, Sly L, Franz LC. Hydrocortisone inhibits IFN-γ production in equine, ovine, and bovine PBMCs. Vet Immunol Immunopathol 2013; 153:128-33. [DOI: 10.1016/j.vetimm.2012.12.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2012] [Revised: 11/29/2012] [Accepted: 12/27/2012] [Indexed: 01/26/2023]
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50
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Luca F, Maranville JC, Richards AL, Witonsky DB, Stephens M, Di Rienzo A. Genetic, functional and molecular features of glucocorticoid receptor binding. PLoS One 2013; 8:e61654. [PMID: 23637875 PMCID: PMC3640037 DOI: 10.1371/journal.pone.0061654] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2012] [Accepted: 03/12/2013] [Indexed: 12/20/2022] Open
Abstract
Glucocorticoids (GCs) are key mediators of stress response and are widely used as pharmacological agents to treat immune diseases, such as asthma and inflammatory bowel disease, and certain types of cancer. GCs act mainly by activating the GC receptor (GR), which interacts with other transcription factors to regulate gene expression. Here, we combined different functional genomics approaches to gain molecular insights into the mechanisms of action of GC. By profiling the transcriptional response to GC over time in 4 Yoruba (YRI) and 4 Tuscans (TSI) lymphoblastoid cell lines (LCLs), we suggest that the transcriptional response to GC is variable not only in time, but also in direction (positive or negative) depending on the presence of specific interacting transcription factors. Accordingly, when we performed ChIP-seq for GR and NF-κB in two YRI LCLs treated with GC or with vehicle control, we observed that features of GR binding sites differ for up- and down-regulated genes. Finally, we show that eQTLs that affect expression patterns only in the presence of GC are 1.9-fold more likely to occur in GR binding sites, compared to eQTLs that affect expression only in its absence. Our results indicate that genetic variation at GR and interacting transcription factors binding sites influences variability in gene expression, and attest to the power of combining different functional genomic approaches.
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Affiliation(s)
- Francesca Luca
- Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America
| | - Joseph C. Maranville
- Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America
| | - Allison L. Richards
- Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America
| | - David B. Witonsky
- Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America
| | - Matthew Stephens
- Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America
- Department of Statistics, University of Chicago, Chicago, Illinois, United States of America
| | - Anna Di Rienzo
- Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America
- * E-mail:
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