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https://www.readbyqxmd.com/read/28087726/benefit-of-mineralocorticoid-receptor-antagonism-in-aki-role-of-vascular-smooth-muscle-rac1
#1
Jonatan Barrera-Chimal, Gwennan André-Grégoire, Aurelie Nguyen Dinh Cat, Sebastian M Lechner, Jérôme Cau, Sonia Prince, Peter Kolkhof, Gervaise Loirand, Vincent Sauzeau, Thierry Hauet, Frédéric Jaisser
AKI is a frequent complication in hospitalized patients. Unfortunately, there is no effective pharmacologic approach for treating or preventing AKI. In rodents, mineralocorticoid receptor (MR) antagonism prevents AKI induced by ischemia-reperfusion (IR). We investigated the specific role of vascular MR in mediating AKI induced by IR. We also assessed the protective effect of MR antagonism in IR-induced AKI in the Large White pig, a model of human AKI. In mice, MR deficiency in smooth muscle cells (SMCs) protected against kidney IR injury...
January 13, 2017: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/28087688/thirty-years-of-evidence-on-the-efficacy-of-drug-treatments-for-chronic-heart-failure-with-reduced-ejection-fraction-a-network-meta-analysis
#2
Heather Burnett, Amy Earley, Adriaan A Voors, Michele Senni, John J V McMurray, Celine Deschaseaux, Shannon Cope
BACKGROUND: Treatments that reduce mortality and morbidity in patients with heart failure with reduced ejection fraction, including angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), β-blockers (BB), mineralocorticoid receptor antagonists (MRA), and angiotensin receptor-neprilysin inhibitors (ARNI), have not been studied in a head-to-head fashion. This network meta-analysis aimed to compare the efficacy of these drugs and their combinations regarding all-cause mortality in patients with heart failure with reduced ejection fraction...
January 2017: Circulation. Heart Failure
https://www.readbyqxmd.com/read/28073850/characterization-of-mineralocorticoid-receptor-antagonist-therapy-initiation-in-high-risk-patients-with-heart-failure
#3
Lauren B Cooper, Bradley G Hammill, Eric D Peterson, Bertram Pitt, Matthew L Maciejewski, Lesley H Curtis, Adrian F Hernandez
BACKGROUND: Heart failure guidelines recommend routine monitoring of serum potassium, and renal function in patients treated with a mineralocorticoid receptor antagonist (MRA). How these recommendations are implemented in high-risk patients or according to setting of drug initiation is poorly characterized. METHODS AND RESULTS: We conducted a retrospective cohort study of Medicare beneficiaries linked to laboratory data in 10 states with prevalent heart failure as of July 1, 2011, and incident MRA use between May 1 and September 30, 2011...
January 2017: Circulation. Cardiovascular Quality and Outcomes
https://www.readbyqxmd.com/read/28069032/glucocorticoid-receptor-gene-polymorphisms-in-hereditary-angioedema-with-c1-inhibitor-deficiency
#4
Zsuzsanna Zotter, Zsolt Nagy, Attila Patócs, Dorottya Csuka, Nóra Veszeli, Kinga Viktória Kőhalmi, Henriette Farkas
BACKGROUND: Hereditary angioedema caused by C1-inhibitor deficiency (C1-INH-HAE) is a rare, autosomal dominant disorder. C1-INH-HAE is characterized by edema-formation, which may occur in response to stress. The individual's response to stress stimuli is partly genetically determined. Activation of the hypothalamic-pituitary-adrenal axis results in the release of cortisol. In turn, the secreted gluco- and mineralocorticoids affect the metabolism, as well as the cardiovascular and immune systems...
January 10, 2017: Orphanet Journal of Rare Diseases
https://www.readbyqxmd.com/read/28064163/predicting-albuminuria-response-to-spironolactone-treatment-with-urinary-proteomics-in-patients-with-type-2-diabetes-and-hypertension
#5
Morten Lindhardt, Frederik Persson, Christina Oxlund, Ib A Jacobsen, Petra Zürbig, Harald Mischak, Peter Rossing, Hiddo J L Heerspink
BACKGROUND: The mineralocorticoid receptor antagonist spironolactone significantly reduces albuminuria in patients with diabetes. Prior studies have shown large between-patient variability in albuminuria treatment response. We previously developed and validated a urinary proteomic classifier that predicts onset and progression of chronic kidney disease. Here, we tested whether the proteomic classifier based on 273 urinary peptides (CKD273) predicts albuminuria response to spironolactone treatment...
January 7, 2017: Nephrology, Dialysis, Transplantation
https://www.readbyqxmd.com/read/28064076/drospirenone-reduces-inflammatory-cytokines-vascular-endothelial-growth-factor-vegf-and-nerve-growth-factor-ngf-expression-in-human-endometriotic-stromal-cells
#6
Tomoko Makabe, Kaori Koga, Mariko Miyashita, Arisa Takeuchi, Fusako Sue, Ayumi Taguchi, Yoko Urata, Gentaro Izumi, Masashi Takamura, Miyuki Harada, Tetsuya Hirata, Yasushi Hirota, Osamu Wada-Hiraike, Tomoyuki Fujii, Yutaka Osuga
Drospirenone has been used as a progestin in oral contraceptives with ethinyl estradiol (DRSP/EE) and is expected to regulate endometriosis, however, the direct effects of drospirenone on endometriosis have not been clarified. The aim of this study was to evaluate the anti-inflammatory, anti-angiogenic and anti-neurogenic effects of drospirenone on endometriotic stromal cells (ESC). ESC isolated from endometriotic tissues were obtained from patients during laparoscopic surgery for ovarian endometriosis. ESC were exposed to IL-1β and cultured in the absence or presence of drospirenone...
December 29, 2016: Journal of Reproductive Immunology
https://www.readbyqxmd.com/read/28062142/aldosterone-pathway-blockade-to-prevent-atrial-fibrillation-a-systematic-review-and-meta-analysis
#7
J Neefs, N W E van den Berg, J Limpens, W R Berger, S M Boekholdt, P Sanders, J R de Groot
BACKGROUND: Despite advances in therapeutic interventions AF remains a progressive and symptomatic disease. Therefore, novel therapeutic interventions targeting the underlying arrhythmogenic substrate for AF is needed. Atrial fibrosis is an important component of the arrhythmogenic substrate of AF and may be initiated by aldosterone binding to the mineralocorticoid receptor. We hypothesized that aldosterone pathway blockade with mineralocorticoid receptor antagonists (MRA) reduces atrial fibrosis, and thus AF...
December 23, 2016: International Journal of Cardiology
https://www.readbyqxmd.com/read/28057868/glucocorticoid-receptor-alters-isovolumetric-contraction-and-restrains-cardiac-fibrosis
#8
Rachel Richardson, Emma Batchen, Adrian Thomson, Rowan Darroch, Xinlu Pan, Eva Rog-Zielinska, Wiktoria Wyrzykowska, Kathleen Scullion, Emad A S Al-Dujaili, Mary Diaz, Carmel Moran, Chris J Kenyon, Gillian A Gray, Karen Chapman
Corticosteroids directly affect the heart and vasculature and are implicated in the pathogenesis of heart failure. Attention has focussed upon the role of the mineralocorticoid receptor (MR) in mediating pro-fibrotic and other adverse effects of corticosteroids upon the heart. In contrast, the role of the glucocorticoid receptor (GR) in the heart and vasculature is less well understood. We addressed this in mice with cardiomyocyte and vascular smooth muscle deletion of GR (SMGRKO mice). Survival of SMGRKO mice to weaning was reduced compared with littermate controls...
January 5, 2017: Journal of Endocrinology
https://www.readbyqxmd.com/read/28052869/nlrp3-inflammasome-activation-contributes-to-aldosterone-induced-podocyte-injury
#9
Mi Bai, Ying Chen, Min Zhao, Yue Zhang, John Cijiang He, Songming Huang, Zhanjun Jia, Aihua Zhang
Aldosterone (Aldo) has been shown as an important contributor of podocyte injury. However, the underlying molecular mechanisms are still elusive. Recently, the pathogenic role of NLRP3 inflammasome in mediating renal tubular damage was identified while its role in podocyte injury still needs evidence. Thus the present study was undertaken to investigate the role of NLRP3 inflammasome in Aldo-induced podocyte damage. In vitro, exposure of podocytes to Aldo enhanced NLRP3, caspase-1 and IL-18 expressions in dose- and time-dependent manners, indicating an activation of NLRP3 inflammasome, which was significantly blocked by a mineralocorticoid receptor antagonist Eplerenone (EPL) or an antioxidant NAC...
January 4, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/28051871/modulating-mineralocorticoid-receptor-with-non-steroid-antagonists-new-opportunities-for-the-development-of-potent-and-selective-ligands-without-off-target-side-effects
#10
Mercedes Martín-Martínez, Felipe Luis Pérez-Gordillo, Diego Alvarez De la Rosa, Yoel Rodríguez, Guillermo Gerona-Navarro, Rosario González-Muñiz, Ming-Ming Zhou
Steroidal mineralocorticoid receptor (MR) antagonists are used for treatment of a range of human diseases, but present challenging issues of complex chemical synthesis, undesirable physical properties and poor selectivity along with unwanted side effects. Therefore, there is a great interest in the discovery of non-steroidal ligands able to bind to the ligand-binding domain (LBD) of the MR, and recruit different coregulators to produce tissue-specific therapeutic effects. Several academic groups and pharmaceutical companies have been developing a series of non-steroidal ligands that consist of different chemical scaffolds, yielding MR antagonists currently evaluated in clinical studies for the treatment of congestive heart failure, hypertension or diabetic nephropathy...
January 4, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28041953/synthetic-approaches-towards-the-multi-target-drug-spironolactone-and-its-potent-analogues-derivatives
#11
REVIEW
Fayaz Ali Larik, Aamer Saeed, Danish Shahzad, Muhammad Faisal, Hesham El-Seedi, Haroon Mehfooz, Pervaiz Ali Channar
Spironolactone is a well-known multi-target drug and is specifically used for the treatment of high blood pressure and heart failure. It is also used for the treatment of edema, cirrhosis of the liver, malignant, pediatric, nephrosis and primary hyperaldosteronism. Spironolactone in association with thiazide diuretics treats hypertension and in association with furosemide treats bronchopulmonary dyspepsia. The therapeutic mechanism of action of spironolactone involves binding to intracellular mineralocorticoids receptors (MRs) in kidney epithelial cells, thereby inhibiting the binding of aldosterone...
December 29, 2016: Steroids
https://www.readbyqxmd.com/read/28025025/a-randomized-controlled-study-of-finerenone-versus-placebo-in-japanese-patients-with-type-2-diabetes-mellitus-and-diabetic-nephropathy
#12
Shigehiro Katayama, Daishiro Yamada, Mikihiro Nakayama, Takashi Yamada, Masafumi Myoishi, Masaharu Kato, Christina Nowack, Peter Kolkhof, Yoshimitsu Yamasaki
AIMS: Finerenone (BAY 94-8862) is a novel non-steroidal mineralocorticoid receptor antagonist. The aim of this study was to compare the efficacy and safety of seven once-daily oral doses of finerenone (1.25-20mg) and placebo in 96 patients with type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) receiving a RAS blocker. METHODS: ARTS-DN Japan was a multicenter, randomized, double-blind, placebo-controlled, phase 2b study. RESULTS: Analysis of the urinary albumin-to-creatinine ratio (UACR) at day 90 relative to baseline indicated a nominally significant effect of finerenone...
December 14, 2016: Journal of Diabetes and its Complications
https://www.readbyqxmd.com/read/28024270/the-stress-hormone-cortisol-blocks-perceptual-learning-in-humans
#13
Hubert R Dinse, J C Kattenstroth, M Lenz, M Tegenthoff, O T Wolf
Cortisol, the primary glucocorticoid (GC) in humans, influences neuronal excitability and plasticity by acting on mineralocorticoid and glucocorticoid receptors. Cellular studies demonstrated that elevated GC levels affect neuronal plasticity, for example through a reduction of hippocampal long-term potentiation (LTP). At the behavioural level, after treatment with GCs, numerous studies have reported impaired hippocampal function, such as impaired memory retrieval. In contrast, relatively little is known about the impact of GCs on cortical plasticity and perceptual learning in adult humans...
December 9, 2016: Psychoneuroendocrinology
https://www.readbyqxmd.com/read/28013353/changes-in-stress-stimulated-allopregnanolone-levels-induced-by-neonatal-estradiol-treatment-are-associated-with-enhanced-dopamine-release-in-adult-female-rats-reversal-by-progesterone-administration
#14
Patrizia Porcu, Valeria Lallai, Andrea Locci, Sandro Catzeddu, Valeria Serra, Maria Giuseppina Pisu, Mariangela Serra, Laura Dazzi, Alessandra Concas
BACKGROUND: Allopregnanolone plays a role in the stress response and homeostasis. Alterations in the estrogen milieu during the perinatal period influence brain development in a manner that persists into adulthood. Accordingly, we showed that a single administration of estradiol benzoate (EB) on the day of birth decreases brain allopregnanolone concentrations in adult female rats. OBJECTIVE: We examined whether the persistent decrease in allopregnanolone concentrations, induced by neonatal EB treatment, might affect sensitivity to stress during adulthood...
December 24, 2016: Psychopharmacology
https://www.readbyqxmd.com/read/28011746/the-pharmacology-of-autonomic-failure-from-hypotension-to-hypertension
#15
REVIEW
Italo Biaggioni
Primary neurodegenerative autonomic disorders are characterized clinically by loss of autonomic regulation of blood pressure. The clinical picture is dominated by orthostatic hypotension, but supine hypertension is also a significant problem. Autonomic failure can result from impairment of central autonomic pathways (multiple system atrophy) or neurodegeneration of peripheral postganglionic autonomic fibers (pure autonomic failure, Parkinson's disease). Pharmacologic probes such as the ganglionic blocker trimethaphan can help us in the understanding of the underlying pathophysiology and diagnosis of these disorders...
January 2017: Pharmacological Reviews
https://www.readbyqxmd.com/read/28008698/prognostic-burden-of-heart-failure-recorded-in-primary-care-acute-hospital-admissions-or-both-a-population-based-linked-electronic-health-record-cohort-study-in-2-1-million-people
#16
Stefan Koudstaal, Mar Pujades-Rodriguez, Spiros Denaxas, Johannes M I H Gho, Anoop D Shah, Ning Yu, Riyaz S Patel, Chris P Gale, Arno W Hoes, John G Cleland, Folkert W Asselbergs, Harry Hemingway
AIMS: The prognosis of patients hospitalized for worsening heart failure (HF) is well described, but not that of patients managed solely in non-acute settings such as primary care or secondary outpatient care. We assessed the distribution of HF across levels of healthcare, and assessed the prognostic differences for patients with HF either recorded in primary care (including secondary outpatient care) (PC), hospital admissions alone, or known in both contexts. METHODS AND RESULTS: This study was part of the CALIBER programme, which comprises linked data from primary care, hospital admissions, and death certificates for 2...
December 23, 2016: European Journal of Heart Failure
https://www.readbyqxmd.com/read/27997270/molecular-interactions-of-dioxins-and-dlcs-with-the-ketosteroid-receptors-an-in-silico-risk-assessment-approach
#17
Mohemmed Faraz Khan, M Mumtaz Alam, Garima Verma, Wasim Akhtar, Moshahid A Rizvi, Asif Ali, Mymoona Akhter, M Shaquiquzzaman
Dioxins and dioxin like compounds (DLCs) are the ones with poor water solubility and low volatility, resistant to physical, chemical and biological processes, persistent in the environment even under extreme conditions. Due to lipophilic nature, they get adhered to the fatty material and concentrate through biomagnification and bioaccumulation, thereby easily getting incorporated into food chains, paving the way to endocrine disruption via modulation of various human receptors. This in turn leads to certain adverse health effects...
December 20, 2016: Toxicology Mechanisms and Methods
https://www.readbyqxmd.com/read/27989961/role-of-mineralocorticoid-receptor-activation-in-cardiac-diastolic-dysfunction
#18
REVIEW
Guanghong Jia, Yan Jia, James R Sowers
The prevalence of cardiac diastolic dysfunction and heart failure with preserved ejection, a major cause of morbidity and mortality in the western world, is increasing due, in part, to increases in obesity and type 2 diabetes. Characteristics of cardiac diastolic dysfunction include increased myocardial stiffness and impaired left ventricular (LV) relaxation that is characterized by prolonged isovolumic LV relaxation and slow LV filling. Obesity, insulin resistance and type 2 diabetes, especially in females promote activation of mineralocorticoid receptor (MR) signaling with resultant increases in oxidative stress, maladaptive immune responses, inflammation, and impairment of coronary blood flow and cardiac interstitial fibrosis...
October 28, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27987541/developing-treatments-for-chronic-kidney-disease-in-the-21st-century
#19
REVIEW
Matthew D Breyer, Katalin Susztak
Chronic kidney disease (CKD) is a lethal and rapidly increasing burden on society. Despite this, there are relatively few therapies in development for the treatment of CKD. Several recent costly phase 3 trials have failed to provide improved renal outcomes, diminishing interest in pharmaceutical investment. Furthermore, poor patient, physician, and payer awareness of CKD as a diagnosis has contributed to slow trial enrollment and successful implementation of these trials. Nevertheless, several therapeutics remain in development for the treatment of CKD, including mineralocorticoid-receptor antagonists, sodium/glucose cotransporter 2 inhibitors, anti-inflammatory drugs, and drugs that mitigate oxidative injury...
November 2016: Seminars in Nephrology
https://www.readbyqxmd.com/read/27981441/distribution-of-cellular-hsv-1-receptor-expression-in-human-brain
#20
Richard Lathe, Juergen G Haas
Herpes simplex virus type 1 (HSV-1) is a neurotropic virus linked to a range of acute and chronic neurological disorders affecting distinct regions of the brain. Unusually, HSV-1 entry into cells requires the interaction of viral proteins glycoprotein D (gD) and glycoprotein B (gB) with distinct cellular receptor proteins. Several different gD and gB receptors have been identified, including TNFRSF14/HVEM and PVRL1/nectin 1 as gD receptors and PILRA, MAG, and MYH9 as gB receptors. We investigated the expression of these receptor molecules in different areas of the adult and developing human brain using online transcriptome databases...
December 15, 2016: Journal of Neurovirology
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