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erythropoiesis hypoxia

Giulia Ravasi, Sara Pelucchi, Gaia Buoli Comani, Federico Greni, Raffaella Mariani, Irene Pelloni, Silvia Bombelli, Roberto Perego, Donatella Barisani, Alberto Piperno
OBJECTIVE: During hypoxia hepcidin expression is inhibited to allow iron mobilization to sustain erythropoietic expansion. We analysed molecular mechanisms underlying hypoxia-induced hepcidin inhibition in an in vivo model of acute hypoxia. METHODS: Mice were kept under normal or hypoxic conditions for 6h and 15h and treated with α-PDGF-BB antibody or PDGF-BB receptor inhibitor. Blood, liver, spleen, and bone marrow were collected to extract RNA and protein or to quantify EPO and PDGF-BB...
March 15, 2018: European Journal of Haematology
Hartmut Beck, Mario Jeske, Kai Thede, Friederike Stoll, Ingo Flamme, Metin Akbaba, Jens-Kerim Ergüden, Gunter Karig, Jörg Keldenich, Felix Oehme, Hans-Christian Militzer, Ingo V Hartung, Uwe Thuss
Small molecule inhibitors of hypoxia inducible factor prolyl hydroxylases (HIF-PHs) are currently under clinical development as novel treatment option for chronic kidney disease (CKD) associated anemia. Inhibition of HIF-PH mimics hypoxia and leads to increased EPO expression and subsequently increased erythropoiesis. Herein we describe the discovery, synthesis, SAR and proposed binding mode of novel 2,4-diheteroaryl-1,2-dihydro-3H-pyrazol-3-ones as orally bioavailable HIF-PH inhibitors for the treatment of anemia...
February 27, 2018: ChemMedChem
Paul Robach, Joar Hansen, Aurélien Pichon, Anne-Kristine Meinild Lundby, Sune Dandanell, Gunnar Slettaløkken Falch, Daniel Hammarström, Dominik H Pesta, Christoph Siebenmann, Stefanie Keiser, Patricia Kérivel, Jon Elling Whist, Bent R Rønnestad, Carsten Lundby
Live high - train low (LHTL) using hypobaric hypoxia was previously found to improve sea-level endurance performance in well-trained individuals, however confirmatory controlled data in athletes are lacking. Here we test the hypothesis that natural-altitude LHTL improves aerobic performance in cross-country skiers, in conjunction with expansion of total hemoglobin mass (Hbmass , carbon-monoxide rebreathing technique) promoted by accelerated erythropoiesis. Following duplicate baseline measurements at sea level over the course of two weeks, nineteen Norwegian cross-country skiers (three women, sixteen men, age 20±2 yr, maximal oxygen uptake (VO2 max) 69±5 ml...
February 22, 2018: Scandinavian Journal of Medicine & Science in Sports
O Hermine, Th Maciel, I Moura
Erythropoietin (EPO) plays an essential role in the regulation of erythropoiesis. Its production is under the control of the Hypoxia Inducible Factor (HIF) protein whose stability varies according to the oxygen level. During chronic renal failure, EPO deficiency is the main cause of anemia, but other factors such as iron deficiency and inflammatory syndrome are also involved. More recently, it is hypothesized that other factors such an excess of GDF-11 production may be also involved. Thus, beside Epo treatment HIF and GDF-11 are potentially new therapeutic targets in anemia of chronic kidney disease...
June 2017: Néphrologie & Thérapeutique
Niraj Kumar Jha, Saurabh Kumar Jha, Renu Sharma, Dhiraj Kumar, Rashmi K Ambasta, Pravir Kumar
For the maintenance of cellular homeostasis and energy metabolism, an uninterrupted supply of oxygen (O2) is routinely required in the brain. However, under the impaired level of O2 (hypoxia) or reduced blood flow (ischemia), the tissues are not sufficiently oxygenated, which triggers disruption of cellular homeostasis in the brain. Hypoxia is known to have a notable effect on controlling the expression of proteins involved in a broad range of biological processes varying from energy metabolism, erythropoiesis, angiogenesis, neurogenesis to mitochondrial trafficking and autophagy, thus facilitating neuronal cells to endure in deprived O2...
2018: Journal of Alzheimer's Disease: JAD
Tzu-Lan Yeh, Thomas M Leissing, Martine I Abboud, Cyrille C Thinnes, Onur Atasoylu, James P Holt-Martyn, Dong Zhang, Anthony Tumber, Kerstin Lippl, Christopher T Lohans, Ivanhoe K H Leung, Helen Morcrette, Ian J Clifton, Timothy D W Claridge, Akane Kawamura, Emily Flashman, Xin Lu, Peter J Ratcliffe, Rasheduzzaman Chowdhury, Christopher W Pugh, Christopher J Schofield
Inhibition of the human 2-oxoglutarate (2OG) dependent hypoxia inducible factor (HIF) prolyl hydroxylases (human PHD1-3) causes upregulation of HIF, thus promoting erythropoiesis and is therefore of therapeutic interest. We describe cellular, biophysical, and biochemical studies comparing four PHD inhibitors currently in clinical trials for anaemia treatment, that describe their mechanisms of action, potency against isolated enzymes and in cells, and selectivities versus representatives of other human 2OG oxygenase subfamilies...
November 1, 2017: Chemical Science
Joshua M Kaplan, Neeraj Sharma, Sean Dikdan
Hypoxia-inducible factor (HIF) plays a crucial role in the response to hypoxia at the cellular, tissue, and organism level. New agents under development to pharmacologically manipulate HIF may provide new and exciting possibilities in the treatment of anemia of chronic kidney disease (CKD) as well as in multiple other disease states involving ischemia-reperfusion injury. This article provides an overview of recent studies describing current standards of care for patients with anemia in CKD and associated clinical issues, and those supporting the clinical potential for targeting HIF stabilization with HIF prolyl-hydroxylase inhibitors (HIF-PHI) in these patients...
January 29, 2018: International Journal of Molecular Sciences
Anita T Layton, Volker Vallon
Sodium-glucose co-transporter 2 (SGLT2) inhibitors enhance urinary glucose, Na+ and fluid excretion and lower hyperglycemia in diabetes by targeting Na+ and glucose reabsorption along the proximal convoluted tubule. A goal of this study is to predict the effects of SGLT2 inhibitors in diabetic and non-diabetic patients with chronic kidney disease. To that end, we employed computational rat kidney models to explore how SGLT2 inhibition affects renal solute transport and metabolism when nephron populations are normal or reduced...
January 17, 2018: American Journal of Physiology. Renal Physiology
Jihyun Song, Josef T Prchal
Hypoxia increases erythropoiesis by hypoxia-inducible factors (HIF), principally by HIF-2, which upregulates erythropoietin transcription. This results in an increase of red blood cell (RBC) production and delivery of more oxygen to tissues. Upon rapid return to normoxia, hypoxia-induced polycythemia is overcorrected by neocytolysis, a transient destruction of preferentially young RBCs bearing low catalase (downregulated by hypoxia-stimulated microRNA(miR)-21) caused by reactive oxygen species (ROS) from expanded mitochondria...
2018: Methods in Molecular Biology
Joseph Sleiman, Ali Tarhini, Rayan Bou-Fakhredin, Antoine N Saliba, Maria Domenica Cappellini, Ali T Taher
Patients with non-transfusion-dependent thalassemia (NTDT) experience many clinical complications despite their independence from frequent transfusions. Morbidities in NTDT stem from the interaction of multiple pathophysiological factors: ineffective erythropoiesis, iron overload (IOL), and hypercoagulability. Ineffective erythropoiesis and hemolysis are associated with chronic hypoxia and a hypercoagulable state. The latter are linked to a high prevalence of thromboembolic and cerebrovascular events, as well as leg ulcers and pulmonary hypertension...
January 8, 2018: International Journal of Molecular Sciences
Shuo Miao, Su-Mei Wang, Xue Cheng, Yao-Feng Li, Qing-Song Zhang, Gang Li, Song-Qing He, Xiao-Ping Chen, Ping Wu
Background: Erythropoietin (EPO) is a hypoxia-inducible stimulator of erythropoiesis. Besides its traditional application in anemia therapy, it offers an effective treatment in the cancer patients, especially those who receive chemotherapy. Several reports indicated that it could promote the tumor cell proliferation through its specific receptor (EPOR). Unfortunately, the role of EPO/EPOR in hepatocellular carcinoma (HCC) progressing is still uncertain. Methods: Protein in tumor tissue from HCC patients or H22 tumor-bearing mice was detected with immunohistochemistry...
2017: Cancer Cell International
Y Zeng, J L Ma, L Chen
Under hypoxia condition, microRNA (miRNA) can interact with transcription factors for regulating the cell metabolism, angiogenesis, erythropoiesis, cellular proliferation, differentiation and apoptosis. The biological processes above may play an important role in mechanical asphyxia death. This article reviews the regulating function of miRNA under hypoxia condition and the influence of hypoxia to biosynthesis of miRNA, which may provide some new ideas to the research of miRNA on determining the cause of mechanical asphyxia death in the field of forensic medicine...
February 2017: Fa Yi Xue za Zhi
Miquel Félez, Nuria Grau, Antonia Ruiz, Encarna Guardiola, Carles Sanjuas, Cristina Estirado, Maribel Navarro-Muñoz, Antoni Pascual, Mauricio Orozco-Levi, Joaquim Gea
INTRODUCTION: Tissue hypoxia stimulates the production of erythropoietin (EPO), the main effect of which is, in turn, to stimulate erythropoiesis. Sleep apnea-hypopnea syndrome (SAHS) is an entity characterized by repeated episodes of hypoxemia during sleep. OBJECTIVE: To analyze whether hypoxemia stimulated increased urinary excretion of EPO, and if so, to evaluate if treatment with continuous positive airway pressure (CPAP) can inhibit this phenomenon. METHODS: We studied 25 subjects with suspected SAHS who underwent a polysomnography study (PSG)...
December 4, 2017: Archivos de Bronconeumología
Marc A Sala, Cong Chen, Qiao Zhang, Hanh Chi Do-Umehara, Wenjiao Wu, Alexander V Misharin, Gregory B Waypa, Deyu Fang, G R Scott Budinger, Shuwen Liu, Navdeep S Chandel, Paul T Schumacker, Jacob I Sznajder, Jing Liu
The hypoxic response is a stress response triggered by low-oxygen tension. Hypoxia-inducible factors (HIFs) play a prominent role in the pathobiology of hypoxia-associated conditions, including pulmonary hypertension (PH) and polycythemia. The c-Jun N-terminal protein kinase (JNK), a stress-activated protein kinase that consists of two ubiquitously expressed isoforms, JNK1 and JNK2, and a tissue-specific isoform, JNK3, has been shown to be activated by hypoxia. However, the physiological role of JNK1 and JNK2 in the hypoxic response remains elusive...
November 8, 2017: Journal of Biological Chemistry
Ingo Flamme, Peter Ellinghaus, Diana Urrego, Thilo Krüger
Plasma levels of FGF23 are increased in patients with chronic kidney disease. Beside its role in phosphate homeostasis, iron deficiency and anemia are associated with increased FGF23 plasma levels. Recently, FGF23 plasma levels were shown to be increased in mice after treatment with hypoxia inducible factor-proline hydroxylase (HIF-PH) inhibitors which are strong inducers of erythropoietin and erythropoiesis and are known to modulate iron uptake and availability. Therefore we investigated a potential context between expression of FGF23 and stimulation of erythropoiesis using a HIF-PH inhibitor and erythropoietin in rats...
2017: PloS One
Daniela Patinha, Wioletta Pijacka, Julian F R Paton, Maarten P Koeners
Oxygen sensing mechanisms are vital for homeostasis and survival. When oxygen levels are too low (hypoxia), blood flow has to be increased, metabolism reduced, or a combination of both, to counteract tissue damage. These adjustments are regulated by local, humoral, or neural reflex mechanisms. The kidney and the carotid body are both directly sensitive to falls in the partial pressure of oxygen and trigger reflex adjustments and thus act as oxygen sensors. We hypothesize a cooperative oxygen sensing function by both the kidney and carotid body to ensure maintenance of whole body blood flow and tissue oxygen homeostasis...
2017: Frontiers in Physiology
Louisa M Lobigs, Ken Sharpe, Laura A Garvican-Lewis, Christopher J Gore, Peter Peeling, Brian Dawson, Yorck O Schumacher
Altitude training is associated with changes in blood markers, which can confound results of the Athlete?s Biological Passport (ABP). This meta-analysis aims to describe the fluctuations during- and post-altitude in key ABP variables; hemoglobin concentration ([Hb]), square-root transformed reticulocyte percentage (sqrt(retic%)) and the OFF-score. Individual de-identified raw data were provided from 17 studies. Separate linear mixed effects analyses were performed for delta values from baseline for [Hb], sqrt(retic%) and OFF-score, by altitude phase (during and post)...
January 2018: American Journal of Hematology
Masaomi Nangaku
Chronic kidney disease leads to dysfunction of renal erythropoietin-producing cells, resulting in a decrease in erythrocyte production. A decrease in oxygen delivery to vital organs due to anemia results in worse quality of life and is associated with poor prognosis of the patients. Treatment with human recombinant erythropoietin or its improved version of erythropoiesis-stimulating agent (ESA) with a longer half-life is effective. However, some patients show hyporesponsiveness to ESA. Hyporesponsiveness to ESA, which can be induced by factors such as inflammation and uremic toxins, is associated with poor prognosis...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Hanna Kletkiewicz, Malwina Hyjek, Krzysztof Jaworski, Anna Nowakowska, Justyna Rogalska
Transcriptional hypoxia-inducible factor-1α (HIF-1α) plays the fundamental role in adaptive processes in response to hypoxia. Specific HIF-1α target genes are involved in glycolysis, erythropoiesis and angiogenesis to promote survival. In our previous study we have demonstrated that naturally low body temperature of newborn rats protects them against damage due to perinatal hypoxia. Therefore, our experiments aimed at checking the effects of body temperature during simulated perinatal anoxia on subsequent changes of expression of HIF-1α and its specific target genes such as vascular endothelial growth factor (VEGF) and erythropoietin (EPO) in the rat brain...
October 23, 2017: International Journal of Hyperthermia
Jon C Cook, Leslie A Obert, Petra Koza-Taylor, Tim Coskran, Alan Opsahl, Daniel Ziemek, Marc Roy, Jessie Qian, Michael P Lawton, Kay Criswell
Pharmaceuticals and chemicals produce hemangiosarcomas (HS) in mice, often by nongenotoxic, proliferative mechanisms. A mode-of-action (MOA) for hemangiosarcoma was proposed based on information presented at an international workshop (Cohen et al., 2009). Five key elements of the MOA were articulated and included hypoxia, macrophage activation, increased angiogenic growth factors, dysregulated angiogenesis/erythropoiesis, and endothial cell proliferation. The goal of the current study was to add to the weight-of-evidence for the proposed MOA by assessing these key elements with three different compounds of varying potency for HS induction: fenretinide (high), troglitazone (intermediate), and elmiron (low)...
September 18, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
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