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erythropoiesis hypoxia

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https://www.readbyqxmd.com/read/28331872/induction-of-erythropoiesis-by-hypoxia-inducible-factor-prolyl-hydroxylase-inhibitors-without-promotion-of-tumor-initiation-progression-or-metastasis-in-a-vegf-sensitive-model-of-spontaneous-breast-cancer
#1
Todd W Seeley, Mark D Sternlicht, Stephen J Klaus, Thomas B Neff, David Y Liu
The effects of pharmacological hypoxia-inducible factor (HIF) stabilization were investigated in the MMTV-Neu(ndl)-YD5 (NeuYD) mouse model of breast cancer. This study first confirmed the sensitivity of this model to increased vascular endothelial growth factor (VEGF), using bigenic NeuYD;MMTV-VEGF-25 mice. Tumor initiation was dramatically accelerated in bigenic animals. Bigenic tumors were also more aggressive, with shortened doubling times and increased lung metastasis as compared to NeuYD controls. In separate studies, NeuYD mice were treated three times weekly from 7 weeks of age until study end with two different HIF prolyl hydroxylase inhibitors (HIF-PHIs), FG-4497 or roxadustat (FG-4592)...
2017: Hypoxia
https://www.readbyqxmd.com/read/28302014/role-of-hepcidin-25-in-chronic-kidney-disease-anemia-and-beyond
#2
Norishi Ueda, Kazuya Takasawa
Iron is an essential element for all living organisms, but produces toxic oxidants. Thus, iron homeostasis is tightly regulated in mammals. Hepcidin-25 (hepcidin) has emerged as a molecule that regulates iron metabolism. Binding of hepcidin to its receptor, ferroportin, inhibits intestinal iron absorption and iron efflux from hepatocytes and macrophages. Decreased hepcidin enhances iron absorption and efflux. Hepcidin could be predictive of iron status and the response to iron supplementation or erythropoietin-stimulating agents...
March 16, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28299673/roles-of-runx-in-hypoxia-induced-responses-and-angiogenesis
#3
Sun Hee Lee, Sarala Manandhar, You Mie Lee
During the past two decades, Runt domain transcription factors (RUNX1, 2, and 3) have been investigated in regard to their function, structural elements, genetic variants, and roles in normal development and pathological conditions. The Runt family proteins are evolutionarily conserved from Drosophila to mammals, emphasizing their physiological importance. A hypoxic microenvironment caused by insufficient blood supply is frequently observed in developing organs, growing tumors, and tissues that become ischemic due to impairment or blockage of blood vessels...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28263291/iron-suppresses-erythropoietin-expression-via-oxidative-stress-dependent-hypoxia-inducible-factor-2-alpha-inactivation
#4
Keisuke Oshima, Yasumasa Ikeda, Yuya Horinouchi, Hiroaki Watanabe, Hirofumi Hamano, Yoshitaka Kihira, Seiji Kishi, Yuki Izawa-Ishizawa, Licht Miyamoto, Tasuku Hirayama, Hideko Nagasawa, Keisuke Ishizawa, Koichiro Tsuchiya, Toshiaki Tamaki
Renal anemia is a major complication in chronic kidney disease (CKD). Iron supplementation, as well as erythropoiesis-stimulating agents, are widely used for treatment of renal anemia. However, excess iron causes oxidative stress via the Fenton reaction, and iron supplementation might damage remnant renal function including erythropoietin (EPO) production in CKD. EPO gene expression was suppressed in mice following direct iron treatment. Hypoxia-inducible factor-2 alpha (HIF-2α), a positive regulator of the EPO gene, was also diminished in the kidney of mice following iron treatment...
March 6, 2017: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/28242135/hypoxia-inducible-factor-prolyl-hydroxylase-inhibitors-a%C3%A2-potential-new-treatment-for-anemia-in-patients-with-ckd
#5
REVIEW
Nupur Gupta, Jay B Wish
Erythropoiesis-stimulating agents (ESAs) increase hemoglobin levels, reduce transfusion requirements, and have been the standard of treatment for anemia in patients with chronic kidney disease (CKD) since 1989. Many safety concerns have emerged regarding the use of ESAs, including an increased occurrence of cardiovascular events and vascular access thrombosis. Hypoxia-inducible factor (HIF) prolyl hydroxylase (PH) enzyme inhibitors are a new class of agents for the treatment of anemia in CKD. These agents work by stabilizing the HIF complex and stimulating endogenous erythropoietin production even in patients with end-stage kidney disease...
February 24, 2017: American Journal of Kidney Diseases: the Official Journal of the National Kidney Foundation
https://www.readbyqxmd.com/read/28142212/neuroprotection-and-endocytosis-erythropoietin-receptors-in-insect-nervous-systems
#6
Natasa Miljus, Bita Massih, Marissa A Weis, Jan Vincent Rison, Christel B Bonnas, Inge Sillaber, Hannelore Ehrenreich, Bart R H Geurten, Ralf Heinrich
Erythropoietin (Epo) plays a dual role as an erythropoiesis-stimulating hormone and a locally produced cytoprotectant in various vertebrate tissues. Splice variants and engineered derivatives of Epo that mediate neuroprotection but do not stimulate erythropoiesis suggest that alternative receptors, different from the 'classical' homodimeric receptor involved in haematopoiesis, mediate neuroprotective Epo functions. Previous studies on grasshoppers demonstrated neuroprotective and neuroregenerative effects of Epo that involved similar transduction pathways as in mammals...
January 31, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28132948/added-value-of-hepcidin-quantification-for-the-diagnosis-and-follow-up-of-anemia-related-diseases
#7
REVIEW
Thibaud Lefebvre, Sigismond Lasocki, Martine Fénéant-Thibault, Pierre-Jean Lamy, Séverine Cunat, Madeleine Ropert-Bouchet, Patricia Aguilar-Martinez, Sylvain Lehmann, Constance Delaby
Iron homeostasis is based on a strict control of both intestinal iron absorption and iron recycling through reticulo-endothelial system. Hepcidin controls the iron fluxes in order to maintain sufficient iron levels for erythropoietic activities, hemoproteins synthesis or enzymes function, but also to limit its toxic accumulation throughout the body. Hepcidin expression is regulated by various stimuli: inflammation and iron stimulate the production of the peptide, while anemia, erythropoiesis and hypoxia repress its production...
February 1, 2017: Annales de Biologie Clinique
https://www.readbyqxmd.com/read/28119134/erythropoietin-as-a-performance-enhancing-drug-its-mechanistic-basis-detection-and-potential-adverse-effects
#8
Olivier Salamin, Tiia Kuuranne, Martial Saugy, Nicolas Leuenberger
Erythropoietin (EPO) is the main hormone regulating red blood cell (RBC) production. The large-scale production of a recombinant human erythropoietin (rHuEPO) by biotechnological methods has made possible its widespread therapeutic use as well as its misuse in sports. Since the marketing of the first epoetin in 1989, the development has progressed to the third-generation analogs. However, the production of rHuEPO is costly, and the frequent administration of an injectable formula is not optimal for compliance of therapeutic patients...
January 21, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28118622/targeting-hypoxia-inducible-factors-for-the-treatment-of-anemia-in-chronic-kidney-disease-patients
#9
Francesco Locatelli, Steven Fishbane, Geoffrey A Block, Iain C Macdougall
BACKGROUND: Anemia, a common complication of chronic kidney disease (CKD), has previously been attributed primarily to decreased production of erythropoietin. More recently, it has become apparent that the etiology of anemia involves several other factors, most notably dysfunctional iron metabolism, mediated via increased hepcidin activity and reduced clearance. Current management of anemia in patients with advanced CKD is based on erythropoiesis-stimulating agents and iron supplementation, along with red blood cell transfusions when necessary; however, safety considerations associated with these therapies highlight the need to pursue alternative treatment options targeting other mechanisms such as hypoxia-inducible factors (HIFs) that act as central regulators of erythropoiesis by coordinating a series of graded hypoxic responses...
2017: American Journal of Nephrology
https://www.readbyqxmd.com/read/28018974/hypoxia-sensing-through-%C3%AE-adrenergic-receptors
#10
Hoi I Cheong, Kewal Asosingh, Olivia R Stephens, Kimberly A Queisser, Weiling Xu, Belinda Willard, Bo Hu, Josephine Kam Tai Dermawan, George R Stark, Sathyamangla V Naga Prasad, Serpil C Erzurum
Life-sustaining responses to low oxygen, or hypoxia, depend on signal transduction by HIFs, but the underlying mechanisms by which cells sense hypoxia are not completely understood. Based on prior studies suggesting a link between the β-adrenergic receptor (β-AR) and hypoxia responses, we hypothesized that the β-AR mediates hypoxia sensing and is necessary for HIF-1α accumulation. Beta blocker treatment of mice suppressed hypoxia induction of renal HIF-1α accumulation, erythropoietin production, and erythropoiesis in vivo...
December 22, 2016: JCI Insight
https://www.readbyqxmd.com/read/28002958/discovery-of-n-bis-4-methoxyphenyl-methyl-4-hydroxy-2-pyridazin-3-yl-pyrimidine-5-carboxamide-mk-8617-an-orally-active-pan-inhibitor-of-hypoxia-inducible-factor-prolyl-hydroxylase-1-3-hif-phd1-3-for-the-treatment-of-anemia
#11
John S Debenham, Christina Madsen-Duggan, Matthew J Clements, Thomas F Walsh, Jeffrey T Kuethe, Mikhail Reibarkh, Scott P Salowe, Lisa M Sonatore, Richard Hajdu, James A Milligan, Denise M Visco, Dan Zhou, Russell B Lingham, Dominique Stickens, Julie A DeMartino, Xinchun Tong, Michael Wolff, Jianmei Pang, Randy R Miller, Edward C Sherer, Jeffrey J Hale
The discovery of novel 4-hydroxy-2-(heterocyclic)pyrimidine-5-carboxamide inhibitors of hypoxia-inducible factor (HIF) prolyl hydroxylases (PHD) is described. These are potent, selective, orally bioavailable across several species, and active in stimulating erythropoiesis. Mouse and rat studies showed hematological changes with elevations of plasma EPO and circulating reticulocytes following single oral dose administration, while 4-week q.d. po administration in rat elevated hemoglobin levels. A major focus of the optimization process was to decrease the long half-life observed in higher species with early compounds...
December 22, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27978511/effects-of-daprodustat-a-novel-hypoxia-inducible-factor-prolyl-hydroxylase-inhibitor-on-anemia-management-in-japanese-hemodialysis-subjects
#12
Tadao Akizawa, Yoshiharu Tsubakihara, Masaomi Nangaku, Yukihiro Endo, Hiromu Nakajima, Tomoko Kohno, Yukiko Imai, Natsumi Kawase, Katsutoshi Hara, John Lepore, Alexander Cobitz
BACKGROUND: Daprodustat (GSK1278863) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor being developed for treatment of anemia associated with chronic kidney disease (CKD). The effect of daprodustat in Japanese CKD patients with anemia has not been previously investigated. METHODS: We evaluated the relationship between daprodustat dose and hemoglobin response in Japanese patients on hemodialysis (HD) with anemia in a 4-week, phase II, double-blind, placebo-controlled study...
2017: American Journal of Nephrology
https://www.readbyqxmd.com/read/27951566/new-strategies-for-anaemia-management-in-chronic-kidney-disease
#13
Francesco Locatelli, Lucia Del Vecchio
Erythropoiesis-stimulating agents (ESAs) and iron therapy are the standard of care for normocytic normochromic anaemia, which is a frequent comorbidity of patients with chronic kidney disease. In a large percentage of patients, ESAs and iron increase haemoglobin levels, thus reducing the risk of blood transfusions and improving patient quality of life. However, randomised trials have raised some concerns about higher haemoglobin targets and/or high ESA dose use. These concerns include higher cardiovascular and thrombosis risk, cancer progression, and increased mortality...
2017: Contributions to Nephrology
https://www.readbyqxmd.com/read/27833947/erythropoietin-and-co-intrinsic-structure-and-functional-disorder
#14
REVIEW
Vladimir N Uversky, Elrashdy M Redwan
Erythropoietin (Epo) is a heavily glycosylated protein, with its main function being related to erythropoiesis, where it controls red blood cell production via interaction with the Epo receptor (EpoR). It also plays a number of important roles in various hormonal, growth factor, and cytokine pathways. These roles are defined by Epo partners, such as the homodimeric (EpoR)2 receptor, the heterodimeric EpoR/βCR receptor and hypoxia inducing factor (HIF). Although the main structural features of both Epo and EpoR are conserved in vertebrates, the secretion sites of Epo in mammals are different from those in other vertebrates...
December 20, 2016: Molecular BioSystems
https://www.readbyqxmd.com/read/27829948/increased-hematocrit-during-sodium-glucose-cotransporter-2-inhibitor-therapy-indicates-recovery-of-tubulointerstitial-function-in-diabetic-kidneys
#15
REVIEW
Motoaki Sano, Makoto Takei, Yasuyuki Shiraishi, Yoshihiko Suzuki
Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been attracting attention for cardiovascular as well as antidiabetic effects since the results of the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME Trial) were reported. The hematocrit increases during treatment with SGLT2 inhibitors, which have a diuretic effect but do not cause sufficient hemoconcentration to increase the risk of cerebral infarction. Elevation of the hematocrit during SGLT2 inhibitor therapy is presumed to involve enhancement of erythropoiesis in addition to hemoconcentration...
December 2016: Journal of Clinical Medicine Research
https://www.readbyqxmd.com/read/27821476/notch-downregulation-and-extramedullary-erythrocytosis-in-hypoxia-inducible-factor-prolyl-4-hydroxylase-2-deficient-mice
#16
Mikko N M Myllymäki, Jenni Määttä, Elitsa Y Dimova, Valerio Izzi, Timo Väisänen, Johanna Myllyharju, Peppi Koivunen, Raisa Serpi
Erythrocytosis is driven mainly by erythropoietin, which is regulated by hypoxia-inducible factor (HIF). Mutations in HIF prolyl 4-hydroxylase 2 (HIF-P4H-2) (PHD2/EGLN1), the major downregulator of HIFα subunits, are found in familiar erythrocytosis, and large-spectrum conditional inactivation of HIF-P4H-2 in mice leads to severe erythrocytosis. Although bone marrow is the primary site for erythropoiesis, spleen remains capable of extramedullary erythropoiesis. We studied HIF-P4H-2-deficient (Hif-p4h-2(gt/gt)) mice, which show slightly induced erythropoiesis upon aging despite nonincreased erythropoietin levels, and identified spleen as the site of extramedullary erythropoiesis...
January 15, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/27800508/phd2-from-hypoxia-regulation-to-disease-progression
#17
REVIEW
Ana M Meneses, Ben Wielockx
Oxygen represents one of the major molecules required for the development and maintenance of life. An adequate response to hypoxia is therefore required for the functioning of the majority of living organisms and relies on the activation of the hypoxia-inducible factor (HIF) pathway. HIF prolyl hydroxylase domain-2 (PHD2) has long been recognized as the major regulator of this response, controlling a myriad of outcomes that range from cell death to proliferation. However, this enzyme has been associated with more pathways, making the role of this protein remarkably complex under distinct pathologies...
2016: Hypoxia
https://www.readbyqxmd.com/read/27742192/hif-stabilization-by-prolyl-hydroxylase-inhibitors-for-the-treatment-of-anemia-in-chronic-kidney-disease
#18
Christina M Wyatt, Tilman B Drüeke
The treatment of anemia with erythropoiesis-stimulating agents and iron supplementation has become the standard of care in patients with chronic kidney disease. Because of the risks associated with this approach, hypoxia inducible factor stabilizing prolyl hydroxylase inhibitors were developed as a potential treatment alternative. In recent phase 2 trials, these agents raised hemoglobin in a predictable and controlled manner and improved markers of iron metabolism. More experience is needed to establish long-term efficacy, tolerability, and safety, and to determine whether their use is associated with lower iron requirements...
November 2016: Kidney International
https://www.readbyqxmd.com/read/27711215/heparanase-overexpression-reduces-hepcidin-expression-affects-iron-homeostasis-and-alters-the-response-to-inflammation
#19
Michela Asperti, Tanja Stuemler, Maura Poli, Magdalena Gryzik, Lena Lifshitz, Esther G Meyron-Holtz, Israel Vlodavsky, Paolo Arosio
Hepcidin is the key regulator of systemic iron availability that acts by controlling the degradation of the iron exporter ferroportin. It is expressed mainly in the liver and regulated by iron, inflammation, erythropoiesis and hypoxia. The various agents that control its expression act mainly via the BMP6/SMAD signaling pathway. Among them are exogenous heparins, which are strong hepcidin repressors with a mechanism of action not fully understood but that may involve the competition with the structurally similar endogenous Heparan Sulfates (HS)...
2016: PloS One
https://www.readbyqxmd.com/read/27690727/cord-blood-erythropoietin-and-cord-blood-nucleated-red-blood-cells-for-prediction-of-adverse-neonatal-outcome-associated-with-maternal-obesity-in-term-pregnancy-prospective-cohort-study
#20
Mahmoud H Ibrahim, Asmaa N Moustafa, Ahmed A Fadil Saedii, Ebtesam E Hassan
OBJECTIVE: To determine the adverse pregnancy outcomes associated with maternal pre-pregnancy overweight and obesity and we measure cord blood erythropoietin and NRBC count as indices of hypoxia and predictors of neonatal outcome. STUDY DESIGN: This prospective cohort study was done in Minia University Hospital, carried out from May 2015 to April 2016. Two hundred and seventy full-term neonates born to mothers of various body mass indices were included. Excluded were neonates with major factors known to be associated with a potential increase in fetal erythropoiesis...
October 20, 2016: Journal of Maternal-fetal & Neonatal Medicine
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