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Glucocorticoid resistance

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https://www.readbyqxmd.com/read/28202869/treatment-of-vasodilator-resistant-mixed-connective-tissue-disease-associated-pulmonary-arterial-hypertension-with-glucocorticoid-and-cyclophosphamide
#1
Eri Sugawara, Masaru Kato, Ryo Hisada, Kenji Oku, Toshiyuki Bohgaki, Tetsuya Horita, Shinsuke Yasuda, Tatsuya Atsumi
Pulmonary arterial hypertension (PAH) associated with systemic lupus erythematosus (SLE) or mixed connective tissue disease (MTCD), in contrast to other types of PAH, may respond to immunosuppressive therapy. Most PAH cases with an immunosuppressant response were in the early stages of the disease (WHO functional class III or less). The present case was a 34-year-old woman with MCTD-associated PAH (WHO functional class IV) who was resistant to a combination of three vasodilators. Afterwards, she was treated with glucocorticoid and cyclophosphamide...
2017: Internal Medicine
https://www.readbyqxmd.com/read/28199000/overexpression-of-pregnane-x-and-glucocorticoid-receptors-and-the-regulation-of-cytochrome-p450-in-human-epileptic-brain-endothelial-cells
#2
Chaitali Ghosh, Mohammed Hossain, Jesal Solanki, Imad M Najm, Nicola Marchi, Damir Janigro
OBJECTIVE: Recent evidence suggests a metabolic contribution of cytochrome P450 enzymes (CYPs) to the drug-resistant phenotype in human epilepsy. However, the upstream molecular regulators of CYP in the epileptic brain remain understudied. We therefore investigated the expression and function of pregnane xenobiotic (PXR) and glucocorticoid (GR) nuclear receptors in endothelial cells established from post-epilepsy surgery brain samples. METHODS: PXR/GR localization was evaluated by immunohistochemistry in specimens from subjects who underwent temporal lobe resections to relieve drug-resistant seizures...
February 15, 2017: Epilepsia
https://www.readbyqxmd.com/read/28196872/muc16-regulates-tspyl5-for-lung-cancer-cell-growth-and-chemoresistance-by-suppressing-p53
#3
Imayavaramban Lakshmanan, Shireen Salfity, Parthasarathy Seshacharyulu, Satyanarayana Rachagani, Abigail Thomas, Srustidhar Das, Prabin D Majhi, Rama Krishna Nimmakayala, Raghupathy Vengoji, Subodh M Lele, Moorthy P Ponnusamy, Surinder K Batra, Apar Kishor Ganti
PURPOSE: MUC16, a tumor biomarker and cell surface associated mucin, is overexpressed in various cancers; however, its role in lung cancer pathogenesis is unknown. Here, we have explored the mechanistic role of MUC16 in lung cancer. EXPERIMENTAL DESIGN: To identify the functional role of MUC16, stable knockdown was carried in lung cancer cells with two different shRNAs. Clinical significance of MUC16 was evaluated in lung cancer patient's tissues using IHC. We have generated genetically engineered mouse model (KrasG12D; AdCre) to evaluate the preclinical significance of MUC16...
February 14, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28191869/aberrant-corticosteroid-metabolism-in-tumor-cells-enables-gr-takeover-in-enzalutamide-resistant-prostate-cancer
#4
Jianneng Li, Mohammad Alyamani, Ao Zhang, Kai-Hsiung Chang, Michael Berk, Zhenfei Li, Ziqi Zhu, Marianne Petro, Cristina Magi-Galluzzi, Mary-Ellen Taplin, Jorge A Garcia, Kevin Courtney, Eric A Klein, Nima Sharifi
Prostate cancer is driven by androgen stimulation of the androgen receptor (AR). The next-generation AR antagonist, enzalutamide, prolongs survival, but resistance and lethal disease eventually prevail. Emerging data suggest that the glucocorticoid receptor (GR) is upregulated in this context, stimulating expression of AR-target genes that permit continued growth despite AR blockade. However, countering this mechanism by administration of GR antagonists is problematic because GR is essential for life. We show that enzalutamide treatment in human models of prostate cancer and patient tissues is accompanied by a ubiquitin E3-ligase, AMFR, mediating loss of 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2), which otherwise inactivates cortisol, sustaining tumor cortisol concentrations to stimulate GR and enzalutamide resistance...
February 13, 2017: ELife
https://www.readbyqxmd.com/read/28186655/chronic-transgenerational-vitamin-b12-deficiency-of-severe-and-moderate-magnitudes-modulates-adiposity-probable-underlying-mechanisms
#5
Shampa Ghosh, Jitendra Kumar Sinha, Bojanapalli Muralikrishna, Uday Kumar Putcha, Manchala Raghunath
We have demonstrated previously that severe but not moderate vitamin B12 deficiency altered body composition and induced adiposity in female C57BL/6 mice. This study aims to elucidate the effects of chronic transgenerational dietary vitamin B12 restriction on body composition and various biochemical parameters in the F1 generation offspring of our mouse models of severe and moderate vitamin B12 deficiency established earlier. Female weanling C57BL/6 mice received, ad libitum, for 4 weeks a (i) control diet, (ii) vitamin B12-restricted diet with pectin as dietary fiber (severely deficient diet), or (iii) vitamin B12-restricted diet with cellulose as dietary fiber (moderately deficient diet) and then mated with control males...
February 10, 2017: BioFactors
https://www.readbyqxmd.com/read/28185649/treatment-by-rituximab-on-six-grave-s-ophthalmopathies-resistant-to-corticosteroids
#6
Flavien Précausta, Sophie Arsène, Peggy Renoult-Pierre, Boris Laure, Lise Crinière, Pierre-Jean Pisella
OBJECTIVES: Graves' ophthalmopathy occurs in 50% of Graves' disease cases. Treatment is based on smoking cessation, and control of the euthyroidism and ocular repercussions associated with the disease. The active orbital forms are treated with glucocorticoids. Non-validated therapies have also been recently tested. Rituximab has been effectively used several times to treat corticosteroid-resistant Graves' ophthalmopathy associated with an optic neuropathy, but its use could be proposed only in inflammatory ophthalmopathies after failure of the corticosteroids...
February 6, 2017: Annales D'endocrinologie
https://www.readbyqxmd.com/read/28177189/acute-physiological-effects-of-glucocorticoids-on-fuel-metabolism-in-humans-are-permissive-but-not-direct
#7
Roland H Stimson, Anna J Anderson, Lynne E Ramage, David P Macfarlane, Andrew C de Beaux, Damian J Mole, Ruth Andrew, Brian R Walker
BACKGROUND AND AIMS: The effects of glucocorticoids on fuel metabolism are complex. Acute glucocorticoid excess promotes lipolysis but chronic glucocorticoid excess causes visceral fat accumulation. We hypothesized that interactions between cortisol with insulin and adrenaline accounts for these conflicting results. We tested the effect of cortisol on lipolysis and glucose production with and without insulin and adrenaline in humans both in vivo and in vitro. MATERIALS AND METHODS: Twenty healthy men were randomised to low and high insulin groups (both n = 10)...
February 8, 2017: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/28174265/sgk3-sustains-er%C3%AE-signaling-and-drives-acquired-aromatase-inhibitor-resistance-through-maintaining-endoplasmic-reticulum-homeostasis
#8
Yuanzhong Wang, Dujin Zhou, Sheryl Phung, Charles Warden, Rumana Rashid, Nymph Chan, Shiuan Chen
Many estrogen receptor alpha (ERα)-positive breast cancers initially respond to aromatase inhibitors (AIs), but eventually acquire resistance. Here, we report that serum- and glucocorticoid-inducible kinase 3 (SGK3), a kinase transcriptionally regulated by ERα in breast cancer, sustains ERα signaling and drives acquired AI resistance. SGK3 is up-regulated and essential for endoplasmic reticulum (EnR) homeostasis through preserving sarcoplasmic/EnR calcium ATPase 2b (SERCA2b) function in AI-resistant cells...
February 7, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28168446/comparing-the-rules-of-engagement-of-androgen-and-glucocorticoid-receptors
#9
REVIEW
Frank Claessens, Steven Joniau, Christine Helsen
Despite the diverse physiological activities of androgens and glucocorticoids, the corresponding receptors are very close members of the nuclear-receptor super family. Their action mechanisms show striking similarities, since both receptors recognize very similar DNA-response elements and recruit the same coactivators to their target genes. The specificity of the responses lies mainly in the tissue-specific expression of the receptors and in their ligand specificity. In cells, where both receptors are expressed, the mechanisms leading to the difference in target genes are less obvious...
February 6, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28162182/-therapeutic-effects-of-histone-deacetylase-inhibitor-givinostat-on-air-inflammation-and-high-airway-resistance-in-a-murine-asthma-model
#10
X M Su, Y Ren, L F Kong, J Kang
Objective: To investigate the therapeutic effects of givinostat, a histone deacetylase inhibitor (HDACI), on the development of chronic asthma with airway inflammation, airway remodeling and airway hyperresponsiveness (AHR). Methods: BALB/C mice were randomly divided into control group, asthma group, dexamethasone group and givinostat group (n=12 per group). AHR was assessed. Total cell numbers and differential counts, interleukin-4(IL-4), interleukin-5(IL-5) and interferon-γ (IFNγ) levels in the bronchoalveolar lavage fluid (BALF) were measured in the above 4 groups...
February 1, 2017: Zhonghua Nei Ke za Zhi [Chinese Journal of Internal Medicine]
https://www.readbyqxmd.com/read/28139699/genome-wide-regulatory-roles-of-the-c2h2-type-zinc-finger-protein-znf764-on-the-glucocorticoid-receptor
#11
Abeer Fadda, Najeeb Syed, Rafah Mackeh, Anna Papadopoulou, Shigeru Suzuki, Puthen V Jithesh, Tomoshige Kino
The C2H2-type zinc finger protein ZNF764 acts as an enhancer for several steroid hormone receptors, and haploinsufficiency of this gene may be responsible for tissue resistance to multiple steroid hormones including glucocorticoids observed in a patient with 16p11.2 microdeletion. We examined genome-wide regulatory actions of ZNF764 on the glucocorticoid receptor (GR) in HeLa cells as a model system. ZNF764- and GR-binding sites demonstrated similar distribution in various genomic features. They positioned predominantly around 50-500 kbs from the transcription start sites of their nearby genes, and were closely localized with each other, overlapping in ~37% of them...
January 31, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28132103/polymorphisms-in-the-multidrug-resistance-1-gene-related-to-glucocorticoid-response-in-rheumatoid-arthritis-treatment
#12
Bart V J Cuppen, Katerina Pardali, Maarten C Kraan, Anne C A Marijnissen, Linda Yrlid, Marita Olsson, Johannes W J Bijlsma, Floris P J G Lafeber, Ruth D E Fritsch-Stork
A substantial proportion of rheumatoid arthritis (RA)-patients experience an insufficient response to glucocorticoids, an important therapeutic agent in RA. The multidrug-resistance 1 (MDR1) gene product P-glycoprotein (P-gp) is an efflux pump that actively transports substrates, such as glucocorticoids, out of the cell. We investigated if the variation in response might be explained by single-nucleotide polymorphisms (SNPs) in the MDR1 gene. RA-patients treated with intravenous methylprednisolone pulses (n = 18) or oral prednisone/prednisolone (n = 22) were included in a prospective cohort, and clinical response was measured after 5 and 30 days, respectively...
January 28, 2017: Rheumatology International
https://www.readbyqxmd.com/read/28117531/late-onset-circulatory-collapse-of-prematurity
#13
Masahiko Kawai
Some very-low-birth-weight (VLBW) infants develop refractory hypotension, which is resistant to intravenous volume expanders and inotropes, but responds to exogenous glucocorticoid dramatically.(1-8) Such refractory hypotension usually occurs just after birth or within the early neonatal period (<Day 7). However, cases of refractory hypotension after the early neonatal period (>Day 7) have been reported since 2000 in Japan.(9) In typical cases, infants are stabilized for a period within the early neonatal period, and the sudden onset of circulatory collapse then subsequently occurs...
January 24, 2017: Pediatrics International: Official Journal of the Japan Pediatric Society
https://www.readbyqxmd.com/read/28112586/genetic-variation-in-the-glucocorticoid-pathway-involved-in-interindividual-differences-in-the-glucocorticoid-treatment
#14
Qian-Qian Song, Wan-Ying Xie, Yong-Jun Tang, Jun Zhang, Jie Liu
Glucocorticoids (GCs) are widely used for treating asthma, rheumatoid arthritis, nephrotic syndrome, acute lymphoblastic leukemia and other autoimmune diseases. However, in a subgroup of patients, failure to respond to GCs is known as GC resistance or GC insensitivity. This represents an important barrier to effective treatment and a clinical problem requiring an urgent solution. Genetic variation in the GC pathway is a significant factor in interindividual differences in GC treatment. This article reviews the pharmacogenetics of GCs in diverse diseases based on the GC pathway...
February 2017: Pharmacogenomics
https://www.readbyqxmd.com/read/28112071/early-life-programming-and-the-risk-of-non-alcoholic-fatty-liver-disease
#15
C Lynch, C S Chan, A J Drake
Non-alcoholic fatty liver disease (NAFLD) is associated with obesity, insulin resistance, type 2 diabetes and cardiovascular disease and can be considered the hepatic manifestation of the metabolic syndrome. NAFLD represents a spectrum of disease, from the relatively benign simple steatosis to the more serious non-alcoholic steatohepatitis, which can progress to liver cirrhosis, hepatocellular carcinoma and end-stage liver failure, necessitating liver transplantation. Although the increasing prevalence of NAFLD in developed countries has substantial implications for public health, many of the precise mechanisms accounting for the development and progression of NAFLD are unclear...
January 23, 2017: Journal of Developmental Origins of Health and Disease
https://www.readbyqxmd.com/read/28091621/differential-susceptibility-and-maturation-of-thymocyte-subsets-during-salmonella-typhimurium-infection-insights-on-the-roles-of-glucocorticoids-and-interferon-gamma
#16
Shamik Majumdar, Mukta Deobagkar-Lele, Vasista Adiga, Abinaya Raghavan, Nitin Wadhwa, Syed Moiz Ahmed, Supriya Rajendra Rananaware, Subhashish Chakraborty, Omana Joy, Dipankar Nandi
The thymus is known to atrophy during infections; however, a systematic study of changes in thymocyte subpopulations has not been performed. This aspect was investigated, using multi-color flow cytometry, during oral infection of mice with Salmonella Typhimurium (S. Typhimurium). The major highlights are: First, a block in the developmental pathway of CD4(-)CD8(-) double negative (DN) thymocytes is observed. Second, CD4(+)CD8(+) double positive (DP) thymocytes, mainly in the DP1 (CD5(lo)CD3(lo)) and DP2 (CD5(hi)CD3(int)), but not DP3 (CD5(int)CD3(hi)), subsets are reduced...
January 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28069826/endostatin-inhibits-androgen-independent-prostate-cancer-growth-by-suppressing-nuclear-receptor-mediated-oxidative-stress
#17
Joo Hyoung Lee, Minsung Kang, Hong Wang, Gurudatta Naik, James A Mobley, Guru Sonpavde, W Timothy Garvey, Victor M Darley-Usmar, Selvarangan Ponnazhagan
Androgen-deprivation therapy has been identified to induce oxidative stress in prostate cancer (PCa), leading to reactivation of androgen receptor (AR) signaling in a hormone-refractory manner. Thus, antioxidant therapies have gained attention as adjuvants for castration-resistant PCa. Here, we report for the first time that human endostatin (ES) prevents androgen-independent growth phenotype in PCa cells through its molecular targeting of AR and glucocorticoid receptor (GR) and downstream pro-oxidant signaling...
January 9, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28068412/a-comparison-of-gene-expression-profiles-between-glucocorticoid-responder-and-non-responder-bovine-trabecular-meshwork-cells-using-rna-sequencing
#18
Jaclyn Y Bermudez, Hannah C Webber, Bartley Brown, Terry A Braun, Abbot F Clark, Weiming Mao
The most common ocular side effect of glucocorticoid (GC) therapy is GC-induced ocular hypertension (OHT) and GC-induced glaucoma (GIG). GC-induced OHT occurs in about 40% of the general population, while the other 60% are resistant. This study aims to determine the genes and pathways involved in differential GC responsiveness in the trabecular meshwork (TM). Using paired bovine eyes, one eye was perfusion-cultured with 100nM dexamethasone (DEX), while the fellow eye was used to establish a bovine TM (BTM) cell strain...
2017: PloS One
https://www.readbyqxmd.com/read/28061324/oral-corticosterone-administration-reduces-insulitis-but-promotes-insulin-resistance-and-hyperglycemia-in-male-nonobese-diabetic-mice
#19
Susan J Burke, Heidi M Batdorf, Adrianna E Eder, Michael D Karlstad, David H Burk, Robert C Noland, Z Elizabeth Floyd, J Jason Collier
Steroid-induced diabetes is the most common form of drug-induced hyperglycemia. Therefore, metabolic and immunological alterations associated with chronic oral corticosterone were investigated using male nonobese diabetic mice. Three weeks after corticosterone delivery, there was reduced sensitivity to insulin action measured by insulin tolerance test. Body composition measurements revealed increased fat mass and decreased lean mass. Overt hyperglycemia (>250 mg/dL) manifested 6 weeks after the start of glucocorticoid administration, whereas 100% of the mice receiving the vehicle control remained normoglycemic...
January 4, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28046097/glucocorticoid-insensitivity-in-virally-infected-airway-epithelial-cells-is-dependent-on-transforming-growth-factor-%C3%AE-activity
#20
Yuxiu C Xia, Asmaa Radwan, Christine R Keenan, Shenna Y Langenbach, Meina Li, Danica Radojicic, Sarah L Londrigan, Rosa C Gualano, Alastair G Stewart
Asthma and chronic obstructive pulmonary disease (COPD) exacerbations are commonly associated with respiratory syncytial virus (RSV), rhinovirus (RV) and influenza A virus (IAV) infection. The ensuing airway inflammation is resistant to the anti-inflammatory actions of glucocorticoids (GCs). Viral infection elicits transforming growth factor-β (TGF-β) activity, a growth factor we have previously shown to impair GC action in human airway epithelial cells through the activation of activin-like kinase 5 (ALK5), the type 1 receptor of TGF-β...
January 2017: PLoS Pathogens
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