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Glucocorticoid resistance

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https://www.readbyqxmd.com/read/29773951/the-role-of-neuroinflammation-and-neurovascular-dysfunction-in-major-depressive-disorder
#1
REVIEW
Sang Won Jeon, Yong-Ku Kim
Although depression has generally been explained with monoamine theory, it is far more multifactorial, and therapies that address the disease's pathway have not been developed. In this context, an understanding of neuroinflammation and neurovascular dysfunction would enable a more comprehensive approach to depression. Inflammation is in a sense a type of allostatic load involving the immune, endocrine, and nervous systems. Neuroinflammation is involved in the pathophysiology of depression by increasing proinflammatory cytokines, activating the hypothalamus-pituitary-adrenal axis, increasing glucocorticoid resistance, and affecting serotonin synthesis and metabolism, neuronal apoptosis and neurogenesis, and neuroplasticity...
2018: Journal of Inflammation Research
https://www.readbyqxmd.com/read/29765971/alopecia-areata-in-a-dog-clinical-dermoscopic-and-histological-features
#2
Fabia Scarampella, Paola Roccabianca
Alopecia areata (AA)-like disease is characterized by multifocal patchy hair loss in humans, rodents, dogs, and horses. Remarkable similarities between human and nonhuman AA cases have been reported in terms of clinical presentation, histology, and immune mechanisms of the disease. Canine AA-like lesions most often consist of well-demarcated alopecic patches, frequently but not only involving the face and the head, which extend to the ear pinnae and legs. In some cases, hair loss can have a more generalized distribution...
April 2018: Skin Appendage Disorders
https://www.readbyqxmd.com/read/29764864/targeting-the-hsp40-hsp70-chaperone-axis-as-a-novel-strategy-to-treat-castration-resistant-prostate-cancer
#3
Michael A Moses, Yeong Sang Kim, Genesis M Rivera-Marquez, Nobu Oshima, Matthew J Watson, Kristin Beebe, Catherine Wells, Sunmin Lee, Abbey D Zuehlke, Hao Shao, William E Bingman, Vineet Kumar, Sanjay Malhotra, Nancy L Weigel, Jason E Gestwicki, Jane Trepel, Leonard M Neckers
Castration-resistant prostate cancer (CRPC) is characterized by reactivation of androgen receptor (AR) signaling in part by elevated expression of AR splice variants (ARv) including ARv7, a constitutively active, ligand binding domain (LBD)-deficient variant whose expression has been correlated with therapeutic resistance and poor prognosis. In a screen to identify small molecule dual inhibitors of both androgen-dependent and androgen-independent AR gene signatures, we identified the chalcone C86. Binding studies using purified proteins and CRPC cell lysates revealed C86 to interact with heat shock protein 40 (Hsp40)...
May 15, 2018: Cancer Research
https://www.readbyqxmd.com/read/29762667/single-nucleotide-variations-of-the-human-gr-gene-manifested-as-pathologic-mutations-or-polymorphisms
#4
Tomoshige Kino
The human genome contains numerous single nucleotide variations (SNVs), and the human GR gene harbors ∼450 of these genetic changes. Among them, extremely rare non-synonymous variants known as pathologic GR gene mutations develop a characteristic pathologic condition, familial/sporadic generalized glucocorticoid resistance syndrome, by replacing the amino acids critical for GR protein structure and functions, whereas others known as pathologic polymorphisms develop mild manifestations recognized mainly at population bases by changing the GR activities slightly...
May 11, 2018: Endocrinology
https://www.readbyqxmd.com/read/29754632/genetics-of-cushing-s-syndrome
#5
REVIEW
Laura C Hernández-Ramírez, Constantine A Stratakis
The knowledge on the molecular and genetic causes of Cushing's syndrome (CS) has greatly increased in the recent years. Somatic mutations leading to overactive 3',5'-cyclic adenosine monophosphate/protein kinase A and wingless-type MMTV integration site family/beta-catenin pathways are the main molecular mechanisms underlying adrenocortical tumorigenesis. Corticotropinomas are characterized by resistance to glucocorticoid negative feedback, impaired cell cycle control and overexpression of pathways sustaining ACTH secretion...
June 2018: Endocrinology and Metabolism Clinics of North America
https://www.readbyqxmd.com/read/29748211/anti-leukemic-efficacy-of-bet-inhibitor-in-a-preclinical-mouse-model-of-mll-af4-infant-all
#6
Michela Bardini, Luca Trentin, Francesca Rizzo, Margherita Vieri, Angela M Savino, Patricia Garrido Castro, Grazia Fazio, Eddy H J Van Roon, Mark Kerstjens, Nicholas N Smithers, Rab K Prinjha, Geertruy Te Kronnie, Giuseppe Basso, Ronald W Stam, Rob Pieters, Andrea Biondi, Giovanni Cazzaniga
MLL-rearranged acute lymphoblastic leukemia occurring in infants is a rare but very aggressive leukemia, typically associated with a dismal prognosis. Despite the development of specific therapeutic protocols, infant patients with MLL-rearranged ALL still suffer from a low cure rate. At present, novel therapeutic approaches are urgently needed. Recently, the use of small molecule inhibitors targeting the epigenetic regulators of the MLL complex emerged as a promising strategy for the development of a targeted therapy...
May 10, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29738549/effect-of-combining-glucocorticoids-with-compound-a-on-glucocorticoid-receptor-responsiveness-in-lymphoid-malignancies
#7
Dorien Clarisse, Karlien Van Wesemael, Jan Tavernier, Fritz Offner, Ilse M Beck, Karolien De Bosscher
Glucocorticoids (GCs) are a cornerstone in the treatment of lymphoid malignancies such as multiple myeloma (MM) and acute lymphoblastic leukemia (ALL). Yet, prolonged GC use is hampered by deleterious GC-related side effects and the emergence of GC resistance. To tackle and overcome these GC-related problems, the applicability of selective glucocorticoid receptor agonists and modulators was studied, in search of fewer side-effects and at least equal therapeutic efficacy as classic GCs. Compound A (CpdA) is a prototypical example of such a selective glucocorticoid receptor modulator and does not support GR-mediated transactivation...
2018: PloS One
https://www.readbyqxmd.com/read/29735021/influence-of-prednisolone-on-parameters-of-de-novo-lipogenesis-and-indices-for-stearoyl-coa-and-%C3%AE-6-desaturase-activity-in-healthy-males-a-post-hoc-analysis-of-a-randomized-placebo-controlled-double-blind-trial
#8
I G Pranger, D H van Raalte, M Brands, M H A Muskiet, I P Kema, M J Serlie, M Diamant, S J L Bakker, F A J Muskiet
Glucocorticoid treatment decreases liver insulin sensitivity and may modify fatty acid metabolism. We investigated the influence of oral prednisolone on indices for de novo lipogenesis (DNLi), stearoyl-CoA desaturase (SCDi) and Δ6-desaturase (D6Di) activity in healthy males. In addition, we explored whether the changes may be associated with prednisolone-induced changes in glucose and lipid metabolism and insulin sensitivity. Thirty-two healthy young males (mean ± SD age 22 ± 3 years, BMI 22.4 ± 1...
May 2018: Prostaglandins, Leukotrienes, and Essential Fatty Acids
https://www.readbyqxmd.com/read/29731739/single-gene-congenic-strain-reveals-the-effect-of-zbtb16-on-dexamethasone-induced-insulin-resistance
#9
Michaela Krupková, František Liška, Ludmila Kazdová, Lucie Šedová, Adéla Kábelová, Drahomíra Křenová, Vladimír Křen, Ondřej Šeda
Background: Glucocorticoids (GCs) are potent therapeutic agents frequently used for treatment of number of conditions, including hematologic, inflammatory, and allergic diseases. Both their therapeutic and adverse effects display significant interindividual variation, partially attributable to genetic factors. We have previously isolated a seven-gene region of rat chromosome 8 sensitizing to dexamethasone (DEX)-induced dyslipidemia and insulin resistance (IR) of skeletal muscle. Using two newly derived congenic strains, we aimed to investigate the effect of one of the prime candidates for this pharmacogenetic interaction, the Zbtb16 gene...
2018: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/29721072/glucocorticoids-inhibit-oncogenic-runx1-eto-in-acute-myeloid-leukemia-with-chromosome-translocation-t-8-21
#10
Lianghao Lu, Yefei Wen, Yuan Yao, Fengju Chen, Guohui Wang, Fangrui Wu, Jingyu Wu, Padmini Narayanan, Michele Redell, Qianxing Mo, Yongcheng Song
Acute myeloid leukemia (AML) is a major blood cancer with poor prognosis. New therapies are needed to target oncogene-driven leukemia stem cells, which account for relapse and resistance. Chromosome translocation t(8;21), which produces RUNX1-ETO (R-E) fusion oncoprotein, is found in ~13% AML. R-E dominance negatively inhibits global gene expression regulated by RUNX1, a master transcription factor for hematopoiesis, causing increased self-renewal and blocked cell differentiation of hematopoietic progenitor cells, and eventually leukemia initiation...
2018: Theranostics
https://www.readbyqxmd.com/read/29719127/glucocorticoid-receptor-isoform-expression-in-peripheral-blood-mononuclear-leukocytes-of-patients-with-chronic-rhinosinusitis
#11
Robert J Taylor, Rodney J Schlosser, Zachary M Soler, Jose L Mattos, Jennifer K Mulligan
BACKGROUND: In several inflammatory disorders, altered peripheral blood mononuclear leukocyte (PBML) glucocorticoid (GC) receptor isoform expression has been associated with GC resistance and disease severity. However, it is unclear if PBML GC receptor isoforms are expressed differentially and are associated with worsened disease severity in chronic rhinosinusitis (CRS). METHODS: PBMLs were isolated from control (n = 8), CRS without nasal polyps (CRSsNP) (n = 8), atopic CRS with nasal polyps (CRSwNP) (n = 8), non-atopic CRSwNP (n = 8), and allergic fungal rhinosinusitis (AFRS) (n = 8) patients...
May 2, 2018: International Forum of Allergy & Rhinology
https://www.readbyqxmd.com/read/29716734/the-difficulties-of-pseudo-cushing-s-syndrome-or-non-neoplastic-hypercortisolism
#12
Olivier Chabre
Pseudo-Cushing's syndrome covers different pathological conditions responsible for mild-to-moderate ACTH-dependent hypercortisolism, related not to an ACTH-secreting tumor but rather to CRH and/or AVP hypothalamic secretion through activation of various neural pathways, in patients generally displaying excess central adiposity. It is better termed "non-neoplastic hypercortisolism" (NNH). The main conditions implicated in NNH comprise: neuropsychiatric disorder, alcohol abuse, insulin-resistant obesity, polycystic ovary syndrome, and end-stage kidney disease...
April 28, 2018: Annales D'endocrinologie
https://www.readbyqxmd.com/read/29691980/glucocorticoids-modulate-multidrug-resistance-transporters-in-the-first-trimester-human-placenta
#13
Phetcharawan Lye, Enrrico Bloise, Lubna Nadeem, William Gibb, Stephen J Lye, Stephen G Matthews
The placental multidrug transporters, P-glycoprotein (P-gp, encoded by ABCB1) and breast cancer resistance protein (BCRP, ABCG2) protect the foetus from exposure to maternally derived glucocorticoids, toxins and xenobiotics. During pregnancy, maternal glucocorticoid levels can be elevated by stress or exogenous administration. We hypothesized that glucocorticoids modulate the expression of ABCB1/P-gp and ABCG2/BCRP in the first trimester human placenta. Our objective was to examine whether dexamethasone (DEX) or cortisol modulate first trimester placental expression of multidrug transporters and determine whether cytotrophoblasts or the syncytiotrophoblast are/is responsible for mediating these effects...
April 24, 2018: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/29689546/eno2-promotes-cell-proliferation-glycolysis-and-glucocorticoid-resistance-in-acute-lymphoblastic-leukemia
#14
Cheng-Cheng Liu, Hua Wang, Wei-da Wang, Liang Wang, Wen-Jian Liu, Jing-Hua Wang, Qi-Rong Geng, Yue Lu
BACKGROUND/AIMS: The metabolic features of cancer cells have long been acknowledged to be altered and to provide new therapeutic opportunities. The expression of glycolytic enzyme enolase 2 (ENO2) was found to be closely associated with the clinical features of acute lymphoblastic leukemia (ALL) patients, but its functions remain unclear in ALL. METHODS: We evaluated the association between ENO2 mRNA expression in bone marrow mononuclear cells (BM-MNCs) and the efficacy of chemotherapy, and further explored the function of ENO2 in ALL...
April 19, 2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29685454/pathophysiology-of-glucocorticoid-signaling
#15
Géraldine Vitellius, Séverine Trabado, Jérôme Bouligand, Brigitte Delemer, Marc Lombès
Glucocorticoids (GC), such as cortisol or dexamethasone, control various physiological functions, notably those involved in development, metabolism, inflammatory processes and stress, and exert most of their effects upon binding to the glucocorticoid receptor (GR, encoded by NR3C1 gene). GC signaling follows several consecutive steps leading to target gene transactivation, including ligand binding, nuclear translocation of ligand-activated GR complexes, DNA binding, coactivator interaction and recruitment of functional transcriptional machinery...
April 20, 2018: Annales D'endocrinologie
https://www.readbyqxmd.com/read/29685115/acquired-modification-of-sphingosine-1-phosphate-lyase-activity-is-not-related-to-adrenal-insufficiency
#16
Gulin Sunter, Ece Oge Enver, Azad Akbarzade, Serap Turan, Pinar Vatansever, Dilek Ince Gunal, Goncagul Haklar, Abdullah Bereket, Kadriye Agan, Tulay Guran
BACKGROUND: Congenital sphingosine-1-phosphate (S1P) lyase deficiency due to biallelic mutations in SGPL1 gene has recently been described in association with primary adrenal insufficiency and steroid-resistant nephrotic syndrome. S1P lyase, on the other hand, is therapeutically inhibited by fingolimod which is an oral drug for relapsing multiple sclerosis (MS). Effects of this treatment on adrenal function has not yet been evaluated. We aimed to test adrenal function of MS patients receiving long-term fingolimod treatment...
April 23, 2018: BMC Neurology
https://www.readbyqxmd.com/read/29677638/gestational-glucocorticoid-exposure-disrupts-glucose-homeostasis-that-is-accompanied-by-increased-endoglin-and-dpp-4-activity-instead-of-gsk-3-in-rats
#17
Olufunto O Badmus, Olugbenga S Michael, Saheed Rabiu, Lawrence A Olatunji
Gestational glucocorticoid (GC) treatment has been associated with cardiometabolic disorder (CMD) in offspring's in later life. Elevated dipeptidyl peptidase-4 (DPP-4) activity, endoglin and glycogen synthase kinase-3 (GSK-3) has also been implicated in the development of insulin resistance (IR) and/or vascular inflammation. We aimed to investigate the impact of GC exposure on glucose metabolism and the circulating levels of inflammatory biomarkers, DPP-4 activity and GSK-3 in pregnant rats. Pregnant Wistar rats received either vehicle or dexamethasone (DEX; 0...
April 13, 2018: Environmental Toxicology and Pharmacology
https://www.readbyqxmd.com/read/29674424/utilizing-radiolabeled-3-deoxy-3-18-f-fluorothymidine-with-positron-emission-tomography-to-monitor-the-effect-of-dexamethasone-on-non-small-cell-lung-cancer
#18
Christopher McHugh, Monica R Thipparthi, Jawana M Lawhorn-Crews, Lisa Polin, Shirish Gadgeel, Janice Akoury, Thomas J Mangner, Kirk A Douglas, Jing Li, Manohar Ratnam, Anthony F Shields
Non-small cell lung cancer (NSCLC) is a leading cause of cancer mortality in the United States and pemetrexed-based therapies are regularly used to treat non-squamous NSCLC. Despite widespread use, pemetrexed has a modest effect on progression-free survival, with varying efficacy between individuals. Recent work has indicated that dexamethasone, given to prevent pemetrexed toxicity, is able to protect a subset of NSCLC cells from pemetrexed cytotoxicity by temporarily suppressing of the S-phase of the cell cycle...
April 19, 2018: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/29672221/glucocorticoid-receptor-isoform-specific-regulation-of-development-circadian-rhythm-and-inflammation-in-mice
#19
Robert H Oakley, Sivapriya Ramamoorthy, Julie F Foley, Jonathan T Busada, Nick Z Lu, John A Cidlowski
Glucocorticoids are primary stress hormones, and their synthetic derivatives are widely used clinically. The therapeutic efficacy of these steroids is limited by side effects and glucocorticoid resistance. Multiple glucocorticoid receptor (GR) isoforms are produced from a single gene by alternative translation initiation; however, the role individual isoforms play in tissue-specific responses to glucocorticoids is unknown. We have generated knockin mice that exclusively express the most active receptor isoform, GR-C3...
April 19, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29666573/psychosocial-stress-and-immunity-what-can-we-learn-from-pig-studies
#20
Ulrike Gimsa, Margret Tuchscherer, Ellen Kanitz
Psychosocial stress may impair immune functions and provoke the development of pathologies. The underlying communication between the brain and the immune system is being studied predominantly in rodents. However, pigs offer several advantages as preclinical models for humans because pigs are more similar to humans than rodents in many anatomical and physiological characteristics. Unlike in rodents, the main stress-induced glucocorticoid in humans and pigs is cortisol with a similar circadian rhythm. In this study, we summarize data on short-term and long-term effects of social stress in pigs for their immunity and neuroendocrine regulation with consequences for their health and well-being...
2018: Frontiers in Behavioral Neuroscience
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