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Glucocorticoid resistance

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https://www.readbyqxmd.com/read/28433687/steroid-resistance-of-airway-type-2-innate-lymphoid-cells-ilc2s-from-severe-asthma-the-role-of-thymic-stromal-cell-lymphopoietin-tslp
#1
Sucai Liu, Mukesh Verma, Lidia Michalec, Weimin Liu, Anand Sripada, Donald Rollins, James Good, Yoko Ito, HongWei Chu, Magdalena M Gorska, Richard J Martin, Rafeul Alam
BACKGROUND: ILC2s represent an important type 2 immune cell. Glucocorticoid regulation of human ILC2s is largely unknown. OBJECTIVE: To assess steroid resistance of human blood and airway ILC2s from asthmatic patients and examine its mechanism of induction. METHODS: We studied human blood and lung ILC2s from asthmatic and control subjects by flow cytometry and ELISA. RESULTS: Dexamethasone (Dex) inhibited (P=0.04) CRTH2 and type 2 cytokine expression by blood ILC2s stimulated with IL25 and IL33...
April 19, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28432472/anti-infective-and-anti-inflammatory-pharmacotherapies
#2
Mark I Rosenblatt
Ocular infection and inflammation are common and are associated with myriad ocular conditions ranging from mild disease to blinding conditions. There are numerous anti-invectives with spectra against inciting pathogens. Given the potential for ocular infections to rapidly progress initial broad spectrum therapy is usually required, with therapy tailored as microbiological identification and sensitivities become available. The emergence of antibiotic resistance has become a major health problem. Anti-inflammatory therapy can be institutes to prevent ocular symptoms and end-organ damage...
April 22, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28428441/selective-glucocorticoid-receptor-modulators-sgrms-delay-castrate-resistant-prostate-cancer-growth
#3
Jacob Kach, Tiha M Long, Phillip Selman, Eva Y Tonsing-Carter, Maria A Bacalao, Ricardo R Lastra, Larischa de Wet, Shane Comiskey, Marc Gillard, Calvin VanOpstall, Diana C West, Wen-Ching Chan, Donald Vander Griend, Suzanne D Conzen, Russell Z Szmulewitz
Increased glucocorticoid receptor (GR) expression and activity following androgen blockade can contribute to castration-resistant prostate cancer (CRPC) progression. Therefore, we hypothesized that GR antagonism will have therapeutic benefit in CRPC. However, the FDA-approved nonselective, steroidal GR antagonist, mifepristone, lacks GR specificity, reducing its therapeutic potential. Here we report that two novel non-steroidal and highly selective GR modulators (SGRMs), CORT118335 and CORT108297, have the ability to block GR activity in prostate cancer (PC) and slow CRPC progression...
April 20, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28424165/suppression-of-b-cell-development-genes-is-key-to-glucocorticoid-efficacy-in-treatment-of-acute-lymphoblastic-leukemia
#4
Karina Kruth, Mimi Fang, Dawne N Shelton, Ossama Abu-Halawa, Ryan Mahling, Hongxing Yang, Jonathan S Weissman, Mignon L Loh, Markus Müschen, Sarah K Tasian, Michael C Bassik, Martin Kampmann, Miles A Pufall
Glucocorticoids (GCs), including dexamethasone (dex), are a central component of combination chemotherapy for childhood B-cell precursor acute lymphoblastic leukemia (B-ALL). GCs work by activating the glucocorticoid receptor (GR), a ligand-induced transcription factor, which in turn regulates genes that induce leukemic cell death. Which GR-regulated genes are required for GC cytotoxicity, which pathways affect their regulation, and how resistance arises are not well understood. Here we systematically integrate the transcriptional response of B-ALL to GCs with a next-generation shRNA screen to identify GC-regulated "effector" genes that contribute to cell death as well as genes that affect the sensitivity of B-ALL cells to dex...
April 19, 2017: Blood
https://www.readbyqxmd.com/read/28423696/improvement-of-dexamethasone-sensitivity-by-chelation-of-intracellular-ca2-in-pediatric-acute-lymphoblastic-leukemia-cells-through-the-prosurvival-kinase-erk1-2-deactivation
#5
Souleymane Abdoul-Azize, Isabelle Dubus, Jean-Pierre Vannier
Previous studies have demonstrated that glucocorticoid hormones, including dexamethasone, induced alterations in intracellular calcium homeostasis in acute lymphoblastic leukemia (ALL) cells. However, the mechanism by which intracellular calcium homeostasis participates in dexamethasone sensitivity and resistance on ALL cells remains elusive. Here, we found that treatment of cells with dexamethasone resulted in increased intracellular calcium concentrations through store-operated calcium entry stimulation, which was curtailed by store-operated calcium channel blockers...
March 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28422753/steroid-metabolome-analysis-reveals-prevalent-glucocorticoid-excess-in-primary-aldosteronism
#6
Wiebke Arlt, Katharina Lang, Alice J Sitch, Anna S Dietz, Yara Rhayem, Irina Bancos, Annette Feuchtinger, Vasileios Chortis, Lorna C Gilligan, Philippe Ludwig, Anna Riester, Evelyn Asbach, Beverly A Hughes, Donna M O'Neil, Martin Bidlingmaier, Jeremy W Tomlinson, Zaki K Hassan-Smith, D Aled Rees, Christian Adolf, Stefanie Hahner, Marcus Quinkler, Tanja Dekkers, Jaap Deinum, Michael Biehl, Brian G Keevil, Cedric H L Shackleton, Jonathan J Deeks, Axel K Walch, Felix Beuschlein, Martin Reincke
BACKGROUND: Adrenal aldosterone excess is the most common cause of secondary hypertension and is associated with increased cardiovascular morbidity. However, adverse metabolic risk in primary aldosteronism extends beyond hypertension, with increased rates of insulin resistance, type 2 diabetes, and osteoporosis, which cannot be easily explained by aldosterone excess. METHODS: We performed mass spectrometry-based analysis of a 24-hour urine steroid metabolome in 174 newly diagnosed patients with primary aldosteronism (103 unilateral adenomas, 71 bilateral adrenal hyperplasias) in comparison to 162 healthy controls, 56 patients with endocrine inactive adrenal adenoma, 104 patients with mild subclinical, and 47 with clinically overt adrenal cortisol excess...
April 20, 2017: JCI Insight
https://www.readbyqxmd.com/read/28421158/cytotoxicity-of-zardaverine-in-embryonal-rhabdomyosarcoma-from-a-costello-syndrome-patient
#7
Donna M Cartledge, Katherine M Robbins, Katherine M Drake, Rachel Sternberg, Deborah L Stabley, Karen W Gripp, E Anders Kolb, Katia Sol-Church, Andrew D Napper
Costello syndrome (CS) patients suffer from a very high 10% incidence of embryonal rhabdomyosarcoma (ERMS). As tools to discover targeted therapeutic leads, we used a CS patient-derived ERMS cell line (CS242 ERMS) harboring a homozygous p.G12A mutation in HRAS, and a control cell line derived from the same patient comprising non-malignant CS242 fibroblasts with a heterozygous p.G12A HRAS mutation. A library of 2,000 compounds with known pharmacological activities was screened for their effect on CS242 ERMS cell viability...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28415682/low-dose-of-2-deoxy-d-glucose-kills-acute-lymphoblastic-leukemia-cells-and-reverses-glucocorticoid-resistance-via-n-linked-glycosylation-inhibition-under-normoxia
#8
Ling Gu, Zhihui Yi, Yanle Zhang, Zhigui Ma, Yiping Zhu, Ju Gao
Recent studies showed that 2-deoxy-D-glucose (2-DG), a glucose analog with dual activity of inhibiting glycolysis and N-linked glycosylation, can be selectively taken up by cancer cells and be used as a potential chemo- and radio-sensitizer. Meanwhile, 2-DG can kill cancer cells under normoxia. However, its efficacy is limited by the high-dose induced systemic toxicity. Here, we showed that low-dose 2-DG could be used as a single agent to kill acute lymphoblastic leukemia (ALL) cells, and as a GC sensitizer to overcome GC resistance under normoxia...
March 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28408143/tetrandrine-potentiates-the-glucocorticoid-pharmacodynamics-via-inhibiting-p-glycoprotein-and-mitogen-activated-protein-kinase-in-mitogen-activated-human-peripheral-blood-mononuclear-cells
#9
Wencheng Xu, Kehan Meng, Yuanchao Tu, Sachiko Tanaka, Kenji Onda, Kentaro Sugiyama, Toshihiko Hirano, Haruki Yamada
Glucocorticoids play significant roles in treatments of inflammatory and autoimmune diseases. Some patients show a poor or absent response even to high doses of glucocorticoids. The purpose of this study was to explore whether tetrandrine combined with glucocorticoids could be a new treatment strategy to resolve glucocorticoids resistance. Information on glucocorticoids sensitivity was usually obtained through mitogen-activated human peripheral blood mononuclear cells in cell culture procedures. Thus, human peripheral blood mononuclear cells was chosen as a model to study the immunosuppressive effect of methylprednisolone combined with tetrandrine, including the possible action mechanisms...
April 10, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28400163/stress-before-extinction-learning-enhances-and-generalizes-extinction-memory-in-a-predictive-learning-task
#10
Shira Meir Drexler, Tanja C Hamacher-Dang, Oliver T Wolf
In extinction learning, the individual learns that a previously acquired association (e.g. between a threat and its predictor) is no longer valid. This learning is the principle underlying many cognitive-behavioral psychotherapeutic treatments, e.g. 'exposure therapy'. However, extinction is often highly-context dependent, leading to renewal (relapse of extinguished conditioned response following context change). We have previously shown that post-extinction stress leads to a more context-dependent extinction memory in a predictive learning task...
April 8, 2017: Neurobiology of Learning and Memory
https://www.readbyqxmd.com/read/28397446/glucocorticoid-receptor-polymorphism-in-obesity-and-glucose-homeostasis
#11
REVIEW
Agnieszka Majer-Łobodzińska, Joanna Adamiec-Mroczek
Glucocorticoid receptor (GR) activity plays a significant role in the etiology of obesity and is essential for glucose homeostasis, the development of hyperinsulinaemia and subsequent increased fat deposition. Several polymorphisms in the GR gene have been described, and at least three of them seem to be associated with altered glucocorticoid sensitivity and changes in glucose homeostasis, and other metabolic parameters. The N363S polymorphism has been associated with increased sensitivity to glucocorticoides, increased insulin response to dexamethasone and increased plasma glucose level...
January 2017: Advances in Clinical and Experimental Medicine: Official Organ Wroclaw Medical University
https://www.readbyqxmd.com/read/28384165/ramadan-fasting-in-saudi-arabia-is-associated-with-altered-expression-of-clock-dusp-and-il-1alpha-genes-as-well-as-changes-in-cardiometabolic-risk-factors
#12
Ghada M A Ajabnoor, Suhad Bahijri, Noor Ahmad Shaik, Anwar Borai, Aliaa A Alamoudi, Jumana Y Al-Aama, George P Chrousos
BACKGROUND: During the fasting month of Ramadan, practicing Saudis develop severe disturbances in sleeping and feeding patterns. Concomitantly, cortisol circadian rhythm is abolished, diurnal cortisol levels are elevated and circulating levels of several adipokines are altered favouring insulin resistance. AIM: To examine changes in the expression of CLOCK and glucocorticoid-controlled genes, such as DUSP1 and IL-1α in Saudi adults before and during Ramadan, and to investigate possible associations with selected cardiometabolic risk factors...
2017: PloS One
https://www.readbyqxmd.com/read/28383396/role-of-endoscopic-esophageal-dilation-in-managing-eosinophilic-esophagitis-a-systematic-review-and-meta-analysis
#13
Harsha Moole, Kavitha Jacob, Abhiram Duvvuri, Vishnu Moole, Sowmya Dharmapuri, Raghuveer Boddireddy, Achuta Uppu, Srinivas R Puli
BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disorder of the esophagus characterized by mucosal eosinophilic infiltration. Topical glucocorticoids are considered standard line of treatment, whereas endoscopic dilations are performed for patients presenting with treatment-resistant disease or manifestations of dysphagia and/or food impactions. Efficacy and safety of esophageal dilation in these patients are currently unclear. AIMS: Primary outcomes were to evaluate the efficacy, adverse events, and mortality rates of endoscopic esophageal dilation in patients with EoE...
April 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/28383056/involvement-of-epithelial-na-channel-in-the-elevated-myogenic-response-in-posterior-cerebral-arteries-from-spontaneously-hypertensive-rats
#14
Soo-Kyoung Choi, Soo-In Yeon, Youngin Kwon, Seonhee Byeon, Young-Ho Lee
Hypertension is characterized by increased peripheral vascular resistance which is related with elevated myogenic response. Recent findings have indicated that epithelial sodium channel (ENaC) is involved in mechanotransduction of the myogenic response. The purpose of this study was to investigate the involvement of ENaC in the elevated myogenic response of posterior cerebral arteries (PCAs) from spontaneously hypertensive rats (SHRs). Sixteen to eighteen weeks old male wistar kyoto rats (WKYs) and SHRs were used in this study...
April 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28380330/to-stress-or-not-to-stress-physiological-responses-to-tetrodotoxin-in-resistant-gartersnakes-vary-by-sex
#15
Lorin A Neuman-Lee, Edmund D Brodie, Tyler Hansen, Edmund D Brodie, Susannah S French
The activation of the hypothalamic pituitary adrenal (HPA) axis is one of the most important physiological processes in coping with any deviation in an organism's homeostasis. This activation and the secretion of glucocorticoids, such as corticosterone, allow organisms to cope with perturbations and return to optimal physiological functioning as quickly as possible. In this study, we examined the HPA axis activation in Common gartersnakes (Thamnophis sirtalis) as a response to a natural toxin, tetrodotoxin (TTX)...
April 2, 2017: Comparative Biochemistry and Physiology. Part A, Molecular & Integrative Physiology
https://www.readbyqxmd.com/read/28379591/fatty-liver-and-drugs-the-two-sides-of-the-same-coin
#16
L Miele, A Liguori, G Marrone, M Biolato, C Araneo, F G Vaccaro, A Gasbarrini, A Grieco
Drug-induced liver injury (DILI) is a common and underestimated cause of liver disease. Several drugs and other xenobiotics can be the cause of different clinicopathologic patterns of liver disease. Steatosis and steatohepatitis are rare but well-documented types of DILI. Over the past decades commonly used drugs like amiodarone, tamoxifen, irinotecan, methotrexate, valproic acid and glucocorticoids have been recognized to be associated with steatosis. Even though the pathophysiological pathways are still only partially understood, inhibition of mitochondrial beta-oxidation, reduced very low-density lipoprotein secretion, insulin resistance induction and increased de novo synthesis or increased liver uptake of fatty acids are considered the main pathogenic mechanisms through which drugs can lead to hepatic steatosis...
March 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/28368470/11%C3%AE-hsd1-modulates-the-set-point-of-brown-adipose-tissue-response-to-glucocorticoids-in-male-mice
#17
Craig L Doig, Rachel S Fletcher, Stuart A Morgan, Emma L McCabe, Dean P Larner, Jeremy W Tomlinson, Paul M Stewart, Andrew Philp, Gareth G Lavery
Glucocorticoids are potent regulators of energy metabolism. Chronic glucocorticoid exposure supresses brown adipose tissue (BAT) thermogenic capacity in mice, with evidence for a similar effect in humans. Intracellular glucocorticoid levels are regulated by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity which can amplify circulating glucocorticoid concentrations. Therefore, 11β-HSD1 could modulate the impact of glucocorticoids on BAT function. Here we investigate how 11β-HSD1 regulates the molecular architecture of BAT in the context of glucocorticoid excess and aging...
March 27, 2017: Endocrinology
https://www.readbyqxmd.com/read/28368468/chronic-mild-stress-causes-bone-loss-via-an-osteoblast-specific-glucocorticoid-dependent-mechanism
#18
Holger Henneicke, Jingbao Li, Sarah Kim, Sylvia J Gasparini, Markus J Seibel, Hong Zhou
Chronic stress and depression are associated with alterations in the hypothalamic-pituitary-adrenal signalling cascade and considered a risk factor for bone loss and fractures. However, the mechanisms underlying the association between stress and poor bone health are unclear. Utilising a transgenic (tg) mouse model in which glucocorticoid signalling is selectively disrupted in mature osteoblasts and osteocytes (HSD2OB-tg mice), the current study examines the impact of chronic stress on skeletal metabolism and structure...
March 22, 2017: Endocrinology
https://www.readbyqxmd.com/read/28364356/diabetes-in-cushing-disease
#19
REVIEW
G Mazziotti, A M Formenti, S Frara, F Maffezzoni, M Doga, A Giustina
PURPOSE OF REVIEW: This review focuses on the pathophysiological and clinical aspects of diabetes mellitus occurring in patients with Cushing disease (CD). RECENT FINDINGS: Insulin resistance and impairment in insulin secretion are both involved in the pathogenesis of glucocorticoid-induced diabetes. Correction of glucocorticoid excess does not always resolve abnormalities of glucose homeostasis, and correction of hyperglycaemia is specifically required. In fact, insulin resistance may persist even after correction of glucocorticoid excess and diabetes needs to be treated for long term...
May 2017: Current Diabetes Reports
https://www.readbyqxmd.com/read/28363435/caffeic-acid-phenethyl-ester-protects-against-glucocorticoid-induced-osteoporosis-in-vivo-impact-on-oxidative-stress-and-rankl-opg-signals
#20
Mai F Tolba, Ahmed T El-Serafi, Hany A Omar
Glucocorticoid-induced osteoporosis (GIO) is one of the most common causes of secondary osteoporosis. Given that glucocorticoids are considered as a main component of the treatment protocols for a variety of inflammation and immune-mediated diseases besides its use as adjuvant to several chemotherapeutic agents, it is crucial to find ways to overcome this critical adverse effect. Caffeic acid phenethyl ester (CAPE), which is a natural compound derived from honeybee propolis displayed promising antiosteoporotic effects against mechanical bone injury in various studies...
March 29, 2017: Toxicology and Applied Pharmacology
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