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Sankar N Maity, Mark A Titus, Revekka Gyftaki, Guanglin Wu, Jing-Fang Lu, S Ramachandran, Elsa M Li-Ning-Tapia, Christopher J Logothetis, John C Araujo, Eleni Efstathiou
Cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1) is a validated treatment target for the treatment of metastatic castration-resistant prostate cancer (CRPC). Abiraterone acetate (AA) inhibits both 17α-hydroxylase (hydroxylase) and 17,20-lyase (lyase) reactions catalyzed by CYP17A1 and thus depletes androgen biosynthesis. However, coadministration of prednisone is required to suppress the mineralocorticoid excess and cortisol depletion that result from hydroxylase inhibition. VT-464, a nonsteroidal small molecule, selectively inhibits CYP17A1 lyase and therefore does not require prednisone supplementation...
October 17, 2016: Scientific Reports
Michael R Bristow, Jorge Silva Enciso, Bernard J Gersh, Christine Grady, Madeline Murguia Rice, Steven Singh, George Sopko, Robin Boineau, Yves Rosenberg, Barry H Greenberg
TOPCAT was a multinational clinical trial of 3,445 heart failure with preserved ejection fraction (HFpEF) patients that enrolled in 233 sites in six countries in North America, Eastern Europe and South America. Patients with a heart failure hospitalization in the last 12 months or an elevated B-type natriuretic peptide (BNP) were randomized to the mineralocorticoid receptor antagonist spironolactone vs. placebo. Sites in Russia and the Republic of Georgia provided the majority of early enrollment, primarily based on the hospitalization criterion since BNP levels were initially unavailable there...
April 2016: JACC. Basic to Translational Science
János Varga, Szilamér Ferenczi, Krisztina J Kovács, Ágnes Csáno, Barbora Prokopova, Daniela Jezova, Dóra Zelena
AIMS: In vasopressin-deficient rat pups stressor-induced adrenocorticotropin (ACTH) and corticosterone elevations markedly dissociate. We have shown recently that during the postnatal period mineralocorticoid secretion is more sensitive to stressor exposure than that of glucocorticoids. We have therefore hypothesized that in vasopressin-deficient pups during hypoglycemia, a stressor triggering aldosterone release mainly via ACTH, aldosterone release will change in parallel with ACTH. An additional aim was to reveal at which stage of the development occurs the shift from aldosterone to corticosterone as primarily stressor-induced adrenocortical hormone...
October 12, 2016: Life Sciences
Kristin Wenzel, Rasmita Samal, Elke Hammer, Vishnu M Dhople, Stefan Gross, Uwe Völker, Stephan B Felix, Stephanie Könemann
Cardiac progenitor cells (CPCs) trigger regenerative processes via paracrine mechanisms in response to changes in their environment. In the present study we explored alterations in the secretory activity of CPCs induced by raised aldosterone levels symptomatic for heart failure. The cytokine profile of the supernatant of CPCs that were treated with the mineralocorticoid showed an induction of interleukin-6 secretion. Mass spectrometric analyses revealed an increase in the abundance of secreted proteins associated with regeneration and cell migration like gelsolin and galectin-1...
October 11, 2016: Molecular and Cellular Endocrinology
Gül Bahtiyar, David Gutterman, Harold Lebovitz
Heart failure (HF) is a major cardiovascular complication of diabetes mellitus (DM). The greatest risk factor for HF is age, and data indicate that 6 to 10 % of individuals over the age of 65 years suffer from HF. Patients with DM have a 2.5-fold increased risk for developing HF than individuals without DM. The 25 to 40 % of patients with HF who have DM have worse outcome (death from cardiovascular disease or hospitalization for worsening HF) than patients without DM. Hyperglycemia is a risk factor for the development of HF with an increase in incidence of HF rising from 10 % at hemoglobin A1c (HbA1c) 8...
November 2016: Current Diabetes Reports
Yuki Kawashima Sonoyama, Toshihiro Tajima, Masanobu Fujimoto, Akiko Hasegawa, Naoki Miyahara, Rei Nishimura, Yuichiro Hashida, Atsushi Hayashi, Keiichi Hanaki, Susumu Kanzaki
Pseudohypoaldosteronism type 1 (PHA1) is a rare genetic disease characterized by resistance to aldosterone, and the renal form of PHA1 is associated with heterozygous inactivating mutations in NR3C2, which encodes mineralocorticoid receptor (MR). Here we report a case of renal PHA1 due to a novel frameshift mutation in NR3C2. A 10-day-old Japanese male infant, born at 39 weeks gestation (birth weight, 2,946 g), was admitted to our hospital because of lethargy and vomiting, with a 6.7% weight loss since birth...
October 5, 2016: Endocrine Journal
Dominique Piber, Katharina Schultebraucks, Sven C Mueller, Christian Deuter, Katja Wingenfeld, Christian Otte
OBJECTIVES: Stress hormones such as cortisol are known to influence a wide range of cognitive functions, including hippocampal based spatial memory. In the brain, cortisol acts via two different receptors: the glucocorticoid (GR) and the mineralocorticoid receptor (MR). As the MR has a high density in the hippocampus, we examined the effects of pharmacological MR stimulation on spatial memory. METHODS: Eighty healthy participants (40 women, 40 men, mean age=23.9years±SD=3...
October 7, 2016: Neurobiology of Learning and Memory
Olivier Malaise, Biserka Relic, Edith Charlier, Mustapha Zeddou, Sophie Neuville, Céline Deroyer, Philippe Gillet, Edouard Louis, Michel G Malaise, Dominique de Seny
BACKGROUND: Glucocorticoid-induced leucine zipper (GILZ) is a mediator of the anti-inflammatory activities of glucocorticoids. However, GILZ deletion does not impair the anti-inflammatory activities of exogenous glucocorticoids in mice arthritis models and GILZ could also mediate some glucocorticoid-related adverse events. Osteoarthritis (OA) is a metabolic disorder that is partly attributed to adipokines such as leptin, and we previously observed that glucocorticoids induced leptin secretion in OA synovial fibroblasts...
October 4, 2016: Arthritis Research & Therapy
Lina Holmqvist, Kristina Bengtsson Boström, Thomas Kahan, Linus Schiöler, Jan Hasselström, Per Hjerpe, Björn Wettermark, Karin Manhem
We aimed to describe the prevalence, treatment, and associated comorbidity of treatment-resistant hypertension (TRH). This registry-based cohort study from The Swedish Primary Care Cardiovascular Database assessed 53,090 hypertensive patients attending primary care. Patients adherent to antihypertensive treatment measured by pharmacy fills and with proportion of days covered ≥80% were included. The prevalence of TRH was 17% when considering all current TRH definitions. Adherence to mineralocorticoid receptor antagonists differed between TRH- and non-TRH patients (8 vs...
September 6, 2016: Journal of the American Society of Hypertension: JASH
Jennifer J DuPont, Amy McCurley, Ana P Davel, Joseph McCarthy, Shawn B Bender, Kwangseok Hong, Yan Yang, Jeung-Ki Yoo, Mark Aronovitz, Wendy E Baur, Demetra D Christou, Michael A Hill, Iris Z Jaffe
Hypertension is nearly universal yet poorly controlled in the elderly despite proven benefits of intensive treatment. Mice lacking mineralocorticoid receptors in smooth muscle cells (SMC-MR-KO) are protected from rising blood pressure (BP) with aging, despite normal renal function. Vasoconstriction is attenuated in aged SMC-MR-KO mice, thus they were used to explore vascular mechanisms that may contribute to hypertension with aging. MicroRNA (miR) profiling identified miR-155 as the most down-regulated miR with vascular aging in MR-intact but not SMC-MR-KO mice...
September 8, 2016: JCI Insight
Danielle M Osborne, Kelsey E O'Leary, Dennis P Fitzgerald, Alvin J George, Michael M Vidal, Brian M Anderson, Ewan C McNay
AIMS/HYPOTHESIS: Recurrent hypoglycaemia is primarily caused by repeated over-administration of insulin to patients with diabetes. Although cognition is impaired during hypoglycaemia, restoration of euglycaemia after recurrent hypoglycaemia is associated with improved hippocampally mediated memory. Recurrent hypoglycaemia alters glucocorticoid secretion in response to hypoglycaemia; glucocorticoids are well established to regulate hippocampal processes, suggesting a possible mechanism for recurrent hypoglycaemia modulation of subsequent cognition...
September 29, 2016: Diabetologia
Rene Baudrand, Nidhi Gupta, Amanda E Garza, Anand Vaidya, Jane A Leopold, Paul N Hopkins, Xavier Jeunemaitre, Claudio Ferri, Jose R Romero, Jonathan Williams, Joseph Loscalzo, Gail K Adler, Gordon H Williams, Luminita H Pojoga
BACKGROUND: Overactivation of the aldosterone and mineralocorticoid receptor (MR) pathway is associated with hyperglycemia and dyslipidemia. Caveolin 1 (cav-1) is involved in glucose/lipid homeostasis and may modulate MR signaling. We investigated the interplay between cav-1 and aldosterone signaling in modulating insulin resistance and dyslipidemia in cav-1-null mice and humans with a prevalent variant in the CAV1 gene. METHODS AND RESULTS: In mouse studies, cav-1 knockout mice exhibited higher levels of homeostatic model assessment of insulin resistance, cholesterol, and resistin and lower ratios of high- to low-density lipoprotein (all P<0...
2016: Journal of the American Heart Association
Dagmara Hering, Carl Schultz, Markus P Schlaich
PURPOSE: Resistant hypertension (RH) is a major and growing public health problem. While noncompliance to antihypertensive medication is a major concern in RH patients, it is estimated that even with adequate multi-drug regimens, approximately 10% of patients diagnosed with hypertension fulfill the criteria of true RH. Patients with sustained blood pressure (BP) elevation display high risk for development of target organ damage and associated cardiovascular morbidity and mortality. While optimized pharmacologic therapy, including the use of mineralocorticoid receptor antagonists to guideline-based antihypertensive drug therapy, is effective for improving BP control in this patient cohort, a sizable proportion of RH patients' BP remains uncontrolled, and alternative therapeutic strategies are warranted...
September 23, 2016: Clinical Therapeutics
Olivera Stojadinovic, Linsey E Lindley, Ivan Jozic, Marjana Tomic-Canic
Skin atrophy and impaired cutaneous wound healing are the recognized side effects of topical glucocorticoid (GC) therapy. Although GCs have high affinity for the glucocorticoid receptor, they also bind and activate the mineralocorticoid receptor. In light of this, one can speculate that some of the GC-mediated side effects can be remedied by blocking activation of the mineralocorticoid receptor. Indeed, according to Nguyen et al., local inhibition of the mineralocorticoid receptor via antagonists (spironolactone, canrenoate, and eplerenone) rescues GC-induced delayed epithelialization and accelerates wound closure in diabetic animals by targeting epithelial sodium channels and stimulating keratinocyte proliferation...
October 2016: Journal of Investigative Dermatology
Karen R Mifsud, Johannes M H M Reul
A stressful event results in secretion of glucocorticoid hormones, which bind to mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) in the hippocampus to regulate cognitive and affective responses to the challenge. MRs are already highly occupied by low glucocorticoid levels under baseline conditions, whereas GRs only become substantially occupied by stress- or circadian-driven glucocorticoid levels. Currently, however, the binding of MRs and GRs to glucocorticoid-responsive elements (GREs) within hippocampal glucocorticoid target genes under such physiological conditions in vivo is unknown...
October 4, 2016: Proceedings of the National Academy of Sciences of the United States of America
Quynh N Dinh, Grant R Drummond, Christopher G Sobey, Sophocles Chrissobolis
No abstract text is available yet for this article.
August 2016: Neural Regeneration Research
Edward J Dougherty, Jason M Elinoff, Gabriela A Ferreyra, Angela Hou, Rongman Cai, Junfeng Sun, Kevin P Blaine, Shuibang Wang, Robert L Danner
Glucocorticoids are commonly used to treat inflammatory disorders. The glucocorticoid receptor (GR) can tether to inflammatory transcription factor complexes such as NFκB and AP-1 and trans-repress the transcription of cytokines, chemokines and adhesion molecules. In contrast, aldosterone and the mineralocorticoid receptor (MR) primarily promote cardiovascular inflammation by incompletely understood mechanisms. While MR has been shown to weakly repress NFκB, its role in modulating AP-1 has not been established...
September 20, 2016: Journal of Biological Chemistry
Wolley Mj, Wu A, Xu S, Gordon Rd, Fenton Ra, Stowasser M
BACKGROUND: Distal tubular sodium retention is a potent driver of hypertension, with the thiazide sensitive sodium-chloride cotransporter (NCC) a key player. The upstream modulators of NCC are unclear, but recent evidence has revealed the kinases 'with-no-lysine kinase 4' (WNK4) and 'STE20/SPS1-related, proline alanine-rich kinase' (SPAK) to be involved. The wider role of mineralocorticoids is poorly understood, but animal models implicate aldosterone as a potent regulator, possibly via effects on plasma potassium...
September 2016: Journal of Hypertension
Brandi Wynne, Trinity Kronk, Otor Al-Khalili, Benjamin Ko, Franziska Theilig, Douglas Eaton, Robert Hoover
OBJECTIVE: Hypertension is characterized by increased sodium reabsorption along the aldosterone-sensitive distal nephron (ASDN) and systemic inflammation. Interleukin-6 (IL-6) is a possible mediator, signaling via the transmembrane IL-6 receptor alpha (IL-6Rα); however, whether IL-6Rα is present in the distal convoluted tubule (DCT) is unknown. Increased sodium reabsorption is not always correlated with increased aldosterone (Aldo). Thus, understanding how Aldo-independent sodium reabsorption occurs is critical...
September 2016: Journal of Hypertension
Martin Wolley, Diane Cowley, Ashraf Ahmed, Richard Gordon, Michael Stowasser
OBJECTIVE: Obstructive sleep apnoea (OSA) is known to commonly co-exist with primary aldosteronism (PA), but it is unknown if treatment via mineralocorticoid receptor blockade or adrenalectomy (for aldosterone producing adenoma, APA), improves sleep apnoea parameters in these patients. We therefore aimed to determine if specific medical or surgical treatment of PA improves OSA, as measured by the apnoea hypopnoea index (AHI). DESIGN AND METHOD: Patients undergoing diagnostic workup for PA were recruited if they had symptoms suggestive of OSA...
September 2016: Journal of Hypertension
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