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Glucocorticoid resistance

Michaël R Laurent
An overview of selected papers related to bone published in 2017 is provided. PURPOSE: This paper accompanies a lecture at the 2018 Belgian Bone Club annual Clinical Update Symposium held in Brussels on January 20th, discussing the best papers (in the opinion of the author) published in the previous year. METHODS: A PubMed search using the keyword "bone" and articles published in 2017. RESULTS: Hot topics include screening for osteoporosis, novel anabolic drugs such as romosozumab and abaloparatide for osteoporosis and rare metabolic bone diseases, as well as long-term efficacy of denosumab and possible risk of multiple vertebral fractures following its discontinuation...
March 15, 2018: Archives of Osteoporosis
L J Li, Y Z Guan, F Lü, Y W Song, X J Xu, Y Jiang, O Wang, W B Xia, X P Xing, M Li
Objective: To investigate the glucose and lipid metabolic disorders in patients with myasthenia gravis (MG) without glucocorticoid therapy, and the relationships between insulin, insulin resistance, muscle strength, serum levels of osteocalcin, 25-hydroxy vitamin D (25OHD) and glucose and lipid metabolism. Methods: A total of 102 MG patients [(40±11) years old, 43 males and 59 females] without glucocorticoid treatment were enrolled in this cross-sectional study. Height, weight and the handgrip of dominant hands were measured...
February 27, 2018: Zhonghua Yi Xue za Zhi [Chinese medical journal]
Maria Maiarù, Oakley B Morgan, Tianqi Mao, Michaela Breitsamer, Harry Bamber, Max Pöhlmann, Mathias V Schmidt, Gerhard Winter, Felix Hausch, Sandrine M Géranton
It is well-established that FKBP51 regulates the stress system by modulating the sensitivity of the glucocorticoid receptor to stress hormones. Recently, we have demonstrated that FKBP51 also drives long-term inflammatory pain states in male mice by modulating glucocorticoid-signalling at spinal cord level. Here, we explored the potential of FKBP51 as a new pharmacological target for the treatment of persistent pain across the sexes. First, we demonstrated that FKBP51 regulates long-term pain states of different aetiologies independently of sex...
March 12, 2018: Pain
(no author information available yet)
Chris S Earl, Teh Wooi Keong, Shi-qi An, Sarah Murdoch, Yvonne McCarthy, Junkal Garmendia, Joseph Ward, J Maxwell Dow, Liang Yang, George A O'Toole & Robert P RyanThe above article, published May 20 2015 in EMBO Molecular Medicine , has been retracted by agreement between the authors of the study, CSE, TWK, SQA, SM, YMcC, JG, JW, JMD, LY, RPR, the journal Chief Editor and the EMBO Head of Scientific Publications in accordance with the outcomes of independent investigations conducted by the University of Dundee and University College Cork...
March 12, 2018: EMBO Molecular Medicine
Elliot M Silver, William Ochoa
BACKGROUND Chronic intake of high-dose corticosteroids is associated with multiple adverse clinical effects, including hypertension, insulin resistance, impaired wound healing, immunosuppression, myopathy, and osteoporosis. In cases of autoimmune disease, use of steroid-sparing treatment modalities is preferred over chronic steroid therapy to limit these side effects. Glucocorticoid-induced myopathy is a less common side effect of chronic steroid use in patients treated with <10 mg/day of prednisone. However, doses exceeding 40-60 mg/day can induce clinically significant myopathy and weakness...
March 11, 2018: American Journal of Case Reports
Anna Kurek, Katarzyna Głombik, Jan Detka, Agnieszka Basta-Kaim, Marta Kubera, Władysław Lasoń, Bogusława Budziszewska
Obesity is a disease that often co-occurs with depression, and some evidence indicates that chronic stress in the perinatal period, in association with overactive glucocorticoids, can cause permanent changes that increase the risk of the development of both depression and obesity later in life. However, the mechanism responsible for the overly potent action of glucocorticoids in both depression and obesity is not known. The aim of the present study was to determine the expression of glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs) and the factors that affect GR function (FKBP51, Bag-1 and HSP70) in a prenatal stress animal model of depression, a model of obesity and a model of both depression and obesity...
March 9, 2018: Journal of Neuroendocrinology
A Bárbara Garcia-Garcia, S Martinez-Hervas, J T Real, P Marin-Garcia, G de Marco, A Priego, J F Martínez-Valls, R Carmena, F J Chaves, J F Ascaso
PURPOSE: Our aim was to evaluate the postprandial effect of an oral fat load test (OFLT) rich in unsaturated fatty acids on gene expression profile in peripheral blood mononuclear cells (PBMC) from subjects with abdominal obesity as an insulin resistance model and controls. METHODS: A total of 20 controls and 20 abdominal obese patients were studied. Metabolic parameters and oxidative stress markers were measured with standardized protocols. The whole gene expression at fasting state and after the OFLT (0, 4 and 8 h) was analysed using human HT-12-v4 expression beadchips, from Illumina...
March 8, 2018: European Journal of Nutrition
Rene Marke, Frank N van Leeuwen, Blanca Scheijen
Transcription factor IKZF1 (IKAROS) acts as a critical regulator of lymphoid differentiation and is frequently deleted or mutated in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). IKZF1 gene defects are associated with inferior treatment outcome in both childhood and adult BCP-ALL and occur in more than 70% of BCR-ABL1 positive and BCR-ABL1-like ALL cases. Over the past few years, much has been learned about the tumor suppressive function of IKZF1 during leukemia development and the molecular pathways that relate to its impact on treatment outcome...
March 8, 2018: Haematologica
Ágnes Molnár, Attila Patócs, István Likó, Gábor Nyírő, Károly Rácz, Miklós Tóth, Beatrix Sármán
BACKGROUND: Glucocorticoid resistance is a rare, sporadic or familial condition caused by mutation of the gene encoding the glucocorticoid receptor (GR). Clinically it is characterized by symptoms developed due to local, tissue-specific, or generalized partial insensitivity to glucocorticoids. CASE PRESENTATION: A 31-year-old woman was evaluated because of infertility at the Endocrine Unit of the 2nd Department of Medicine, Semmelweis University. During her laboratory investigations, elevated serum and salivary cortisol were observed which failed to be suppressed after administration of 1 mg dexamethasone...
March 6, 2018: BMC Medical Genetics
Xue Zhang, Wuping Bao, Xia Fei, Yingying Zhang, Guoqing Zhang, Xin Zhou, Min Zhang
Airway remodeling is a vital component of chronic obstructive pulmonary disease (COPD). Despite the broad anti-inflammation effects of glucocorticoids, they exhibit relatively little therapeutic benefit in COPD, indicating the accelerating demands of new agents for COPD. We aim to explore the effect of progesterone on airway remodeling in a murine modeling of exposing to ozone and to further examine the potential effect of progesterone on glucocorticoid insensitivity. C57/BL6 mice were exposed to ozone for 12 times over 6 weeks, and were administered with progesterone alone or combined with budesonide (BUD) after each exposure until the 10th week...
March 1, 2018: Molecular Immunology
Claudio Ponticelli, Francesco Locatelli
Glucocorticoids exert anti-inflammatory and immunosuppressive activities by genomic and nongenomic effects. The classic genomic effects are mediated by cytosolic glucocorticoid receptors that can upregulate the expression of anti-inflammatory proteins in the nucleus (transactivation) or repress the translocation of proinflammatory transcription factors from the cytosol into the nucleus (transrepression). The nongenomic effects are probably mediated by membrane glucocorticoid receptors. Glucocorticoid receptors are expressed also in podocytes and experimental data suggest that glucocorticoids may protect from podocyte injury...
February 23, 2018: Clinical Journal of the American Society of Nephrology: CJASN
Lei Lei, Yuanjie Mao
The common ultimate pathological feature for all cardiovascular diseases, congestive heart failure (CHF), is now considered as one of the main public health burdens that is associated with grave implications. Neurohormonal systems play a critical role in cardiovascular homeostasis, pathophysiology, and cardiovascular diseases. Hormone treatments such as the newly invented dual-acting drug valsartan/sacubitril are promising candidates for CHF, in addition to the conventional medications encompassing beta receptor blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists...
January 1, 2018: Journal of International Medical Research
Jianjun Wu, Xin Li, Yang Qin, Juan Cheng, Gaimei Hao, Ruifeng Jin, Chenjun Zhu
The aim of the present study was to investigate the effect of a Traditional Chinese Herbal Medicine (TCHM), named Jinwei Tang on histone deacetylase 2 (HDAC2) and its role in the regulation of corticosteroid resistance in a rat model of chronic obstructive pulmonary disease (COPD). Male Wistar rats were divided into five groups (each n=10): COPD group, established by the intratracheal instillation of lipopolysaccharide and passive smoke exposure, and control, budesonide, theophylline + budesonide and Jinwei Tang + budesonide groups...
March 2018: Experimental and Therapeutic Medicine
Zeyu Zeng, Xixi Lin, Rongying Zheng, Hui Zhang, Weixi Zhang
Severe airway hyperresponsiveness (AHR) is a clinical feature of asthma, which has been associated with obesity and has shown a poor response to standard asthma treatments such as glucocorticoids. Numerous studies have shown that Interleukin (IL)-17 producing CD4 + T cells (Th17 cells), which could be inhibited by celastrol, is essential in mediating steroid-resistant AHR. The following study investigates the impact of celastrol and its mechanism on the regulation of AHR in murine model of obesity and asthma...
2018: Frontiers in Pharmacology
Geraldine Vitellius, Séverine Trabado, Christine Hoeffel-Fornes, Jerome Bouligand, Antoine Bennet, Frédéric Castinetti, Bénédicte Decoudier, Anne Guiochon-Mantel, Marc Lombes, Brigitte Delemer
Recently discovered mutations of NR3C1 gene, encoding for the Glucocorticoid Receptor (GR), in patients with glucocorticoid resistance and bilateral adrenal incidentalomas prompted us to investigate whether GR mutations might be associated with adrenal hyperplasia. OBJECTIVE: The multicenter French Clinical Research Program (Muta-GR) was set up to determine the prevalence of GR mutations and polymorphisms in patients harboring bilateral adrenal incidentalomas associated with hypertension and/or biological hypercortisolism without clinical Cushing's signs...
February 14, 2018: European Journal of Endocrinology
Jungki Min, Lalith Perera, Juno M Krahn, Christine M Jewell, Andrea F Moon, John A Cidlowski, Lars C Pedersen
Glucocorticoid receptor β (GRβ) is associated with glucocorticoid resistance via dominant negative regulation of GRα. To better understand how GRβ functions as a dominant negative inhibitor of GRα at a molecular level, we determined the crystal structure of the ligand binding domain of GRβ complexed with antagonist RU-486. The structure reveals that RU-486 binds in the same ligand binding pocket as in GRα and the unique C-terminal amino acids of GRβ are mostly disordered. Binding energy analysis suggests that these C-terminal residues of GRβ do not contribute to RU-486 binding...
February 5, 2018: Molecular and Cellular Biology
Y Y Zhang, H F Lou, C S Wang, L Zhang
Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammatory disease that occurs in the nasal and sinus mucosa, which is a common disease in otorhinolaryngology. At present, CRSwNP can be effectively treated by glucocorticoids (GC). GC binds to GC receptors in the nasal mucosa, affects the expression of inflammatory genes, inhibits the activation and action of eosinophils, T cell-associated inflammatory responses in nasal polyps, as well as tissue remodeling. However, there are some patients fall reponse to GC, so called GC resistance...
February 7, 2018: Zhonghua Er Bi Yan Hou Tou Jing Wai Ke za Zhi, Chinese Journal of Otorhinolaryngology Head and Neck Surgery
Maria A Sacta, Bowranigan Tharmalingam, Maddalena Coppo, David A Rollins, Dinesh K Deochand, Bradley Benjamin, Li Yu, Bin Zhang, Xiaoyu Hu, Rong Li, Yurii Chinenov, Inez Rogatsky
The Glucocorticoid Receptor (GR) potently represses macrophage-elicited inflammation, however, the underlying mechanisms remain obscure. Our genome-wide analysis in mouse macrophages reveals that pro-inflammatory paused genes, activated via global negative elongation factor (NELF) dissociation and RNA Polymerase (Pol)2 release from early elongation arrest, and non-paused genes, induced by de novo Pol2 recruitment, are equally susceptible to acute glucocorticoid repression. Moreover, in both cases the dominant mechanism involves rapid GR tethering to p65 at NF-kB binding sites...
February 9, 2018: ELife
Xiaojing Wang, Jianli Shi, Deqiang Gong
OBJECTIVES: Acute lymphoblastic leukemia (ALL) is the most common cancer before the age of 15 years, seriously endangering the health of children. The main treatment for Childhood ALL was pharmacotherapy. But these drugs have many side effects and some of them could develop drug resistance quickly. Mometasone furoate (MF) is an efficient glucocorticoid for topical treatment of inflammation on the skin, lung and nose. METHODS: In this study, we investigated whether the MF had effects on ALL cells proliferation and migration...
February 8, 2018: Hematology (Amsterdam, Netherlands)
Roberta Bortolozzi, Elena Mattiuzzo, Luca Trentin, Benedetta Accordi, Giuseppe Basso, Giampietro Viola
Dysregulation of the cyclin D1-CDK4/CDK6 complex is frequently observed in almost all human cancer and contributes to aberrant cell proliferation and consequent tumorigenesis. Although many reports described the importance of CDK4/CDK6 in different set of human tumors, only few studies have been performed on leukemia. By gene expression analysis performed in a cohort of childhood patients affected by B-acute lymphoblastic leukemia (B-ALL) we found that both CDK4 and CDK6 are highly expressed. Moreover, Reverse Phase Protein Array (RPPA) analysis showed that cyclin D1 levels are higher in patients undergoing relapse...
February 3, 2018: Biochemical Pharmacology
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