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Sample records for carbamylated erythropoietin protects

  1. Pharmacological Effects of Erythropoietin and its Derivative Carbamyl erythropoietin in Cerebral White Matter Injury

    Science.gov (United States)

    Liu, Wei

    Periventricular leukomalacia (PVL) is the predominant form of brain injury in the premature infant and the most common cause of cerebral palsy, yet no therapy currently exists for this serious human disorder. As PVL often occurs in preterm infants suffering from cerebral hypoxia/ischemia with or without prior exposure to maternal-fetal infection/inflammation, we used hypoxia/ischemia with or without lipopolysaccharide (LPS) injection, to produce clinically relevant PVL-like lesions in the white matter in postnatal day six (P6) mice. We studied the white matter pathology under different conditions, such as different durations of hypoxia and different doses of LPS, to evaluate the effects of those etiological factors on neonatal white matter injury. Distinct related pathological events were investigated at different time points during the progression of PVL. We used immunohistochemistry, histological analysis, and electron microscopy (EM) to study demylination that occurs in the white matter area, which is consistent with the pathology of human PVL. Previous studies have shown that erythropoietin (EPO) and its derivative carbamylated EPO (CEPO) are neuroprotective in various experimental models of brain injury. However, none of these studies investigated their efficacy against white matter injury using appropriate animal models of PVL. We produced unilateral or bilateral white matter injury in P6 mice using unilateral carotid ligation (UCL) followed by hypoxia (6% oxygen, 35 min) or by UCL/hypoxia plus LPS injection, respectively. We administered a single intraperitoneal (i.p.) dose of EPO or CEPO (5000 IU/kg) immediately after the insult, and found both drugs to provide significant protection against white matter injury in PVL mice compared to vehicle-treated groups. In addition, EPO and CEPO treatments attenuated neurobehavioral dysfunctions in an acute manner after PVL injury. EPO and CEPO have relatively few adverse effects, and thus may be a therapeutic agent

  2. Erythropoietin and carbamylated erythropoietin promote histone deacetylase 5 phosphorylation and nuclear export in rat hippocampal neurons

    Energy Technology Data Exchange (ETDEWEB)

    Jo, Hye-Ryeong [Department of Biomedical Sciences, Graduate School of Biomedical Science and Engineering (Korea, Republic of); Kim, Yong-Seok [Department of Biomedical Sciences, Graduate School of Biomedical Science and Engineering (Korea, Republic of); Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, 17 Haengdang-dong, Sungdong-gu, Seoul 133-791 (Korea, Republic of); Son, Hyeon, E-mail: hyeonson@hanyang.ac.kr [Department of Biomedical Sciences, Graduate School of Biomedical Science and Engineering (Korea, Republic of); Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, 17 Haengdang-dong, Sungdong-gu, Seoul 133-791 (Korea, Republic of)

    2016-01-29

    Erythropoietin (EPO) produces neurotrophic effects in animal model of neurodegeneration. However, clinical use of EPO is limited due to thrombotic risk. Carbamylated EPO (cEPO), devoid of thrombotic risk, has been proposed as a novel neuroprotective and neurotrophic agent although the molecular mechanisms of cEPO remain incomplete. Here, we show a previously unidentified role of histone deacetylase 5 (HDAC5) in the actions of EPO and cEPO. EPO and cEPO regulate the HDAC5 phosphorylation at two critical sites, Ser259 and Ser498 through a protein kinase D (PKD) dependent pathway. In addition, EPO and cEPO rapidly stimulates nuclear export of HDAC5 in rat hippocampal neurons which expressing HDAC5-GFP. Consequently, EPO and cEPO enhanced the myocyte enhancer factor-2 (MEF2) target gene expression. Taken together, our results reveal that EPO and cEPO mediate MEF2 target gene expression via the regulation of HDAC5 phosphorylation at Ser259/498, and suggest that HDAC5 could be a potential mechanism contributing to the therapeutic actions of EPO and cEPO.

  3. Cytoprotective doses of erythropoietin or carbamylated erythropoietin have markedly different procoagulant and vasoactive activities

    NARCIS (Netherlands)

    Coleman, TR; Westenfelder, C; Togel, FE; Yang, Y; Hu, ZM; Swenson, L; Leuvenink, HGD; Ploeg, RJ; d'Uscio, LV; Katusic, ZS; Ghezzi, P; Zanetti, A; Kaushansky, K; Fox, NE; Cerami, A; Brines, M

    2006-01-01

    Recombinant human erythropoietin (rhEPO) is receiving increasing attention as a potential therapy for prevention of injury and restoration of function in nonhematopoietic tissues. However, the minimum effective dose required to mimic and augment these normal paracrine functions of erythropoietin (EP

  4. Comparison of Neurite Outgrowth Induced by Erythropoietin (EPO) and Carbamylated Erythropoietin (CEPO) in Hippocampal Neural Progenitor Cells.

    Science.gov (United States)

    Oh, Dong Hoon; Lee, In Young; Choi, Miyeon; Kim, Seok Hyeon; Son, Hyeon

    2012-08-01

    A previous animal study has shown the effects of erythropoietin (EPO) and its non-erythropoietic carbamylated derivative (CEPO) on neurogenesis in the dentate gyrus. In the present study, we sought to investigate the effect of EPO on adult hippocampal neurogenesis, and to compare the ability of EPO and CEPO promoting dendrite elongation in cultured hippocampal neural progenitor cells. Two-month-old male BALB/c mice were given daily injections of EPO (5 U/g) for seven days and were sacrificed 12 hours after the final injection. Proliferation assays demonstrated that EPO treatment increased the density of bromodeoxyuridine (BrdU)-labeled cells in the subgranular zone (SGZ) compared to that in vehicle-treated controls. Functional differentiation studies using dissociated hippocampal cultures revealed that EPO treatment also increased the number of double-labeled BrdU/microtubule-associated protein 2 (MAP2) neurons compared to those in vehicle-treated controls. Both EPO and CEPO treatment significantly increased the length of neurites and spine density in MAP2(+) cells. In summary, these results provide evidences that EPO and CEPO promote adult hippocampal neurogenesis and neuronal differentiation. These suggest that EPO and CEPO could be a good candidate for treating neuropsychiatric disorders such as depression and anxiety associated with neuronal atrophy and reduced hippocampal neurogenesis.

  5. High-dose erythropoietin for tissue protection

    DEFF Research Database (Denmark)

    Lund, Anton; Lundby, Carsten; Olsen, Niels Vidiendal

    2014-01-01

    BACKGROUND: The discovery of potential anti-apoptotic and cytoprotective effects of recombinant human erythropoietin (rHuEPO) has led to clinical trials investigating the use of high-dose, short-term rHuEPO therapy for tissue protection in conditions such as stroke and myocardial infarction....... Experimental studies have been favourable, but the clinical efficacy has yet to be validated. MATERIALS AND METHODS: We have reviewed clinical studies regarding the use of high-dose, short-term rHuEPO therapy for tissue protection in humans with the purpose to detail the safety and efficacy of r...... no effect of rHuEPO therapy on measures of tissue protection. Five trials including 1025 patients reported safety concerns in the form of increased mortality or adverse event rates. No studies reported reduced mortality. CONCLUSIONS: Evidence is sparse to support a tissue-protective benefit of r...

  6. Erythropoietin-mediated tissue protection: reducing collateral damage from the primary injury response.

    Science.gov (United States)

    Brines, M; Cerami, A

    2008-11-01

    In its classic hormonal role, erythropoietin (EPO) is produced by the kidney and regulates the number of erythrocytes within the circulation to provide adequate tissue oxygenation. EPO also mediates other effects directed towards optimizing oxygen delivery to tissues, e.g. modulating regional blood flow and reducing blood loss by promoting thrombosis within damaged vessels. Over the past 15 years, many unexpected nonhaematopoietic functions of EPO have been identified. In these more recently appreciated nonhormonal roles, locally-produced EPO signals through a different receptor isoform and is a major molecular component of the injury response, in which it counteracts the effects of pro-inflammatory cytokines. Acutely, EPO prevents programmed cell death and reduces the development of secondary, pro-inflammatory cytokine-induced injury. Within a longer time frame, EPO provides trophic support to enable regeneration and healing. As the region immediately surrounding damage is typically relatively deficient in endogenous EPO, administration of recombinant EPO can provide increased tissue protection. However, effective use of EPO as therapy for tissue injury requires higher doses than for haematopoiesis, potentially triggering serious adverse effects. The identification of a tissue-protective receptor isoform has facilitated the engineering of nonhaematopoietic, tissue-protective EPO derivatives, e.g. carbamyl EPO, that avoid these complications. Recently, regions within the EPO molecule mediating tissue protection have been identified and this has enabled the development of potent tissue-protective peptides, including some mimicking EPO's tertiary structure but unrelated in primary sequence.

  7. Erythropoietin in heart failure : pathology and protection

    NARCIS (Netherlands)

    Westenbrink, Berend Daan

    2008-01-01

    Anemia is common in chronic heart failure (CHF) patients and related to impaired survival. The etiology of anemia in CHF-patients is often unknown. We hypothesized that dysregulation of erythropoietin (EPO) synthesis by the kidney or an altered sensitivity of the bone marrow to EPO might represent c

  8. Erythropoietin

    DEFF Research Database (Denmark)

    Miskowiak, Kamilla W; Vinberg, Maj; Harmer, Catherine J

    2012-01-01

    Current pharmacological treatments for depression have a significant treatment-onset-response delay, an insufficient efficacy for many patients and fail to reverse cognitive dysfunction. Erythropoietin (EPO) has neuroprotective and neurotrophic actions and improves cognitive function in animal...

  9. Tissue protection by erythropoietin: new findings in a moving field.

    Science.gov (United States)

    Nangaku, Masaomi

    2013-09-01

    Two groups elucidate novel mechanisms of tissue protection by erythropoietin (EPO). Hu et al. demonstrate that Klotho's protective effect against oxidant-induced cytotoxicity is partially mediated by an increase in the endogenous expression of the classical EPO receptor (EpoR). While erythropoiesis is stimulated by the canonical EpoR homodimer, the tissue-protective effects of EPO are mediated through a heterodimeric 'tissue-protective' receptor. Coldewey et al. demonstrate a protective role of the 'tissue-protective' EpoR against acute kidney injury.

  10. Relationship between serum carbamylation and erythropoietin resistance in dialysis patients%透析患者血清氨甲酰化水平与促红细胞生成素抵抗的关系研究

    Institute of Scientific and Technical Information of China (English)

    吴红艳

    2016-01-01

    Objective To explore the relationship between the level of serum carbamylation and erythropoietin (EPO) resistance in dialysis patients .Methods A total of 40 patients were enrolled in the study who accepted maintenance hemodialysis therapy .The patients were divided into the EPO resistance group and non‐EPO resistance group according to the dose of recombinant human erythropoietin (EPO) and hemoglobin/hematocrit (Hb/Hct) .The level of carbamylated albumin (c‐Alb) ,albumin (Alb) ,high sen‐sitivity C reactive protein (hs‐CRP) ,interleukin‐6 (IL‐6) ,serum phosphate (P) ,myeloperoxidase (MPO) ,usea nitrogen (BUN ) , ferritin (Fer) and parathyroid hormone (PT H) were detected and compared between the two groups .Results The level of c‐Alb in EPO resistance group was significantly higher than that of the non‐EPO resistance group(P < 0 .05) .And the level of c‐Alb was positively correlated with the the dose of EPO which was quantized by the weight per week .Conclusion The level of c‐Alb could reflect the load of carbamylation in dialysis patients ,in addition ,c‐Alb is correlated with EPO resistance as well as could predict the patients′ condition .%目的:探讨维持性血液透析患者血清氨甲酰化水平与促红细胞生成素抵抗的关系。方法选取于血液净化科行常规血液透析治疗的患者40例,根据重组人红细胞生成素(rhEPO)用量和血红蛋白/红细胞压积(Hb/Hct)是否达标分为促红细胞生成素(EPO)抵抗组和非 EPO 抵抗组。其中 EPO 抵抗组15例,非 EPO 抵抗组25例。检测两组患者血清氨甲酰化清蛋白(c‐Alb)、清蛋白(Alb)、高敏 C 反应蛋白(hs‐CRP)、白细胞介素‐6(IL‐6)、血磷(P)、髓过氧化物酶(MPO )、尿素氮(BUN )、铁蛋白(Fer)、甲状旁腺素(PT H)。结果促 EPO 抵抗组的 c‐Alb 水平明显高于非 EPO 抵抗组,差异有统计学意义(P<0.05

  11. Protein carbamylation is a hallmark of aging

    Science.gov (United States)

    Gorisse, Laëtitia; Pietrement, Christine; Vuiblet, Vincent; Schmelzer, Christian E. H.; Duca, Laurent; Debelle, Laurent; Fornès, Paul; Jaisson, Stéphane; Gillery, Philippe

    2016-01-01

    Aging is a progressive process determined by genetic and acquired factors. Among the latter are the chemical reactions referred to as nonenzymatic posttranslational modifications (NEPTMs), such as glycoxidation, which are responsible for protein molecular aging. Carbamylation is a more recently described NEPTM that is caused by the nonenzymatic binding of isocyanate derived from urea dissociation or myeloperoxidase-mediated catabolism of thiocyanate to free amino groups of proteins. This modification is considered an adverse reaction, because it induces alterations of protein and cell properties. It has been shown that carbamylated proteins increase in plasma and tissues during chronic kidney disease and are associated with deleterious clinical outcomes, but nothing is known to date about tissue protein carbamylation during aging. To address this issue, we evaluated homocitrulline rate, the most characteristic carbamylation-derived product (CDP), over time in skin of mammalian species with different life expectancies. Our results show that carbamylation occurs throughout the whole lifespan and leads to tissue accumulation of carbamylated proteins. Because of their remarkably long half-life, matrix proteins, like type I collagen and elastin, are preferential targets. Interestingly, the accumulation rate of CDPs is inversely correlated with longevity, suggesting the occurrence of still unidentified protective mechanisms. In addition, homocitrulline accumulates more intensely than carboxymethyl-lysine, one of the major advanced glycation end products, suggesting the prominent role of carbamylation over glycoxidation reactions in age-related tissue alterations. Thus, protein carbamylation may be considered a hallmark of aging in mammalian species that may significantly contribute in the structural and functional tissue damages encountered during aging. PMID:26712018

  12. Renal Cell Protection of Erythropoietin beyond Correcting The Anemia in Chronic Kidney Disease Patients.

    Science.gov (United States)

    Nasri, Hamid

    2014-01-01

    -erythropoietic tissue/ organ protective efficacy of erythropoietin has become evident, especially in the kidneys (5-12). Various investigations have shown the kidney protective property of erythropoietin in acute kidney injury. In a study to evaluate the ameliorative effects of erythropoietin on renal tubular cells, we studied 40 male rats. We found that erythropoietin was able to prevent the increase in serum creatinine and blood urea nitrogen. Furthermore, co-administration of gentamicin and erythropoietin effectively reduced kidney tissue damage compared to the control group. However, the protective properties of erythropoietin were also evident in our study. When the drug was applied after gentamicin- induced tubular damage we were able to show that the drug was still effective after tissue injury onset. This indicates that erythropoietin may have curative effects in addition to its preventive properties (13). Thus, erythropoietin is a promising kidney protective agent to prevent, ameliorate or attenuate tubular damage induced by gentamicin or other nephrotoxic agents that act in a similar manner to this drug (14-17). Recent studies have elucidated the cellular mechanism involved in kidney erythropoietin production and the consequent events that lead to kidney fibrosis, showing that they are closely related to each other (18-20). In contrast to previous findings, fibroblasts originating from damaged renal tubular epithelial cells do not have an important role in kidney fibrosis, but renal erythropoietin- producing cells, stemming from neural crests, have been shown to trans-differentiate into myofibroblasts after long-term exposure to inflammatory situations related to kidney fibrosis. In fact, almost all myofibroblasts expressing α-smooth muscle actin originate from renal erythropoietin-producing cells, which are naturally peritubular interstitial fibroblastic cells expressing neural cell marker genes but not α-smooth muscle actin. Macrophages and myofibroblasts are responsible

  13. No evidence for protective erythropoietin alpha signalling in rat hepatocytes

    Directory of Open Access Journals (Sweden)

    Frede Stilla

    2009-04-01

    Full Text Available Abstract Background Recombinant human erythropoietin alpha (rHu-EPO has been reported to protect the liver of rats and mice from ischemia-reperfusion injury. However, direct protective effects of rHu-EPO on hepatocytes and the responsible signalling pathways have not yet been described. The aim of the present work was to study the protective effect of rHu-EPO on warm hypoxia-reoxygenation and cold-induced injury to hepatocytes and the rHu-EPO-dependent signalling involved. Methods Loss of viability of isolated rat hepatocytes subjected to hypoxia/reoxygenation or incubated at 4°C followed by rewarming was determined from released lactate dehydrogenase activity in the absence and presence of rHu-EPO (0.2–100 U/ml. Apoptotic nuclear morphology was assessed by fluorescence microscopy using the nuclear fluorophores H33342 and propidium iodide. Erythropoietin receptor (EPOR, EPO and Bcl-2 mRNAs were quantified by real time PCR. Activation of JAK-2, STAT-3 and STAT-5 in hepatocytes and rat livers perfused in situ was assessed by Western blotting. Results In contrast to previous in vivo studies on ischemia-reperfusion injury to the liver, rHu-EPO was without any protective effect on hypoxic injury, hypoxia-reoxygenation injury and cold-induced apoptosis to isolated cultured rat hepatocytes. EPOR mRNA was identified in these cells but specific detection of the EPO receptor protein was not possible due to the lack of antibody specificity. Both, in the cultured rat hepatocytes (10 U/ml for 15 minutes and in the rat liver perfused in situ with rHu-EPO (8.9 U/ml for 15 minutes no evidence for EPO-dependent signalling was found as indicated by missing effects of rHu-EPO on phosphorylation of JAK-2, STAT-3 and STAT-5 and on the induction of Bcl-2 mRNA. Conclusion Together, these results indicate the absence of any protective EPO signalling in rat hepatocytes. This implies that the protection provided by rHu-EPO in vivo against ischemia-reperfusion and

  14. Protection against cisplatin-induced nephrotoxicity by recombinant human erythropoietin.

    Science.gov (United States)

    Yalcin, Suayib; Müftüoğlu, Sevda; Cetin, Eren; Sarer, Banu; Yildirim, Berna Akkuş; Zeybek, Dilara; Orhan, Bülent

    2003-01-01

    Cisplatin (CDDP) is a potent nephrotoxin, and nephrotoxicity is its most important dose-limiting toxicity. In this study, we aimed to investigate the role of recombinant human erythropoietin (rhEPO) in the protection of cisplatin-induced nephrotoxicity and compare its efficacy with the cell-protective agent amifostine. All experiments were conducted on female Wistar albino rats. Animals were randomly assigned to four groups, each including six rats. Group A received only CDDP, group B received CDDP plus rhEPO, group C received CDDP plus amifostine, and group D received only rhEPO. At the end of 7 wk, hemoglobin (Hgb), hematocrite (Htc), blood urea nitrogen (BUN), and creatinine (Cr) levels were determined and kidneys of the rats were removed. The weights of the kidneys were measured and sent for histopathological examination. Proximal tubules from four areas of the kidney (outer cortex, inner cortex, the medullary ray, and outer stripe of outer medulla [OSOM]) were evaluated. There were statistically significant differences among the groups in terms of tubular scores, including overall renal tubular score, cortex, inner cortex, OSOM, and medullary ray tubular scores, and Htc levels. Group A rats had the worse tubular scores in all categories when compared to group D rats. When the results of groups B and C were compared, there were no differences in terms of BUN, Cr levels, and tubular scores, but the Htc level was significantly higher in group B. Group B rats had better overall and OSOM tubular scores when compared to group A. Group C also had better overall and OSOM tubular scores compared to group A. The present study showed for the first time that rhEPO plays an important role in the prevention of cisplatin-induced nephrotoxicity and it is as effective as amifostine.

  15. [Carbamylation of proteins--mechanism, causes and consequences].

    Science.gov (United States)

    Pieniążek, Anna; Gwoździński, Krzysztof

    2016-05-16

    Carbamylation (carbamoylation) is a post-translational modification resulting from the nonenzymatic reaction between isocyanic acid and free functional groups of proteins, in particular with the free amino groups. This reaction alters structural and functional properties of proteins and results in faster aging of proteins. Urea present in the body can be transformed into cyanate and its more reactive form, isocyanic acid. High concentration of urea is associated with some diseases, especially with chronic renal failure and atherosclerosis. In human tissues, urea and cyanate are in equilibrium in aqueous solutions. Surprisingly, concentration of isocyanate in the body is much lower than it would appear from the kinetic parameters of urea decomposition. The low concentration of isocyanic acid results from its high reactivity and short half-life. In this review we describe the biochemical mechanism of carbamylation of proteins and free amino acids. We summarize the literature data for carbamylation of hemoglobin, lipoproteins, albumin, membrane proteins and erythropoietin in chronic renal failure. In summary, the carbamylation of proteins may have a negative impact on their biological activity and may contribute to the deterioration of patients with chronic renal failure.

  16. Erythropoietin-mediated protection in kidney transplantation : Nonerythropoietic EPO derivatives improve function without increasing risk of cardiovascular events

    NARCIS (Netherlands)

    van Rijt, Willem G; van Goor, Harry; Ploeg, Rutger J; Leuvenink, Henri G D

    2014-01-01

    The protective, nonerythropoietic effects of erythropoietin (EPO) have become evident in preclinical models in renal ischaemia/reperfusion injury and kidney transplantation. However, four recently published clinical trials using high-dose EPO treatment following renal transplantation did not reveal

  17. The potential protective effects of erythropoietin and estrogen on ...

    African Journals Online (AJOL)

    Noha I. Hussien

    2015-12-30

    Dec 30, 2015 ... Conclusion: It seems that EPO could protect the kidney against RIR, while this protective effect ... EPO is an essential growth factor of hemopoietic progeni- ...... Jerald Mahesh, Kuncha Madhusudana, Rachamalla Shyam Sun-.

  18. The protective effect of erythropoietin pretreatment on ischemic acute renal failure in rats

    Institute of Scientific and Technical Information of China (English)

    Jing-Guang Liao; Min-Yan Li; Xiao-Hua Wang; Qiang Xie

    2016-01-01

    Objective: To investigate the protective effect of erythropoietin (EPO) pretreatment on ischemic acute renal failure in rats and its molecular mechanism. Methods: Male Sprague–Dawley rats were selected as experimental animals and they were randomly divided into the sham operation group (sham group), ischemia-reperfusion injury group (IRI group) and EPO pretreatment group (EPO group). Each group had 15 rats. Serum specimens and renal specimens were collected after a IRI model was built for 4, 12 and 24 h. The contents of creatinine, urea nitrogen tumor necrosis factor-alpha (TNF-a), interleukin-1 (IL-1), IL-6 and IL-8 in serum and the contents of TNF-a, IL-1, IL-6, IL-8, toll like receptor 4 (TLR4) and nuclear factor-kappa B (NF-kB) in the kidney tissue were determined. Results: After 4, 12 and 24 h reperfusion, there were differences between the contents of creatinine, urea nitrogen TNF-a, IL-1, IL-6 and IL-8 in serum and the contents of TNF-a, IL-1, IL-6, IL-8, TLR4 and NF-kB in rats of the three groups (P Conclusions: EPO pretreatment can protect the renal function of rats with ischemic acute renal failure by inhibiting the TLR4/NF-kB pathway mediated inflammatory responses.

  19. Protective effects of erythropoietin pretreatment on myocardium with hypoxia/reoxygenation injury in rats

    Institute of Scientific and Technical Information of China (English)

    QIN Chuan; XIAO Ying-bin; ZHONG Qan-jin; CHEN Lin; WANG Xue-feng

    2004-01-01

    To establish the rat model with myocardial hypoxia/reoxygenation (H/R) injury, and investigatethe protective effect of EPO pretreatment on the myocardium. Methods: Sixty male adult Wistar rats were randomly divided in-to 3 groups: control group, H/R group, and EPO group, 20 in each group. The rats in EPO group accepted injection of 5 000U/kg recombinant human erythropoietin (RHuEPO) through vein, and the other rats accepted the injection of the same volumeof saline. Twenty-four hours after the injection, rats in the EPO and H/R groups were put into the hypoxia environment for 12h and then returned to the normoxic environment for 2 h, and then the samples of blood and myocardium were collected. Serummyocardial enzyme activity, apoptosis, ultrastructure, myocardial MDA contents, EPO receptor (EPOR) expression in cardiacmyocytes and cardiac functions were tested. Results: EPOR expression was positive in cardiac myocytes of adult rat according to the result of immunohistochemitry assaying. Compared to those in H/R group, rats in EPO group presented lighter injury ofmyocardial ultrastructure, the reduction of serum myocardial enzyme activity, inhibition of apoptosis, the better recovery ofcardiac functions, and the Ness production of oxygen-derived free radicals. Conclusion: Adult rat cardiac myocytes could ex-press EPOR, and EPO pretreatment produced protective effects on myocardium with H/R injury.

  20. 21 CFR 862.1535 - Ornithine carbamyl transferase test system.

    Science.gov (United States)

    2010-04-01

    ... carbamyl transferase (OCT) in serum. Ornithine carbamyl transferase measurements are used in the diagnosis and treatment of liver diseases, such as infectious hepatitis, acute cholecystitis (inflammation of the gall bladder), cirrhosis, and liver metastases. (b) Classification. Class I (general controls...

  1. Renal Cell Protection of Erythropoietin beyond Correcting The Anemia in Chronic Kidney Disease Patients

    OpenAIRE

    Hamid Nasri

    2013-01-01

    Currently many patients with chronic renal failure have profited from the use of erythropoietin to correct anemia (1,2). In chronic kidney disease, anemia is believed to be a surrogate index for tissue hypoxia that continues preexisting renal tissue injury (1-3). Erythropoietin is an essential glycoprotein that accelerates red blood cell maturation from erythroid progenitors and facilitates erythropoiesis. It is a 30.4 kD glycoprotein and class I cytokine containing 165 amino acids (3,4). App...

  2. Erythropoietin protects myocardin-expressing cardiac stem cells against cytotoxicity of tumor necrosis factor-{alpha}

    Energy Technology Data Exchange (ETDEWEB)

    Madonna, Rosalinda [The Center for Cardiovascular Biology and Atherosclerosis Research, The University of Texas Health Science Center at Houston, Texas (United States); Institute of Cardiology, and Center of Excellence on Aging, ' G. d' Annunzio' University, Chieti (Italy); Shelat, Harnath; Xue, Qun; Willerson, James T. [The Center for Cardiovascular Biology and Atherosclerosis Research, The University of Texas Health Science Center at Houston, Texas (United States); The Texas Heart Institute at St. Luke' s Episcopal Hospital, Houston, Texas (United States); De Caterina, Raffaele [Institute of Cardiology, and Center of Excellence on Aging, ' G. d' Annunzio' University, Chieti (Italy); Geng, Yong-Jian, E-mail: yong-jian.geng@uth.tmc.edu [The Center for Cardiovascular Biology and Atherosclerosis Research, The University of Texas Health Science Center at Houston, Texas (United States); The Texas Heart Institute at St. Luke' s Episcopal Hospital, Houston, Texas (United States)

    2009-10-15

    Cardiac stem cells are vulnerable to inflammation caused by infarction or ischemic injury. The growth factor, erythropoietin (Epo), ameliorates the inflammatory response of the myocardium to ischemic injury. This study was designed to assess the role of Epo in regulation of expression and activation of the cell death-associated intracellular signaling components in cardiac myoblasts stimulated with the proinflammatory cytokine tumor necrosis factor (TNF)-{alpha}. Cardiac myoblasts isolated from canine embryonic hearts characterized by expression of myocardin A, a promyogenic transcription factor for cardiovascular muscle development were pretreated with Epo and then exposed to TNF-{alpha}. Compared to untreated cells, the Epo-treated cardiac myoblasts exhibited better morphology and viability. Immunoblotting revealed lower levels of active caspase-3 and reductions in iNOS expression and NO production in Epo-treated cells. Furthermore, Epo pretreatment reduced nuclear translocation of NF-{kappa}B and inhibited phosphorylation of inhibitor of kappa B (I{kappa}B) in TNF-{alpha}-stimulated cardiac myoblasts. Thus, Epo protects cardiac myocyte progenitors or myoblasts against the cytotoxic effects of TNF-{alpha} by inhibiting NF-{kappa}B-mediated iNOS expression and NO production and by preventing caspase-3 activation.

  3. Investigation of the protective effect of erythropoietin on spinal cord injury in rats.

    Science.gov (United States)

    Hong, Zhenghua; Hong, Huaxing; Chen, Haixiao; Wang, Zhangfu; Hong, Dun

    2011-09-01

    Erythropoietin (EPO) is a promising therapeutic agent used in a variety of spinal cord injuries. Therefore, identifying the specific molecular pathway mediating the neuronal protective effect of EPO after spinal cord injury (SCI) is of great value to the patients concerned. Platelet-derived growth factor (PDGF)-B is an important factor in the recovery of neurological function. We explored changes in the expression of PDGF-B in spinal cord injury rats after receiving EPO treatment. We used a weight-drop contusion SCI model, and EPO treatment group rats received single doses of EPO (1,000 U/kg i.p.) immediately after the operation. Seven days after the operation, the results revealed a more rapid recovery as noted by the higher BBB scores, less disruption and more neuronal regeneration of the spinal cord in the EPO treatment group than that in the SCI group. PDGF-B expression also increased in the EPO treatment group compared to that in the SCI group (PEPO on spinal cord injury in rats, which may help to explain the quick recovery after EPO treatment of spinal cord injury.

  4. Erythropoietin-derived nonerythropoietic peptide ameliorates experimental autoimmune neuritis by inflammation suppression and tissue protection.

    Directory of Open Access Journals (Sweden)

    Yuqi Liu

    Full Text Available Experimental autoimmune neuritis (EAN is an autoantigen-specific T-cell-mediated disease model for human demyelinating inflammatory disease of the peripheral nervous system. Erythropoietin (EPO has been known to promote EAN recovery but its haematopoiesis stimulating effects may limit its clinic application. Here we investigated the effects and potential mechanisms of an EPO-derived nonerythropoietic peptide, ARA 290, in EAN. Exogenous ARA 290 intervention greatly improved EAN recovery, improved nerve regeneration and remyelination, and suppressed nerve inflammation. Furthermore, haematopoiesis was not induced by ARA 290 during EAN treatment. ARA 290 intervention suppressed lymphocyte proliferation and altered helper T cell differentiation by inducing increase of Foxp3+/CD4+ regulatory T cells and IL-4+/CD4+ Th2 cells and decrease of IFN-γ+/CD4+ Th1 cells in EAN. In addition, ARA 290 inhibited inflammatory macrophage activation and promoted its phagocytic activity. In vitro, ARA 290 was shown to promote Schwann cell proliferation and inhibit its inflammatory activation. In summary, our data demonstrated that ARA 290 could effectively suppress EAN by attenuating inflammation and exerting direct cell protection, indicating that ARA 290 could be a potent candidate for treatment of autoimmune neuropathies.

  5. Erythropoietin protects epithelial cells from excessive autophagy and apoptosis in experimental neonatal necrotizing enterocolitis.

    Directory of Open Access Journals (Sweden)

    Yueyue Yu

    Full Text Available Neonatal necrotizing enterocolitis (NEC is a devastating gastrointestinal disease of preterm infants. Increased intestinal epithelium permeability is an early event in NEC pathogenesis. Autophagy and apoptosis are induced by multiple stress pathways which may impact the intestinal barrier, and they have been associated with pathogenesis of diverse gastrointestinal diseases including inflammatory bowel disease. Using both in vitro and in vivo models, this study investigates autophagy and apoptosis under experimental NEC stresses. Furthermore this study evaluates the effect of erythropoietin (Epo, a component of breast milk previously shown to decrease the incidence of NEC and to preserve intestinal barrier function, on intestinal autophagy and apoptosis. It was found that autophagy and apoptosis are both rapidly up regulated in NEC in vivo as indicated by increased expression of the autophagy markers Beclin 1 and LC3II, and by evidence of apoptosis by TUNEL and cleaved caspase-3 staining. In the rat NEC experimental model, autophagy preceded the onset of apoptosis in intestine. In vitro studies suggested that Epo supplementation significantly decreased both autophagy and apoptosis via the Akt/mTOR signaling pathway and the MAPK/ERK pathway respectively. These results suggest that Epo protects intestinal epithelium from excessive autophagy and apoptosis in experimental NEC.

  6. PROTECTIVE EFFECTS OF ERYTHROPOIETIN ON MYO-CARDIUM AGAINST ISCHEMIA-REPERFUSION INJURY

    Institute of Scientific and Technical Information of China (English)

    YANG Di-cheng; XIAO Ming-di; LU Cheng-bao; LV Zhi-qian; DUAN Liang

    2008-01-01

    Objective To explore the protective effects of erythropoietin (EPO) on myocardium against ischemia-reperfusion injury (IRI). Methods The Langendorff model of isolated rat heart was set up and a 3-stage protocol was performed: 20 min stabilization, 30 min global ischemia, and 120 min reperfusion. Sixty SD rats were randomly divided into sham group, ischemia-reperfusion group (I/R group ) and EPO treated group (EPO group). Heart rate (HR), left ventricular developed pressure (LVDP), the first derivative (△dp/dt max) and coronary flow (CF) were recorded at the 20th minute of stabilization and the 120th minute of reperfusion. Lactate dehydrogenase (LDH) and creatine phosphokinase (CK) in the coronary effluent at the 60th minute of reperfusion, the levels of myocardial nuclear factor-kappa B (NF-KB) and the myocardial content of tumor necrosis factor-α (TNF-α) ,interleukin-1β (IL-1β) were measured at the end of reperfusion. Results No statistically significant differences were observed on the aspect of hemodynamic parameters among the groups at the 20th minute of stabilization, but at the 120th minute of reperfusion, the recovery ratio of EPO group was higher than I/R group (P<0.05). LDH and CK in the coronary effluent, the levels of myocardial NF-κB and TNF-α,IL-1β expression in EPO group were significantly lower than those in I/R group, but higher than sham group (P<0.05). Conclusion EPO has protective effects on myocardium against IRI possibly through the mechanism of relieving the myocardial inflammatory reaction by regulating the activation of NF-κB and then decreasing the expression of proinflammatory factors TNF-α and IL-1β.

  7. Protective effects of erythropoietin in cardiac ischemia - From bench to bedside

    NARCIS (Netherlands)

    Lipsic, Erik; Schoemaker, Regien G.; van der Meer, Peter; Voors, Adriaan A.; van Veldhuisen, Dirk J.; van Gilst, Wiek H.

    2006-01-01

    Erythropoietin (EPO) is a hypoxia-induced hormone produced in the kidneys that stimulates hematopoiesis in the bone marrow. However, recent studies have also shown important nonhematopoietic effects of EPO. A functional EPO receptor is found in the cardiovascular system, including endothelial cells

  8. The protective effect of erythropoietin pretreatment on ischemic acute renal failure in rats

    Directory of Open Access Journals (Sweden)

    Jing-Guang Liao

    2016-09-01

    Full Text Available Objective: To investigate the protective effect of erythropoietin (EPO pretreatment on ischemic acute renal failure in rats and its molecular mechanism. Methods: Male Sprague–Dawley rats were selected as experimental animals and they were randomly divided into the sham operation group (sham group, ischemia-reperfusion injury group (IRI group and EPO pretreatment group (EPO group. Each group had 15 rats. Serum specimens and renal specimens were collected after a IRI model was built for 4, 12 and 24 h. The contents of creatinine, urea nitrogen tumor necrosis factor-alpha (TNF-a, interleukin-1 (IL-1, IL-6 and IL-8 in serum and the contents of TNF-a, IL- 1, IL-6, IL-8, toll like receptor 4 (TLR4 and nuclear factor-kappa B (NF-kB in the kidney tissue were determined. Results: After 4, 12 and 24 h reperfusion, there were differences between the contents of creatinine, urea nitrogen TNF-a, IL-1, IL-6 and IL-8 in serum and the contents of TNF-a, IL-1, IL-6, IL-8, TLR4 and NF-kB in rats of the three groups (P < 0.05. The contents of creatinine, urea nitrogen TNF-a, IL-1, IL-6 and IL-8 in serum and the contents of TNF-a, IL-1, IL-6, IL-8, TLR4 and NF-kB in the kidney tissue in rats of the IRI group were significantly higher than those of the sham group; and the contents of creatinine, urea nitrogen TNF-a, IL-1, IL-6 and IL-8 in serum and the contents of TNF-a, IL-1, IL-6, IL- 8, TLR4 and NF-kB in the kidney tissue in rats of the EPO group were distinctly lower than those of the IRI group. Conclusions: EPO pretreatment can protect the renal function of rats with ischemic acute renal failure by inhibiting the TLR4/NF-kB pathway mediated inflammatory responses.

  9. Protective effect of bone marrow mesenchymal stem cells combined with erythropoietin therapy on spinal cord injury rat model

    Institute of Scientific and Technical Information of China (English)

    Peng Xie; Wen-Hui Ruan

    2016-01-01

    Objective:To study the protective effect of bone marrow mesenchymal stem cells combined with erythropoietin therapy on spinal cord injury rat model.Methods: SD rats were selected as experimental animals, spinal cord injury rat model was built by striking spinal cord with Hatteras Instruments PCI3000, and model rats were divided into control group, bone marrow mesenchymal stem cells (BMSCs) group, erythropoietin (EPO) group and BMSCs combined with EPO group according to different treatment methods. Then number of apoptotic cells in spinal cord tissue, contents of neural markers and neurotrophic factors as well as expression of apoptosis and injury molecules was detected.Results:Number of apoptotic cells as well as mRNA contents of Caspase-3 and c-fos of BMSCs group, EPO group and BMSCs+EPO group was lower than those of control group, and number of apoptotic cells as well as mRNA contents of Caspase-3 and c-fos of BMSCs+EPO group were lower than those of BMSCs group and EPO group; mRNA contents of NF-200 and MBP as well as protein contents of NGF and BDNF in spinal cord tissue of BMSCs group, EPO group and BMSCs+EPO group were higher than those of control group, and mRNA contents of NF-200 and MBP as well as protein contents of NGF and BDNF in spinal cord tissue of BMSCs+EPO group were higher than those of BMSCs group and EPO group.Conclusions:Bone marrow mesenchymal stem cells combined with erythropoietin therapy can inhibit cell apoptosis in the injured spinal cord tissue, increase neurotrophic factor levels and inhibit apoptosis and injury molecule expression; it has protective effect on spinal cord injury.

  10. Erythropoietin-mediated protection in kidney transplantation: nonerythropoietic EPO derivatives improve function without increasing risk of cardiovascular events.

    Science.gov (United States)

    van Rijt, Willem G; van Goor, Harry; Ploeg, Rutger J; Leuvenink, Henri G D

    2014-03-01

    The protective, nonerythropoietic effects of erythropoietin (EPO) have become evident in preclinical models in renal ischaemia/reperfusion injury and kidney transplantation. However, four recently published clinical trials using high-dose EPO treatment following renal transplantation did not reveal any protective effect for short-term renal function and even reported an increased risk of thrombosis. This review focusses on the current status of protective pathways mediated by EPO, the safety concerns using high EPO dosage and discusses the discrepancies between pre-clinical and clinical studies. The protective effects are mediated by binding of EPO to a heteromeric receptor complex consisting of two β-common receptors and two EPO receptors. An important role for the activation of endothelial nitric oxide synthase is proposed. EPO-mediated cytoprotection still has enormous potential. However, only nonerythropoietic EPO derivatives may induce protection without increasing the risk of cardiovascular events. In preclinical models, nonerythropoietic EPO derivatives, such as carbamoylated EPO and ARA290, have been tested. These EPO derivatives improve renal function and do not affect erythropoiesis. Therefore, nonerythropoietic EPO derivatives may be able to render EPO-mediated cytoprotection useful and beneficial for clinical transplantation.

  11. Modulation of Protein Fragmentation Through Carbamylation of Primary Amines

    Science.gov (United States)

    Greer, Sylvester M.; Holden, Dustin D.; Fellers, Ryan; Kelleher, Neil L.; Brodbelt, Jennifer S.

    2017-08-01

    We evaluate the impact of carbamylation of the primary amines of the side-chains of Lys and the N-termini on the fragmentation of intact protein ions and the chromatographic properties of a mixture of E. coli ribosomal proteins. The fragmentation patterns of the six unmodified and carbamylated proteins obtained by higher energy collision dissociation (HCD) and ultraviolet photodissociation (UVPD) were compared. Carbamylation significantly reduced the total number of protons retained by the protein owing to the conversion of basic primary amines to non-basic carbamates. Carbamylation caused a significant negative impact on fragmentation of the protein by HCD (i.e., reduced sequence coverage and fewer diagnostic fragment ions) consistent with the mobile proton model, which correlates peptide fragmentation with charge distribution and the opportunity for charge-directed pathways. In addition, fragmentation was enhanced near the N- and C-termini upon HCD of carbamylated proteins. For LCMS/MS analysis of E. coli ribosomal proteins, the retention times increased by 16 min on average upon carbamylation, an outcome attributed to the increased hydrophobicity of the proteins after carbamylation. As noted for both the six model proteins and the ribosomal proteins, carbamylation had relatively little impact on the distribution or types of fragment ions product by UVPD, supporting the proposition that the mechanism of UVPD for intact proteins does not reflect the mobile proton model.

  12. Enzymatic syntheses of carbamyl phosphate, L-citrulline, and N-carbamyl L-aspartate labeled with either 13N or 11C.

    Science.gov (United States)

    Gelbard, A S; Kaseman, D S; Rosenspire, K C; Meister, A

    1985-01-01

    [13N]- and [11C]carbamyl phosphate, L-[omega-13N]citrulline, L-[ureido-11C]citrulline, [carbamyl-13N]- and [carbamyl-11C]carbamyl-L-aspartate were synthesized using carbamyl phosphate synthetase co-immobilized with either aspartate transcarbamylase or ornithine transcarbamylase. Carbamyl L-[13N]aspartate was enzymatically prepared from carbamyl phosphate and L-[13N]aspartate. The tissue distribution of radioactivity in mice after injection of radiolabeled ammonia, carbamyl phosphate or citrulline was studied. The tissue distribution of isotope derived from [13N]carbamyl phosphate and [13N]ammonia were similar, with the exception of liver, brain and pancreas, in which 13NH3 uptake was higher after retroorbital injection. The distribution of label derived from L-[omega-13N]- and L-[ureido-11C]citrulline was similar. Substantial tumor (Sarcoma-180) uptake of label from L-citrulline was observed.

  13. Erythropoietin: Recent Developments in the Treatment of Spinal Cord Injury

    Directory of Open Access Journals (Sweden)

    Stephana Carelli

    2011-01-01

    Full Text Available Erythropoietin (EPO, originally identified for its critical function in regulating production and survival of erythrocytes, is a member of the type 1 cytokine superfamily. Recent studies have shown that EPO has cytoprotective effects in a wide variety of cells and tissues. Here is presented the analysis of EPO effects on spinal cord injury (SCI, considering both animal experiments concerning to mechanisms of neurodegeneration in SCI and EPO as a neuroprotective agent, and some evidences coming from ongoing clinical trials. The evidences underling that EPO could be a promising therapeutic agent in a variety of neurological insults, including trauma, are mounting. In particular, it is highlighted that administration of EPO or other recently generated EPO analogues such as asialo-EPO and carbamylated-EPO demonstrate interesting preclinical and clinical characteristics, rendering the evaluation of these tissue-protective agents imperative in human clinical trials. Moreover the demonstration of rhEPO and its analogues’ broad neuroprotective effects in animal models of cord lesion and in human trial like stroke, should encourage scientists and clinicians to design clinical trials assessing the efficacy of these pharmacological compounds on SCI.

  14. Erythropoietin and Nonhematopoietic Effects.

    Science.gov (United States)

    Nekoui, Alireza; Blaise, Gilbert

    2017-01-01

    Erythropoietin (EPO) is the main regulator of red blood cell production. Since the 1990s, EPO has been used for the treatment of anemia associated with end-stage renal failure and chemotherapy. The erythropoietin receptors were found on other organs such as the brain, spinal cord, heart and skin. In addition, it has been shown that many tissues produce and locally release EPO in response to hypoxic, biochemical and physical stress. In cellular, animal and clinical studies, EPO protects tissues from ischemia and reperfusion injury, has antiapoptotic effects and improves regeneration after injury. In this article, we mainly review the nonhematopoietic effects and new possible clinical indications for EPO.

  15. β Common Receptor Mediates Erythropoietin-Conferred Protection on OxLDL-Induced Lipid Accumulation and Inflammation in Macrophages

    Directory of Open Access Journals (Sweden)

    Tzong-Shyuan Lee

    2015-01-01

    Full Text Available Erythropoietin (EPO, the key factor for erythropoiesis, also protects macrophage foam cells from lipid accumulation, yet the definitive mechanisms are not fully understood. β common receptor (βCR plays a crucial role in the nonhematopoietic effects of EPO. In the current study, we investigated the role of βCR in EPO-mediated protection in macrophages against oxidized low-density lipoprotein- (oxLDL- induced deregulation of lipid metabolism and inflammation. Here, we show that βCR expression was mainly in foamy macrophages of atherosclerotic aortas from apolipoprotein E-deficient mice. Results of confocal microscopy and immunoprecipitation analyses revealed that βCR was colocalized and interacted with EPO receptor (EPOR in macrophages. Inhibition of βCR activation by neutralizing antibody or small interfering RNA (siRNA abolished the EPO-conferred protection in oxLDL-induced lipid accumulation. Furthermore, EPO-promoted cholesterol efflux and upregulation of ATP-binding cassette (ABC transporters ABCA1 and ABCG1 were prevented by pretreatment with βCR neutralizing antibody or βCR siRNA. Additionally, blockage of βCR abrogated the EPO-conferred anti-inflammatory action on oxLDL-induced production of macrophage inflammatory protein-2. Collectively, our findings suggest that βCR may play an important role in the beneficial effects of EPO against oxLDL-elicited dysfunction of macrophage foam cells.

  16. The Protective Effects of Erythropoietin on Rat Glomerular Podocytes in Culture are Modulated by Extracellular Matrix Proteins

    Directory of Open Access Journals (Sweden)

    Jan Krtil

    2014-03-01

    Full Text Available Background/Aims: Podocytes are typically cultured on collagen I; however, collagen I is absent from healthy glomerular basement membranes. Erythropoietin (EPO is thought to protect podocytes in vivo. Here, we studied how various types of extracellular matrix (ECM proteins and EPO affect podocytes in culture. Methods: Primary rat podocytes were replated on collagen I, collagen IV, whole ECM extract, laminin, or bare plastic. Cellular adhesion (8 hours after plating, proliferation (5 days, 10 % serum, and resistance to serum deprivation (3 days, 0.5 % serum were assessed. BrdU incorporation and expression of podocyte-specific markers were employed as measures of cellular proliferation and differentiation, respectively. qPCR was used to verify expression of EPO receptor in cultured podocytes. Results: Cellular adhesion was similar on all ECM proteins and unaffected by EPO. Proliferation was accelerated by laminin and the ECM extract, but the final cell density was similar on all ECM surfaces. Collagen IV supported the serum-deprived cells better than the other ECM proteins. EPO (2-20 ng/ml improved viability of serum-deprived podocytes on collagen I, collagen IV, and ECM, but not on laminin or bare plastic. The cells expressed mRNA for EPO receptor. Conclusion: The physiological ECM proteins are more supportive of primary podocytic cultures compared with collagen I. The protective effects of EPO during serum deprivation are modulated by the cultivation surface.

  17. Neuronal erythropoietin overexpression protects mice against age-related hearing loss (presbycusis).

    Science.gov (United States)

    Naldi, Arianne Monge; Belfrage, Celina; Jain, Neha; Wei, Eric T; Martorell, Belén Canto; Gassmann, Max; Vogel, Johannes

    2015-12-01

    So far, typical causes of presbycusis such as degeneration of hair cells and/or primary auditory (spiral ganglion) neurons cannot be treated. Because erythropoietin's (Epo) neuroprotective potential has been shown previously, we determined hearing thresholds of juvenile and aged mice overexpressing Epo in neuronal tissues. Behavioral audiometry revealed in contrast to 5 months of age, that 11-month-old Epo-transgenic mice had up to 35 dB lower hearing thresholds between 1.4 and 32 kHz, and at the highest frequencies (50-80 kHz), thresholds could be obtained in aged Epo-transgenic only but not anymore in old C57BL6 control mice. Click-evoked auditory brainstem response showed similar results. Numbers of spiral ganglion neurons in aged C57BL6 but not Epo-transgenic mice were dramatically reduced mainly in the basal turn, the location of high frequencies. In addition, there was a tendency to better preservation of inner and outer hair cells in Epo-transgenic mice. Hence, Epo's known neuroprotective action effectively suppresses the loss of spiral ganglion cells and probably also hair cells and, thus, development of presbycusis in mice.

  18. Interplay between Endothelin and Erythropoietin in Astroglia: The Role in Protection against Hypoxia

    Directory of Open Access Journals (Sweden)

    Richard Schäfer

    2014-02-01

    Full Text Available We show that, under in vitro conditions, the vulnerability of astroglia to hypoxia is reflected by alterations in endothelin (ET-1 release and capacity of erythropoietin (EPO to regulate ET-1 levels. Exposure of cells to 24 h hypoxia did not induce changes in ET-1 release, while 48–72 h hypoxia resulted in increase of ET-1 release from astrocytes that could be abolished by EPO. The endothelin receptor type A (ETA antagonist BQ123 increased extracellular levels of ET-1 in human fetal astroglial cell line (SV-FHAS. The survival and proliferation of rat primary astrocytes, neural precursors, and neurons upon hypoxic conditions were increased upon administration of BQ123. Hypoxic injury and aging affected the interaction between the EPO and ET systems. Under hypoxia EPO decreased ET-1 release from astrocytes, while ETA receptor blockade enhanced the expression of EPO mRNA and EPO receptor in culture-aged rat astroglia. The blockade of ETA receptor can increase the availability of ET-1 to the ETB receptor and can potentiate the neuroprotective effects of EPO. Thus, the new therapeutic use of combined administration of EPO and ETA receptor antagonists during hypoxia-associated neurodegenerative disorders of the central nervous system (CNS can be suggested.

  19. Delayed administration of darbepoetin or erythropoietin protects against ischemic acute renal injury and failure.

    Science.gov (United States)

    Johnson, D W; Pat, B; Vesey, D A; Guan, Z; Endre, Z; Gobe, G C

    2006-05-01

    Administration of human recombinant erythropoietin (EPO) at time of acute ischemic renal injury (IRI) inhibits apoptosis, enhances tubular epithelial regeneration, and promotes renal functional recovery. The present study aimed to determine whether darbepoetin-alfa (DPO) exhibits comparable renoprotection to that afforded by EPO, whether pro or antiapoptotic Bcl-2 proteins are involved, and whether delayed administration of EPO or DPO 6 h following IRI ameliorates renal dysfunction. The model of IRI involved bilateral renal artery occlusion for 45 min in rats (N = 4 per group), followed by reperfusion for 1-7 days. Controls were sham-operated. Rats were treated at time of ischemia or sham operation (T0), or post-treated (6 h after the onset of reperfusion, T6) with EPO (5000 IU/kg), DPO (25 mug/kg), or appropriate vehicle by intraperitoneal injection. Renal function, structure, and immunohistochemistry for Bcl-2, Bcl-XL, and Bax were analyzed. DPO or EPO at T0 significantly abrogated renal dysfunction in IRI animals (serum creatinine for IRI 0.17 +/- 0.05 mmol/l vs DPO-IRI 0.08 +/- 0.03 mmol/l vs EPO-IRI 0.04 +/- 0.01 mmol/l, P = 0.01). Delayed administration of DPO or EPO (T6) also significantly abrogated subsequent renal dysfunction (serum creatinine for IRI 0.17 +/- 0.05 mmol/l vs DPO-IRI 0.06 +/- 0.01 mmol/l vs EPO-IRI 0.03 +/- 0.03 mmol/l, P = 0.01). There was also significantly decreased tissue injury (apoptosis, P EPO at T0 or T6. These results reaffirm the potential clinical application of DPO and EPO as novel renoprotective agents for patients at risk of ischemic acute renal failure or after having sustained an ischemic renal insult.

  20. Erythropoietin protects cardiomyocytes from cell death during hypoxia/reperfusion injury through activation of survival signaling pathways.

    Directory of Open Access Journals (Sweden)

    Asiya A Parvin

    Full Text Available Hypoxia/Reoxygenation (H/R cardiac injury is of great importance in understanding Myocardial Infarctions, which affect a major part of the working population causing debilitating side effects and often-premature mortality. H/R injury primarily consists of apoptotic and necrotic death of cardiomyocytes due to a compromise in the integrity of the mitochondrial membrane. Major factors associated in the deregulation of the membrane include fluctuating reactive oxygen species (ROS, deregulation of mitochondrial permeability transport pore (MPTP, uncontrolled calcium (Ca2+ fluxes, and abnormal caspase-3 activity. Erythropoietin (EPO is strongly inferred to be cardioprotective and acts by inhibiting the above-mentioned processes. Surprisingly, the underlying mechanism of EPO's action and H/R injury is yet to be fully investigated and elucidated. This study examined whether EPO maintains Ca2+ homeostasis and the mitochondrial membrane potential (ΔΨm in cardiomyocytes when subjected to H/R injury and further explored the underlying mechanisms involved. H9C2 cells were exposed to different concentrations of EPO post-H/R, and 20 U/ml EPO was found to significantly increase cell viability by inhibiting the intracellular production of ROS and caspase-3 activity. The protective effect of EPO was abolished when H/R-induced H9C2 cells were treated with Wortmannin, an inhibitor of Akt, suggesting the mechanism of action through the activation Akt, a major survival pathway.

  1. Erythropoietin over-expression protects against diet-induced obesity in mice through increased fat oxidation in muscles.

    Science.gov (United States)

    Hojman, Pernille; Brolin, Camilla; Gissel, Hanne; Brandt, Claus; Zerahn, Bo; Pedersen, Bente Klarlund; Gehl, Julie

    2009-06-12

    Erythropoietin can be over-expressed in skeletal muscles by gene electrotransfer, resulting in 100-fold increase in serum EPO and significant increases in haemoglobin levels. Earlier studies have suggested that EPO improves several metabolic parameters when administered to chronically ill kidney patients. Thus we applied the EPO over-expression model to investigate the metabolic effect of EPO in vivo.At 12 weeks, EPO expression resulted in a 23% weight reduction (Pfat diet) and 28.8+/-2.6 g (EPO, high-fat diet). Correspondingly, DXA scanning revealed that this was due to a 28% reduction in adipose tissue mass.The decrease in adipose tissue mass was accompanied by a complete normalisation of fasting insulin levels and glucose tolerance in the high-fat fed mice. EPO expression also induced a 14% increase in muscle volume and a 25% increase in vascularisation of the EPO transfected muscle. Muscle force and stamina were not affected by EPO expression. PCR array analysis revealed that genes involved in lipid metabolism, thermogenesis and inflammation were increased in muscles in response to EPO expression, while genes involved in glucose metabolism were down-regulated. In addition, muscular fat oxidation was increased 1.8-fold in both the EPO transfected and contralateral muscles.In conclusion, we have shown that EPO when expressed in supra-physiological levels has substantial metabolic effects including protection against diet-induced obesity and normalisation of glucose sensitivity associated with a shift to increased fat metabolism in the muscles.

  2. Erythropoietin-mediated protection of insect brain neurons involves JAK and STAT but not PI3K transduction pathways.

    Science.gov (United States)

    Miljus, N; Heibeck, S; Jarrar, M; Micke, M; Ostrowski, D; Ehrenreich, H; Heinrich, R

    2014-01-31

    The cytokine erythropoietin (Epo) initiates adaptive cellular responses to both moderate environmental challenges and tissue damaging insults in various non-hematopoietic mammalian tissues including the nervous system. Neuroprotective and neuroregenerative functions of Epo in mammals are mediated through receptor-associated Janus kinase 2 and intracellular signaling cascades that modify the transcription of Epo-regulated genes. Signal transducers and activators of transcription (STAT) and phosphoinositol-3-kinase (PI3K) represent key components of two important Epo-induced transduction pathways. Our previous study on insects revealed neuroprotective and regenerative functions of recombinant human Epo (rhEpo) similar to those in mammalian nervous tissues. Here we demonstrate that rhEpo effectively rescues primary cultured locust brain neurons from apoptotic cell death induced by hypoxia or the chemical compound H-7. The Janus kinase inhibitor AG-490 and the STAT inhibitor sc-355797 abolished protective effects of rhEpo on locust brain neurons. In contrast, inhibition of PI3K with LY294002 had no effect on rhEpo-mediated neuroprotection. The results indicate that rhEpo mediates the protection of locust brain neurons through interference with apoptotic pathways by the activation of a Janus kinase-associated receptor and STAT transcription factor(s). The involvement of similar transduction pathways in mammals and insects for the mediation of neuroprotection and support of neural regeneration by Epo indicates that an Epo/Epo receptor-like signaling system with high structural and functional similarity exists in both groups of animals. Epo-like signaling involved in tissue protection appears to be an ancient beneficial function shared by vertebrates and invertebrates.

  3. Carbamylated LL-37 as a modulator of the immune response

    DEFF Research Database (Denmark)

    Koro, Catalin; Hellvard, Annelie; Delaleu, Nicolas;

    2016-01-01

    Carbamylation of lysine residues and protein N-termini is an ubiquitous, non-enzymatic post-translational modification. Carbamylation at sites of inflammation is due to cyanate formation during the neutrophil oxidative burst and may target lysine residues within the antimicrobial peptide LL-37...... to investigate how this modification affects the bactericidal, cytotoxic and immunomodulatory function of the peptide. The results indicated that LL-37 undergoes rapid modification in the presence of physiological concentrations of cyanate, yielding a spectrum of diverse carbamylated peptides. Mass spectrometry...... analyses revealed that the N-terminal amino group of Leu-1 was highly reactive and was modified almost instantly by cyanate to generate the predominant form of the modified peptide, named LL-37(C1). This was followed by the sequential carbamylation of Lys-8 and Lys-12 to yield LL-37(C8), and Lys-15...

  4. Protective effects of erythropoietin against acute lung injury in a rat model of acute necrotizing pancreatitis

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    AIM: To investigate the effect of exogenous erythropoietin (EPO) administration on acute lung injury (ALI) in an experimental model of sodium taurodeoxycholateinduced acute necrotizing pancreatitis (ANP).METHODS: Forty-seven male Wistar albino rats were randomly divided into 7 groups: sham group (n = 5),3 ANP groups (n = 7 each) and 3 EPO groups (n = 7each). ANP was induced by retrograde infusion of 5% sodium taurodeoxycholate into the common bile duct.Rats in EPO groups received 1000 U/kg intramuscular EPO immediately after induction of ANP. Rats in ANP groups were given 1 mL normal saline instead. All animals were sacrificed at postoperative 24 h, 48 h and 72 h. Serum amilase, IL-2, IL-6 and lung tissue malondialdehyde (MDA) were measured. Pleural effusion volume and lung/body weight (LW/BW) ratios were calculated. Tissue levels of TNF-α, IL-2 and IL-6 were screened immunohistochemically. Additionally, ox-LDL accumulation was assessed with immune-fluorescent staining. Histopathological alterations in the lungs were also scored.RESULTS: The mean pleural effusion volume, calculated LW/BW ratio, serum IL-6 and lung tissue MDA levels were significantly lower in EPO groups than in ANP groups. No statistically significant difference was observed in either serum or tissue values of IL-2 among the groups. The level of tumor necrosis factor-α (TNF-α)and IL-6 and accumulation of ox-LDL were evident in the lung tissues of ANP groups when compared to EPO groups, particularly at 72 h. Histopathological evaluation confirmed the improvement in lung injury parameters after exogenous EPO administration, particularly at 48 h and 72 h.CONCLUSION: EPO administration leads to a significant decrease in ALI parameters by inhibiting polymorphonuclear leukocyte (PMNL) accumulation,decreasing the levels of proinflammatory cytokines in circulation, preserving microvascular endothelial cell integrity and reducing oxidative stress-associated lipid peroxidation and therefore, can be

  5. Human recombinant erythropoietin protects the striated muscle microcirculation of the dorsal skinfold from postischemic injury in mice.

    Science.gov (United States)

    Contaldo, Claudio; Meier, Christoph; Elsherbiny, Ahmed; Harder, Yves; Trentz, Otmar; Menger, Michael D; Wanner, Guido A

    2007-07-01

    Erythropoietin (EPO) has been proposed as a novel cytoprotectant in ischemia-reperfusion (I/R) injury of the brain, heart, and kidney. However, whether EPO exerts its protection by prevention of postischemic microcirculatory deterioration is unknown. We have investigated the effect of EPO on I/R-induced microcirculatory dysfunctions. We used the mouse dorsal skinfold chamber preparation to study nutritive microcirculation and leukocyte-endothelial cell interaction in striated muscle of the dorsal skinfold by in vivo fluorescence microscopy before 3 h of ischemia and during 5 days of reperfusion. Animals were pretreated with EPO (5,000 U/kg body wt) 1 or 24 h before ischemia. Vehicle-treated I/R-injured animals served as controls. Additional animals underwent sham operation only or were pretreated with EPO but not subjected to I/R. I/R significantly (P < 0.05) reduced functional capillary density, increased microvascular permeability, and enhanced venular leukocyte-endothelial cell interaction during early reperfusion. These findings were associated with pronounced (P < 0.05) arteriolar constriction and diminution of blood flow during late reperfusion. Pretreatment with EPO induced EPO receptor and endothelial nitric oxide synthase expression at 6 h of reperfusion (P < 0.05). In parallel, EPO significantly (P < 0.05) reduced capillary perfusion failure and microvascular hyperpermeability during early reperfusion and arteriolar constriction and flow during late reperfusion. EPO pretreatment substantially (P < 0.05) diminished I/R-induced leukocytic inflammation by reducing the number of rolling and firmly adhering leukocytes in postcapillary venules. EPO applied 1 h before ischemia induced angiogenic budding and sprouting at 1 and 3 days of reperfusion and formation of new capillary networks at 5 days of reperfusion. Thus our study demonstrates for the first time that EPO effectively attenuates I/R injury by preserving nutritive perfusion, reducing leukocytic

  6. Intraosseous Erythropoietin for Acute Tissue Protection in Battlefield Casualties Suffering Hypovolemic Shock

    Science.gov (United States)

    2015-07-01

    Batavia IL) using a vacuum suction device (Easy Go, Precision Medical; Northampton, PA). An additional suction catheter was placed in the left...to also activate potent cell survival mechanisms prompting organs to resist better ischemia and reperfusion injury – could reduce organ injury...were in part associated with non-genomic activation of mitochondrial protective pathways (e.g., Akt and PKCe) leading to lesser myocardial injury and

  7. Erythropoietin (EPO) protects against high glucose-induced apoptosis in retinal ganglional cells.

    Science.gov (United States)

    Wang, Yunxiao; Zhang, Hui; Liu, Yanping; Li, Ping; Cao, Zhihong; Cao, Yu

    2015-03-01

    The aim of this study was to investigate the protective effect and mechanism of EPO on the apoptosis induced by high levels of glucose in retinal ganglial cells (RGCs). High glucose-induced apoptosis model was established in RGCs isolated from SD rats (1-3 days old) and identified with Thy1.1 mAb and MAP-2 pAb. The apoptosis was determined by Hochest assay. The levels of ROS were quantitated by staining the cells with dichloro-dihydro-fluorescein diacetate (DCFH-DA) and measure by flow cytometry. The SOD, GSH-Px, CAT activities, and levels of T-AOC and MDA were determined by ELISA. Change in mitochondrial membrane potential (Δψm) was also assessed by flow cytometry, and expressions of Bcl-2, Bax, caspase-3, caspase-9, and cytochrome C were assessed by western blotting. The RGCs treated with high glucose levels exhibited significantly increased apoptotic rate and concentrations of ROS and MDA. Pretreatment of the cells with EPO caused a significant blockade of the high glucose-induced increase in ROS and MDA levels and apoptotic rate. EPO also increased the activities of SOD, GSH-Px, and CAT, and recovered the levels of T-AOC levels. As a consequence, the mitochondrial membrane potential was improved and Cyt c release into the cytoplasm was prevented which led to significantly suppressed up-regulation of Bax reducing the Bax/Bcl-2 ratio. The expressions of caspase-3 and caspase-9 induced by high glucose exposure were also ameliorated in the RGCs treated with EPO. The protective effect of EPO against apoptosis was mediated through its antioxidant action. Thus, it blocked the generation of pro-apoptotic proteins and apoptotic degeneration of the RGCs by preventing the mitochondrial damage.

  8. 促红细胞生成素及其受体与视神经视网膜疾病%The protective effects of erythropoietin/erythropoietin receptor system on optic nerve and retinal diseases

    Institute of Scientific and Technical Information of China (English)

    解正高; 庄朝荣

    2011-01-01

    Erythropoietin(EPO) has an anti-apoptotic effect,and promotes the proliferation and differentiation of erythroid progenitor cells. Several studies have indicated that EPO can protect photoreceptor cells from the lightinduced retinal degeneration ;protect retinal neurons from ischemia-reperfusion injury and retinal ganglion cells after acute and chronic ocular hypertension; promote ganglion cell survival and axonal regeneration after optic nerve transaction; attenuate inflammation in multiple sclerosis optic neuritis; reduce the permeability of the retinal barrier and protect retinal neurons in diabetic retinopathy; enhance the stability of hypoxic retinal vessels in retinopathy of prematurity. Herein,we review the distribution of EPO and its receptor in retina,their expression in animal model of retinal diseases,and their effects and mechanisms in protection of retinal neurons and optic nerve.%促红细胞生成素(EPO)具有促进红系祖细胞增生和分化的作用,其在光诱导性视网膜变性、视网膜缺血-再灌注损伤、急慢性高眼压、视神经损伤、多发性硬化性视神经炎、糖尿病视网膜病变(DR)、早产儿视网膜病变(ROP)等视神经视网膜疾病模型中的神经保护作用也受到了关注.就EPO及其受体在视网膜的分布、其在视神经视网膜病变模型中的表达情况及其对视网膜神经元的保护作用和机制方面的研究进展进行综述.

  9. Increased erythropoietin production after myocardial infarction in mice

    OpenAIRE

    Mengozzi, M; Latini, Renato; Salio, M.; Sfacteria, Alessandra; Piedimonte, G; Gammeltoft Gerwien, Jens; Leist, Marcel; Sirén, Anna-Leena; Ghezzi, Pietro; Chimenti, Simona

    2006-01-01

    In addition to its role as the main regulator of erythropoiesis, erythropoietin has a wide range of protective, antiapoptotic activities in vitro and in vivo, particularly in the brain and, as more recently shown, in the heart.1 Of note, erythropoietin is not exclusively produced by fetal liver and adult kidney but is expressed also in the brain, where it can be induced by hypoxia or ischaemia. Several studies underline the potential role of erythropoietin in mediating hypoxic ischaemic preco...

  10. Donor pretreatment with carbamylated erythropoietin in a brain death model reduces inflammation more effectively than erythropoietin while preserving renal function

    NARCIS (Netherlands)

    Nijboer, Willemijn N.; Ottens, Petra J.; van Dijk, Antony; van Goor, Harry; Ploeg, Rutger J.; Leuvenink, Henri G. D.

    2010-01-01

    Objective: We hypothesized that donor treatment of deceased brain dead donors would lead to a decrease in inflammatory responses seen in brain death and lead to a restoration of kidney function. Design: A standardized slow-induction rat brain death model followed by evaluation of kidney function in

  11. Donor pretreatment with carbamylated erythropoietin in a brain death model reduces inflammation more effectively than erythropoietin while preserving renal function.

    NARCIS (Netherlands)

    Nijboer, W.N.; Ottens, P.J.; Dijk, A.P.J. van; Goor, H. van; Ploeg, R.J.; Leuvenink, H.G.

    2010-01-01

    OBJECTIVE: We hypothesized that donor treatment of deceased brain dead donors would lead to a decrease in inflammatory responses seen in brain death and lead to a restoration of kidney function. DESIGN: A standardized slow-induction rat brain death model followed by evaluation of kidney function in

  12. The Nasal Route as a Potential Pathway for Delivery of Erythropoietin in the Treatment of Acute Ischemic Stroke in Humans

    Directory of Open Access Journals (Sweden)

    Julio Cesar García-Rodríguez

    2009-01-01

    Full Text Available Intranasal delivery provides a practical, noninvasive method of bypassing the blood-brain barrier (BBB in order to deliver therapeutic agents to the brain. This method allows drugs that do not cross the BBB to be delivered to the central nervous system in a few minutes. With this technology, it will be possible to eliminate systemic administration and its potential side effects. Using the intranasal delivery system, researchers have demonstrated neuroprotective effects in different animal models of stroke using erythropoietin (EPO as a neuroprotector or other different types of EPO without erythropoiesis-stimulating activity. These new molecules retain their ability to protect neural tissue against injury and they include Asialoerythropoietin (asialoEPO carbamylated EPO (CEPO, and rHu-EPO with low sialic acid content (Neuro-EPO. Contrary to the other EPO variants, Neuro-EPO is not chemically modified, making it biologically similar to endogenous EPO, with the advantage of less adverse reactions when this molecule is applied chronically. This constitutes a potential benefit of Neuro-EPO over other variants of EPO for the chronic treatment of neurodegenerative illnesses. Nasal administration of EPO is a potential, novel, neurotherapeutic approach. However, it will be necessary to initiate clinical trials in stroke patients using intranasal delivery in order to obtain the clinical evidence of its neuroprotectant capacity in the treatment of patients with acute stroke and other neurodegenerative disorders. This new therapeutic approach could revolutionize the treatment of neurodegenerative disorders in the 21st century.

  13. Novel applications of recombinant erythropoietin.

    Science.gov (United States)

    Sharples, Edward J; Thiemermann, Christoph; Yaqoob, Magdi M

    2006-04-01

    Recombinant erythropoietin (EPO) was introduced into clinical practice after the identification of EPO as the major haemopoietic growth factor determining survival and maturation of erythroid precursors. Advances in our understanding of the novel sites of action of EPO in the vasculature, brain, heart and kidney have opened new avenues of therapeutic potential for EPO, and have led to an increased understanding of the biological roles of EPO and its mechanisms of cell protection.

  14. Effects of Rumen-Protected Lysine, Conjugated Linoleic Acid and N-Carbamyl Glutamic Acid on Meat Performance and Meat Quality of Stabling Tan Sheep%过瘤胃赖氨酸、共轭亚油酸和N-氨甲酰谷氨酸对舍饲滩羊产肉性能和肉品质的影响

    Institute of Scientific and Technical Information of China (English)

    周玉香; 杨宇为

    2015-01-01

    This experiment was devoted to study the effects of different additives [ rumen-protected lysine ( RPLys) , conjugated linoleic acid ( CLA) and N-carbamyl glutamic acid ( NCG) ] on meat production per-formance and meat quality of stabling Tan Sheep. Thirty two fattening Tan sheep with were chosen and ran-domly divided into 4 groups by body weight similarity. Each group had 8 sheep ( 3 rams and 5 ewes) . The control group was fed a basal diet, test groupⅠwas fed basal diet+8 g/d RPLys, test group Ⅱ was fed basal diet+2% CLA, and test group Ⅲ was fed basal diet+0.2% NCG. The testing period lasted for 60 d. The re-sults showed as follows:1) there was no significant effects of RPLys, CLA and NCG on dressing percentage, carcass meat rate and meat/bone (P>0.05). 2) Compared with control group, lean meat percentage in test group Ⅰ tended to be decreased ( P>0.05) , and that in test groups Ⅱ ( P0.05). 4) Compared with test group Ⅰ, the backfat thickness of test group Ⅱ was significantly lower (P0.05);compared with control group, test group Ⅱ significantly increased red degree ( a?) value of meat color ( P0.05) . 6) Test group Ⅱ was the highest in intramuscular fat content, which was significantly higher than that in control group and test group Ⅰ ( P0.05). 2)与对照组相比,试验Ⅰ组胴体瘦肉率有降低的趋势( P>0.05) ,试验Ⅱ组和试验Ⅲ组瘦肉率分别极显著(P0.05). 4)试验Ⅱ组背膘厚显著低于试验Ⅰ组( P0.05);与对照组相比,试验Ⅱ组显著提高了肉色红度( a?)值( P0.05). 6)肌内脂肪含量以试验Ⅱ组最高,显著高于对照组和试验Ⅰ组( P<0.05) ,试验Ⅲ组肌内脂肪含量显著高于试验Ⅰ组( P<0.05). 综上所述,舍饲滩羊饲粮中添加2% CLA能有效提高其胴体瘦肉率,改善肉品质.

  15. Effect of recombinant erythropoietin on functional activity of cultured human cells.

    Science.gov (United States)

    Emel'yanova, E A; Kosykh, A V; Sukhanov, Yu V; Vorotelyak, E A; Vasil'ev, A V

    2012-08-01

    We studied the effect of recombinant human erythropoietin on functional activity of skin cells in vitro. It was found that erythropoietin stimulated proliferation of mesenchymal and epithelial cells and effectively protected epidermal HaCaT cells from apoptosis. Insignificant effect of erythropoietin on contraction of collagen gel by mesenchymal cells was revealed. These findings suggest that erythropoietin can be a promising component of wound-healing preparations.

  16. Erythropoietin and small molecule agonists of the tissue-protective erythropoietin receptor increase FXN expression in neuronal cells in vitro and in Fxn-deficient KIKO mice in vivo.

    Science.gov (United States)

    Miller, James L; Rai, Myriam; Frigon, Normand L; Pandolfo, Massimo; Punnonen, Juha; Spencer, Jeffrey R

    2017-09-01

    Friedreich's ataxia (FA) is a progressive neurodegenerative disease caused by reduced levels of the mitochondrial protein frataxin (FXN). Recombinant human erythropoietin (rhEPO) increased FXN protein in vitro and in early clinical studies, while no published reports evaluate rhEPO in animal models of FA. STS-E412 and STS-E424 are novel small molecule agonists of the tissue-protective, but not the erythropoietic EPO receptor. We find that rhEPO, STS-E412 and STS-E424 increase FXN expression in vitro and in vivo. RhEPO, STS-E412 and STS-E424 increase FXN by up to 2-fold in primary human cortical cells and in retinoic-acid differentiated murine P19 cells. In primary human cortical cells, the increase in FXN protein was accompanied by an increase in FXN mRNA, detectable within 4 h. RhEPO and low nanomolar concentrations of STS-E412 and STS-E424 also increase FXN in normal and FA patient-derived PBMC by 20%-40% within 24 h, an effect that was comparable to that by HDAC inhibitor 4b. In vivo, STS-E412 increased Fxn mRNA and protein in wild-type C57BL6/j mice. RhEPO, STS-E412, and STS-E424 increase FXN expression in the heart of FXN-deficient KIKO mice. In contrast, FXN expression in the brains of KIKO mice increased following treatment with STS-E412 and STS-E424, but not following treatment with rhEPO. Unexpectedly, rhEPO-treated KIKO mice developed severe splenomegaly, while no splenomegaly was observed in STS-E412- or STS-E424-treated mice. RhEPO, STS-E412 and STS-E424 upregulate FXN expression in vitro at equal efficacy, however, the effects of the small molecules on FXN expression in the CNS are superior to rhEPO in vivo. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Erythropoietin Modification Enhances the Protection of Mesenchymal Stem Cells on Diabetic Rat-Derived Schwann Cells: Implications for Diabetic Neuropathy

    Directory of Open Access Journals (Sweden)

    Shuyun Zhang

    2017-01-01

    Full Text Available Diabetes-triggered apoptosis of Schwann cells (SC contributes to the degradation of diabetic peripheral neuropathy (DNP. In recent years, mesenchymal stem cells (MSC were applied to DPN repair and it was demonstrated that paracrine secretion played a key role in neuroprotection exerted by MSC. Erythropoietin (EPO is a potent cytokine capable of reducing apoptosis of SC. However, the expression of EPO in MSC is limited. In this study, we hypothesized that overexpression of EPO in MSC (EPO-MSC may significantly improve their neuroprotective potentials. The EPO overexpression in MSC was achieved by lentivirus transduction. SC derived from the periphery nerve of diabetic rats were cocultured with MSC or EPO-MSC in normal or high glucose culture condition, respectively. In normal glucose culture condition, the overexpression of EPO in MSC promoted the MSC-induced restoration of SC from diabetic rats, including increases in GSH level and cell viability, decrease in TUNEL apoptosis, upregulation of antiapoptotic proteins, p-Akt, and Bcl-2, and downregulation of proapoptotic proteins, cleaved caspase-3, and Bax. The subsequent results in high glucose culture condition showed similar promotions achieved by EPO-MSC. Thus, it could be concluded that EPO-MSC possessed a potent potential in hampering apoptosis of SC, and the suppression was probably attributed to attenuating oxidative stress and regulating apoptosis related protein factors.

  18. The Ovario-Protective Effect of Erythropoietin against Oxidative Damage Associated with Reperfusion Following Ovarian Torsion in Rat

    Directory of Open Access Journals (Sweden)

    S.-M. Manizheh

    2011-01-01

    Full Text Available Problem statement: To show the effect of recombinant Erythropoietin (rhEPO on the ovarian viability and histology in the twisted ischemic ovaries in rats, followed by detorsion. Approach: An experimental study was conducted in primate clinic of the School of Medicine, Tabriz University of Medical Sciences from Dec. 2008 to Apr. 2009. Forty, 4 month old Wistar rats are cased in the present study divided into 4 groups. Ovarian ischemia was performed by torsion which was kept stable by using a vascular microclip for 4 h. In group 1, the ovary were surgically removed, fixed and analyzed histochemically. In group 2, the same procedure was repeated after 3 h reperfusion. In the next two groups, the same was performed rhEPO was administrated 400 u kg−1 1 h after torsion of the ovaries. Results: Thirty-two out of 40 rats were followed. There was a significant difference between groups in the levels of Malondialdehyde (MDA, Total Antioxidants (TA, Superoxidase (SOD, Nitric Oxide (NO glutathione ( pConclusion: Administration of rhEPO was effective in reducing the ischemic effect and free radicals damages of ovarian torsion in rats.

  19. Erythropoietin Modification Enhances the Protection of Mesenchymal Stem Cells on Diabetic Rat-Derived Schwann Cells: Implications for Diabetic Neuropathy

    Science.gov (United States)

    Zhang, Shuyun

    2017-01-01

    Diabetes-triggered apoptosis of Schwann cells (SC) contributes to the degradation of diabetic peripheral neuropathy (DNP). In recent years, mesenchymal stem cells (MSC) were applied to DPN repair and it was demonstrated that paracrine secretion played a key role in neuroprotection exerted by MSC. Erythropoietin (EPO) is a potent cytokine capable of reducing apoptosis of SC. However, the expression of EPO in MSC is limited. In this study, we hypothesized that overexpression of EPO in MSC (EPO-MSC) may significantly improve their neuroprotective potentials. The EPO overexpression in MSC was achieved by lentivirus transduction. SC derived from the periphery nerve of diabetic rats were cocultured with MSC or EPO-MSC in normal or high glucose culture condition, respectively. In normal glucose culture condition, the overexpression of EPO in MSC promoted the MSC-induced restoration of SC from diabetic rats, including increases in GSH level and cell viability, decrease in TUNEL apoptosis, upregulation of antiapoptotic proteins, p-Akt, and Bcl-2, and downregulation of proapoptotic proteins, cleaved caspase-3, and Bax. The subsequent results in high glucose culture condition showed similar promotions achieved by EPO-MSC. Thus, it could be concluded that EPO-MSC possessed a potent potential in hampering apoptosis of SC, and the suppression was probably attributed to attenuating oxidative stress and regulating apoptosis related protein factors.

  20. The protective effect of erythropoietin on diaphragm injury induced by doxorubicin in rats%促红细胞生成素对阿霉素致大鼠膈肌损伤的保护作用

    Institute of Scientific and Technical Information of China (English)

    郭晓磊; 方迎艳; 胡杰; 关宿东

    2012-01-01

    Objective: To explore the mechanism of protective effect of erythropoietin on the doxorubicin induced diaphragm injury in rats. Methods:Thirty rats were divided into three groups: normal control group(ra = 10) ,model group(ra = 10) and erythropoietin group ( n = 10). Diaphragm strips was isolated to observe peak twitch tension (Pt) , maximum titanic tension (Po) , time to peak contraction ( CT) ,half relaxation time( 1/2RT) , maximal rates of contraction( + dT/dtmax) , maximal rates of relaxation( - dT/dtmax) and force-frequency curve. Meanwhile, the activity of superoxide dismutase ( SOD ) and content of malondialdehyde ( MDA ) in diaphragm were also measured. Electron microscope was used to observe the changes of diaphragm cell ultrastructure. Results: Pt, Po, + dT/dtmax, - dT/dtmax in model group were lower than those in control group ( P < 0. 01 ) , the above four indexes in erythropoietin group did not differ from those in control group. CT,1/2RT in model group were prolonged compared with that in control group and erythropoietin group(P <0. 01). Stimulated by the frequency of 10,20,40,60,100 Hz, diaphragm tension in model group was obviously decreased compared with that in control group and erythropoietin group ( P < 0. 01) . SOD activity was decreased and MDA content was increased in model group compared with control group (P <0. 01) ,the difference of MDA was insignificant between control group and erythropoietin group ( P > 0. 05 ). Electron microscopy showed myofibrils were swollen and mitochondria were vacuolization in model group, erythropoietin can ameliorate the injury. Conclusions: Doxorubicin can depress the contraction of diaphragm and increase the production of oxygen free radicals and reduce their clearance; erythropoietin can protect diaphragm from damage by counteracting the above effects of doxorubicin.%目的:探讨促红细胞生成素(erythropoietin,EPO)对阿霉素致大鼠膈肌损伤的保护作用.方法:雄性SD大鼠30只,

  1. Citrullination and carbamylation in the pathophysiology of rheumatoid arthritits

    Directory of Open Access Journals (Sweden)

    Ger J.M. Pruijn

    2015-04-01

    Full Text Available The discovery that citrullination was crucial for the recognition of antigens by the most disease-specific class of autoantibodies in rheumatoid arthritis had a huge impact on studies aimed at understanding autoimmunity in this disease. In addition to the detailed characterization of anti-citrullinated protein antibodies, various studies have addressed the identity of citrullinated antigens. These investigations were facilitated by new methods to characterize these proteins, the analysis of protein citrullination by peptidylarginine deiminases, the generation of a catalogue of citrullinated proteins present in the inflamed joints of patients and the finding that the formation of extracellular traps is dependent on the activity of peptidylarginine deiminase activity. Recently, it was found that in addition to citrullination also carbamylation, which results in chemically highly related modified proteins, yields antigens that are targeted by rheumatoid arthritis patient sera. Here, all of these aspects will be discussed, culminating in current ideas about the involvement of citrullination and carbamylation in pathophysiological processes in autoimmunity, especially rheumatoid arthritis.

  2. Citrullination and carbamylation in the pathophysiology of rheumatoid arthritis.

    Science.gov (United States)

    Pruijn, Ger J M

    2015-01-01

    The discovery that citrullination was crucial for the recognition of antigens by the most disease-specific class of autoantibodies in rheumatoid arthritis (RA) had a huge impact on studies aimed at understanding autoimmunity in this disease. In addition to the detailed characterization of anti-citrullinated protein antibodies, various studies have addressed the identity of citrullinated antigens. These investigations were facilitated by new methods to characterize these proteins, the analysis of protein citrullination by peptidylarginine deiminases, the generation of a catalog of citrullinated proteins present in the inflamed joints of patients and the finding that the formation of extracellular traps is dependent on the activity of peptidylarginine deiminase activity. Recently, it was found that in addition to citrullination also carbamylation, which results in chemically highly related modified proteins, yields antigens that are targeted by rheumatoid arthritis patient sera. Here, all of these aspects will be discussed, culminating in current ideas about the involvement of citrullination and carbamylation in pathophysiological processes in autoimmunity, especially RA.

  3. Protection of erythropoietin on experimental spinal cord injury by reducing the expression of thrombospondin-1 and transforming growth factor-β

    Institute of Scientific and Technical Information of China (English)

    FANG Xiang-qian; FANG Mei; FAN Shun-wu; GU Chuan-long

    2009-01-01

    Background Erythropoietin (EPO) functions as a tissue-protective cytokine in addition to its crucial hormonal role in red cell production and neuron protection. This study aimed to determine the neuron protective effect of erythropoietin on experimental rats enduring spinal cord injury (SCI) by assessing thrombospondin-1 (TSP-1) level and transforming growth factor-β (TGF-β) in the development of a rat model of SCI. Methods Sixty Sprague-Dawley rats were randomly assigned to three groups: sham operation control group, SCI group and EPO treatment group. By using a weight-drop contusion SCI model, the rats in the SCI group and EPO treatment group were sacrificed at 24 hours and 7 days subsequently. The Basso, Beattie, and Bresnahan (BBB) scores were examined for locomotor function. Pathological changes were observed after HE staining. The expressions of thrombospondin-2 (TSP-1) and TGF-β were determined by immunohistochemical staining and Western blotting. Results Slighter locomotor dysfunction was discovered and it was recovered abruptly as higher BBB scores were found in the EPO treatment group than in the SCI group (P <0.01). Pathologically, progressive disruption of the dorsal white matter and regeneration of a few neurons were also observed in SCI rats. TSP-1 and TGF-β expression increased at 24 hours and 7 days after SCI in the injured segment, and it was higher in the SCI group than in the EPO treatment group. Spinal cord samples from the animals demonstrated a TSP-1 optical density of 112.2±6.8 and TSP-1 positive cells of 5.7±1.3 respectively. After injury, the TSP-1 optical density and cell number increased to 287.2±14.3/mm2 and 23.2±2.6/mm2 at 24 hours and to 232.1±13.2/mm2 and 15.2±2.3/mm2 at 7 days respectively. When EPO treated rats compared with the SCI rats, the TSP-1 optical density and cell number decreased to 213.1±11.6/mm2 and 11.9±1.6/mm2 at 24 hours and to 189.9±10.5/mm2 and 9.3±1.5/mm2 at 7 days, respectively (P <0.01 ). In the SCI

  4. Long-term moderate dose exogenous erythropoietin treatment protects from intermittent hypoxia-induced spatial learning deficits and hippocampal oxidative stress in young rats.

    Science.gov (United States)

    Al-Qahtani, Jobran M; Abdel-Wahab, Basel A; Abd El-Aziz, Samy M

    2014-01-01

    Exposure to intermittent hypoxia (IH) is associated with cognitive impairments and oxidative stress in brain regions involved in learning and memory. In earlier studies, erythropoietin (EPO) showed a neuroprotective effect in large doses. The aim of the present study was to explore the effect of smaller doses of EPO, such as those used in the treatment of anemia, on IH-induced cognitive deficits and hippocampal oxidative stress in young rats. The effect of concurrent EPO treatment (500 and 1,000 IU/kg/day ip) on spatial learning and memory deficits induced by long-term exposure to IH for 6 weeks was tested using the Morris water maze (MWM) test and the elevated plus maze (EPM) test. Moreover, the effect on hippocampal glutamate and oxidative stress were assessed. Exposure to IH induced a significant impairment of spatial learning and cognition of animals in both MWM and EPM performance parameters. Moreover, hippocampal glutamate and thiobarbituric acid reactive substances (TBARS) increased while antioxidant defenses (GSH and GSH-Px) decreased. EPO in the tested doses significantly reduced the IH-induced spatial learning deficits in both MWM and EPM tests and dose-dependently antagonized the effects of IH on hippocampal glutamate, TBARS, GSH levels, and GSH-Px activity. Treatment with EPO in moderate doses that used for anemia, concurrently with IH exposure can antagonize IH-induced spatial learning deficits and protect hippocampal neurons from IH-induced lipid peroxidation and oxidative stress-induced damage in young rats, possibly through multiple mechanisms involving a potential antioxidative effect.

  5. Prediction of carbamylated lysine sites based on the one-class k-nearest neighbor method.

    Science.gov (United States)

    Huang, Guohua; Zhou, You; Zhang, Yuchao; Li, Bi-Qing; Zhang, Ning; Cai, Yu-Dong

    2013-11-01

    Protein carbamylation is one of the important post-translational modifications, which plays a pivotal role in a number of biological conditions, such as diseases, chronic renal failure and atherosclerosis. Therefore, recognition and identification of protein carbamylated sites are essential for disease treatment and prevention. Yet the mechanism of action of carbamylated lysine sites is still not realized. Thus it remains a largely unsolved challenge to uncover it, whether experimentally or theoretically. To address this problem, we have presented a computational framework for theoretically predicting and analyzing carbamylated lysine sites based on both the one-class k-nearest neighbor method and two-stage feature selection. The one-class k-nearest neighbor method requires no negative samples in training. Experimental results showed that by using 280 optimal features the presented method achieved promising performances of SN=82.50% for the jackknife test on the training set, and SN=66.67%, SP=100.00% and MCC=0.8097 for the independent test on the testing set, respectively. Further analysis of the optimal features provided insights into the mechanism of action of carbamylated lysine sites. It is anticipated that our method could be a potentially useful and essential tool for biologists to theoretically investigate carbamylated lysine sites.

  6. Erythropoietin over-expression protects against diet-induced obesity in mice through increased fat oxidation in muscles

    DEFF Research Database (Denmark)

    Hojman, Pernille; Brolin, Camilla; Gissel, Hanne

    2009-01-01

    in the high-fat fed mice. EPO expression also induced a 14% increase in muscle volume and a 25% increase in vascularisation of the EPO transfected muscle. Muscle force and stamina were not affected by EPO expression. PCR array analysis revealed that genes involved in lipid metabolism, thermogenesis...... and inflammation were increased in muscles in response to EPO expression, while genes involved in glucose metabolism were down-regulated. In addition, muscular fat oxidation was increased 1.8-fold in both the EPO transfected and contralateral muscles.In conclusion, we have shown that EPO when expressed in supra......-physiological levels has substantial metabolic effects including protection against diet-induced obesity and normalisation of glucose sensitivity associated with a shift to increased fat metabolism in the muscles....

  7. Cell encoding recombinant human erythropoietin

    Energy Technology Data Exchange (ETDEWEB)

    Beck, A.K.; Withy, R.M.; Zabrecky, J.R.; Masiello, N.C.

    1990-09-04

    This patent describes a C127 cell transformed with a recombinant DNA vector. It comprises: a DNA sequence encoding human erythropoietin, the transformed cell being capable of producing N-linked and O-linked glycosylated human erythropoietin.

  8. Erythropoietin (EPO) in acute kidney injury

    OpenAIRE

    Moore, Elizabeth; Bellomo, Rinaldo

    2011-01-01

    Erythropoietin (EPO) is a 30.4 kDa glycoprotein produced by the kidney, and is mostly well-known for its physiological function in regulating red blood cell production in the bone marrow. Accumulating evidence, however, suggests that EPO has additional organ protective effects, which may be useful in the prevention or treatment of acute kidney injury. These protective mechanisms are multifactorial in nature and include inhibition of apoptotic cell death, stimulation of cellular regeneration, ...

  9. DNA sequences encoding erythropoietin

    Energy Technology Data Exchange (ETDEWEB)

    Lin, F.K.

    1987-10-27

    A purified and isolated DNA sequence is described consisting essentially of a DNA sequence encoding a polypeptide having an amino acid sequence sufficiently duplicative of that of erythropoietin to allow possession of the biological property of causing bone marrow cells to increase production of reticulocytes and red blood cells, and to increase hemoglobin synthesis or iron uptake.

  10. Erythropoietin and oxidative stress.

    Science.gov (United States)

    Maiese, Kenneth; Chong, Zhao Zhong; Hou, Jinling; Shang, Yan Chen

    2008-05-01

    Unmitigated oxidative stress can lead to diminished cellular longevity, accelerated aging, and accumulated toxic effects for an organism. Current investigations further suggest the significant disadvantages that can occur with cellular oxidative stress that can lead to clinical disability in a number of disorders, such as myocardial infarction, dementia, stroke, and diabetes. New therapeutic strategies are therefore sought that can be directed toward ameliorating the toxic effects of oxidative stress. Here we discuss the exciting potential of the growth factor and cytokine erythropoietin for the treatment of diseases such as cardiac ischemia, vascular injury, neurodegeneration, and diabetes through the modulation of cellular oxidative stress. Erythropoietin controls a variety of signal transduction pathways during oxidative stress that can involve Janus-tyrosine kinase 2, protein kinase B, signal transducer and activator of transcription pathways, Wnt proteins, mammalian forkhead transcription factors, caspases, and nuclear factor kappaB. Yet, the biological effects of erythropoietin may not always be beneficial and may be poor tolerated in a number of clinical scenarios, necessitating further basic and clinical investigations that emphasize the elucidation of the signal transduction pathways controlled by erythropoietin to direct both successful and safe clinical care.

  11. Protective effects of erythropoietin against myocardial infarction%促红细胞生成素对急性心肌梗死心脏保护性作用的研究进展

    Institute of Scientific and Technical Information of China (English)

    刘园园; 崔丽

    2013-01-01

    Erythropoietin (EPO) which belongs to cytokine superfamily, plays an important role in protecting diseased heart. Large number of animal experiments confirmed that EPO could against apoptosis, antioxi-dant, inflammation and promote blood vessel regeneration, reduce infarct size and left ventricular remodeling, thus improve cardiac function.%促红细胞生成素(EPO)是细胞因子超家族成员之一,对发生疾病的心脏发挥重要的保护作用.大量动物实验证实,EPO可以发挥抗细胞凋亡、抗氧化、抗炎及促进血管再生等作用,减小梗死面积、减轻左室重构,并改善心功能.

  12. Augmenting ureagenesis in patients with partial carbamyl phosphate synthetase 1deficiency with N-carbamylglutamate

    Science.gov (United States)

    Ah Mew, Nicholas; McCarter, Robert; Daikhin, Yevgeny; Lichter, Uta; Nissim, Ilana; Yudkoff, Marc; Tuchman, and Mendel

    2014-01-01

    Identical studies employing stable isotopes were performed before and after a 3-day trial of oral N-carbamylglutamate (NCG) in 5 subjects with late onset carbamyl phosphate synthetase deficiency. NCG augmented ureagenesis and decreased plasma ammonia in 4 of 5 subjects. There was marked improvement in nitrogen metabolism with long-term NCG administration in one subject. PMID:24880889

  13. Augmenting ureagenesis in patients with partial carbamyl phosphate synthetase 1deficiency with N-carbamylglutamate

    OpenAIRE

    Ah Mew, Nicholas; McCarter, Robert; Daikhin, Yevgeny; Lichter, Uta; Nissim, Ilana; Yudkoff, Marc; Tuchman, and Mendel

    2014-01-01

    Identical studies employing stable isotopes were performed before and after a 3-day trial of oral N-carbamylglutamate (NCG) in 5 subjects with late onset carbamyl phosphate synthetase deficiency. NCG augmented ureagenesis and decreased plasma ammonia in 4 of 5 subjects. There was marked improvement in nitrogen metabolism with long-term NCG administration in one subject.

  14. Regenerative medicine: does Erythropoietin have a role?

    Science.gov (United States)

    Buemi, Michele; Lacquaniti, Antonio; Maricchiolo, Giulia; Bolignano, Davide; Campo, Susanna; Cernaro, Valeria; Sturiale, Alessio; Grasso, Giovanni; Buemi, Antoine; Allegra, Alessandro; Donato, Valentina; Genovese, Lucrezia

    2009-01-01

    Regenerative Medicine, a recent new medical domain, aims to develop new therapies through the stimulation of natural regenerative processes also in human beings. In this field, Erythropoietin (EPO) represents a significant subject of research. Several studies allow the assertion that EPO, in different concentrations, has protective effects mainly on the central nervous system, cardiovascular system and renal tissue. This action is carried out through one of few regenerative activities of human beings: angiogenesis. This mechanism, which involves endothelial stem cells and VEGF (Vascular Endothelial Growth Factor), has been experimentally demonstrated with Recombinant human erythropoietin (rHuEPO) and Darbepoetin, a long-acting EPO derivate. Furthermore, the demonstration of a cardiac production of EPO in Fugu rubripes and in Zebrafish has led cardiologists to "discover" Erythropoietin, postulating a hypothetical role in treatment of cardiovascular disease for this hormone. This is some of the experimental evidence which demonstrates that EPO can be in reason considered an important element of research of Regenerative Medicine and put in the network of drugs able to regenerate tissues and organs.

  15. Erythropoietin and radiotherapy; Erythropoietine et radiotherapie

    Energy Technology Data Exchange (ETDEWEB)

    Le Fur, E.; Albarghach, M.N.; Pradier, O. [CHU de Morvan, Dept. de radiotherapie, 29 - Brest (France)

    2010-01-15

    Erythropoietin (E.P.O.) is a glycoprotein hormone. This hormone is a growth factor for red blood cells precursors in the bone marrow. The decrease of oxygen partial pressure, a reduced number of erythrocytes caused by bleeding or excessive destruction, or increased tissues oxygen requirements lead to increased secretion of E.P.O.. Its action takes place on bone marrow erythroblastic cells through specific receptors. E.P.O. stimulates the proliferation of red cell precursors stem cells in the bone marrow, thus increasing their production in one to two weeks. The effectiveness of E.P.O. at increasing haemoglobin and improving patients quality of life has been demonstrated by several studies. However, its use in radiotherapy remains controversial. While tumour hypoxia caused by anaemia is a factor of radio resistance and thus a source of local failure, tumour expression of E.P.O. receptors presents a significant risk for tumour progression and neo-angiogenesis, which would be increased during the administration of E.P.O.. The purpose of this article is to answer the question: is there a place for E.P.O. in combination with radiotherapy in the management of cancer?

  16. Erythropoietin Activates Mitochondrial Biogenesis and Couples Red Cell Mass to Mitochondrial Mass in the Heart

    Science.gov (United States)

    RATIONALE: Erythropoietin (EPO) is often administered to cardiac patients with anemia, particularly from chronic kidney disease, and stimulation of erythropoiesis may stabilize left ventricular and renal function by recruiting protective effects beyond the correction of anemia. O...

  17. Erythropoietin (EPO) in acute kidney injury.

    Science.gov (United States)

    Moore, Elizabeth; Bellomo, Rinaldo

    2011-03-21

    Erythropoietin (EPO) is a 30.4 kDa glycoprotein produced by the kidney, and is mostly well-known for its physiological function in regulating red blood cell production in the bone marrow. Accumulating evidence, however, suggests that EPO has additional organ protective effects, which may be useful in the prevention or treatment of acute kidney injury. These protective mechanisms are multifactorial in nature and include inhibition of apoptotic cell death, stimulation of cellular regeneration, inhibition of deleterious pathways, and promotion of recovery.In this article, we review the physiology of EPO, assess previous work that supports the role of EPO as a general tissue protective agent, and explain the mechanisms by which it may achieve this tissue protective effect. We then focus on experimental and clinical data that suggest that EPO has a kidney protective effect.

  18. Erythropoietin use and abuse

    Directory of Open Access Journals (Sweden)

    M Joseph John

    2012-01-01

    Full Text Available Recombinant human erythropoietin (rhEPO is arguably the most successful therapeutic application of recombinant DNA technology till date. It was isolated in 1977 and the gene decoded in 1985. Since then, it has found varied applications, especially in stimulating erythropoiesis in anemia due to chronic conditions like renal failure, myelodysplasia, infections like HIV, in prematurity, and in reducing peri-operative blood transfusions. The discovery of erythropoietin receptor (EPO-R and its presence in non-erythroid cells has led to several areas of research. Various types of rhEPO are commercially available today with different dosage schedules and modes of delivery. Their efficacy in stimulating erythropoiesis is dose dependent and differs according to the patient′s disease and nutritional status. EPO should be used carefully according to guidelines as unsolicited use can result in serious adverse effects. Because of its capacity to improve oxygenation, it has been abused by athletes participating in endurance sports and detecting this has proved to be a challenge.

  19. A hemoglobin A1C immunoassay method not affected by carbamylated hemoglobin.

    Science.gov (United States)

    Rose, A M; Tongate, C; Valdes, R

    1995-01-01

    Hemoglobin A1C (HbA1C) methods based on charge separation of Hb species are subject to interference from carbamylated Hb (carb Hb). Carb Hb adducts are formed via interaction of terminal amino groups of HbA with isocyanic acid, after the spontaneous dissociation of urea to cyanate. It is hypothesized that a new immunoassay method, using a monoclonal antibody that recognizes the N-terminus of the Hb beta-chain and its sugar moiety, should be refractory to cross-reactive interference from carb Hb. To test this hypothesis, Hb was carbamylated in vitro and co-migration of carb Hb assessed with HbA1C using an electrophoretic method. Densitometric scans - post sodium cyanate incubation and electrophoretic separation - showed a 5 to 7 fold elevation of the HbA1C peak only, while HbA1C values obtained using immunoassay were unaffected. Also assessed was carbamylation interference in vivo, and a positive proportional bias with the electrophoretic system (Y) was observed compared to the immunoassay system (X) (y = 1.2x - 0.21 percent). Others have shown that carb Hb may cause a clinically significant false elevation in patient HbA1C values, when methods based on charge separation of Hb species are used. It is our conclusion, however, that while carb Hb may play a role, the differences observed in this study are largely due to calibration.

  20. Alkylation and Carbamylation Effects of Lomustine and Its Major Metabolites and MGMT Expression in Canine Cells

    Directory of Open Access Journals (Sweden)

    Thushara Chakkath

    2015-04-01

    Full Text Available DNA Alkylation is thought to be the reason for the efficacy of lomustine while carbamylation has been implicated as the cause for the side effects seen with lomustine treatment such as hepatotoxicity. In the alkylation study we show that lomustine and its metabolites form similar levels of the DNA adducts N7 hydroxyethylguanine and O6 hydroxyethyldeoxyguanosine. In terms of carbamylation, lomustine showed greater extent of carbamylation in the canine hepatocytes and lymphoma cell lines. The DNA repair enzyme O6 methylguanine DNA methyltransferase (MGMT causes resistance of tumor cells to bifunctional nitrosourea, like lomustine. There is no data available regarding MGMT expression/activity in canine cells or tissues. Our study shows that there is low MGMT activity in the canine lymphoid cell line 17–71 while the GL-1 cells did not show any detectable enzyme activity or mRNA expression. The MGMT enzyme activity measured in canine hepatocytes is about 250–350 fmol/mg protein as compared to about 90 fmol/mg protein in 17–71 cells. We also show that MGMT mRNA expression in 17–71 cells and canine hepatocytes positively correlates with its enzyme activity in these cells.

  1. Is there a link between carbamylation and citrullination in periodontal disease and rheumatoid arthritis?

    Science.gov (United States)

    Bright, R; Proudman, S M; Rosenstein, E D; Bartold, P M

    2015-06-01

    The remarkable similarity in inflammatory response and pathology of periodontal disease and rheumatoid arthritis has been recognized for several decades. However, how these two disease may be interrelated has been less clear. During the pathogenesis of rheumatoid arthritis there is a preclinical immunological phase which precedes the clinical manifestation of rheumatoid arthritis. During this phase serum autoantibodies appear many years before the clinical signs and symptoms of rheumatoid arthritis become apparent. To date, the two best studied autoantibodies have been rheumatoid factor and anti-citrullinated protein antibodies (ACPA). Of these the production of ACPA has been considered very important due to their high predictive value in future manifestation of rheumatoid arthritis. Citrullination is a common post-translational modification of proteins based on the enzymatic conversion of arginine into citrulline. Extra-articular citrullination and production of ACPA, as a priming immunological experience, is well documented in many tissues including the inflamed gingival tissues associated with periodontal disease. More recently, carbamylation of proteins has also been implicated in the pathogenesis of rheumatoid arthritis in a manner similar to citrullination. Carbamylation is a post translational modification of proteins by an enzyme-independent modification of lysine residues against which autoantibodies are subsequently induced. In this article we hypothesise that, like citrullination, carbamylation of proteins and associated antibody production during the gingival inflammation associated with gingivitis and periodontitis may play a role in the pathogenesis of rheumatoid arthritis.

  2. Post-translational modifications in rheumatoid arthritis and atherosclerosis: Focus on citrullination and carbamylation.

    Science.gov (United States)

    Spinelli, Francesca Romana; Pecani, Arbi; Conti, Fabrizio; Mancini, Riccardo; Alessandri, Cristiano; Valesini, Guido

    2016-09-01

    Coronary heart disease is the main cause of mortality in patients with rheumatoid arthritis (RA), a disease known to be associated with accelerated atherosclerosis. The role of inflammation and immunity in atherosclerotic process offers possible explanations for the increased cardiovascular risk in patients with RA. The immune response to citrullinated peptides has been extensively studied in RA; antibodies directed to citrullinated peptides are now a cornerstone for RA diagnosis. However, few studies have investigated the response to citrullinated peptides and the development of atherosclerotic plaque. Antibodies to carbamylated proteins can be detected before the clinical onset of RA, suggesting a potential predictive role for these antibodies; on the other hand, carbamylation of lipoproteins has been described in patients with cardiovascular disease. This review examines the role of citrullination and carbamylation, two post-translational protein modifications that appear to be involved in the pathogenesis of both RA and atherosclerosis, expanding the similarities between these two diseases. Further investigation on the role of the immune response to modified proteins may contribute to a better comprehension of cardiovascular disease in patients with RA.

  3. [Overview of erythropoietin].

    Science.gov (United States)

    Lacombe, C; Mayeux, P; Casadevall, N

    1991-01-01

    Erythropoietin (Epo) is a glycoprotein that promotes the proliferation and differentiation of erythrocyte precursors. The major site of Epo production is the kidney and the liver is the main extra renal site of Epo production. Epo producing cells were identified by in situ hybridization, in the kidney, they are peritubular cells, most likely endothelial cells of the cortex and outer medulla; in the liver, they are mainly hepatocytes. The Epo secretion is stimulated by hypoxia, which is detected by an oxygen sensor. The Epo receptor is a multimeric protein, one chain which binds Epo has been cloned. However the structure of the Epo receptor is still puzzling, and one or more accessory chains remain to be identified. Since the clonage of the Epo gene, recombinant Epo has been available and allowed the treatment of patients with renal diseases with a constant efficacy.

  4. Erythropoietin and diabetes mellitus.

    Science.gov (United States)

    Maiese, Kenneth

    2015-10-25

    Erythropoietin (EPO) is a 30.4 kDa growth factor and cytokine that governs cell proliferation, immune modulation, metabolic homeostasis, vascular function, and cytoprotection. EPO is under investigation for the treatment of variety of diseases, but appears especially suited for the treatment of disorders of metabolism that include diabetes mellitus (DM). DM and the complications of this disease impact a significant portion of the global population leading to disability and death with currently limited therapeutic options. In addition to its utility for the treatment of anemia, EPO can improve cardiac function, reduce fatigue, and improve cognition in patients with DM as well as regulate cellular energy metabolism, obesity, tissue repair and regeneration, apoptosis, and autophagy in experimental models of DM. Yet, EPO can have adverse effects that involve the vasculature system and unchecked cellular proliferation. Critical to the cytoprotective capacity and the potential for a positive clinical outcome with EPO are the control of signal transduction pathways that include protein kinase B, the mechanistic target of rapamycin, Wnt signaling, mammalian forkhead transcription factors of the O class, silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae), and AMP activated protein kinase. Therapeutic strategies that can specifically target and control EPO and its signaling pathways hold great promise for the development of new and effective clinical treatments for DM and the complications of this disorder.

  5. Testing for recombinant erythropoietin.

    Science.gov (United States)

    Delanghe, Joris R; Bollen, Mathieu; Beullens, Monique

    2008-03-01

    Erythropoietin (Epo) is a glycoprotein hormone that promotes the production of red blood cells. Recombinant human Epo (rhEpo) is illicitly used to improve performance in endurance sports. Doping in sports is discouraged by the screening of athletes for rhEpo. Both direct tests (indicating the presence of exogeneous Epo isoforms) and indirect tests (indicating hematological changes induced by exogenous Epo administration) can be used for Epo detection. At present, the test adopted by the World Anti Doping Agency is based on a combination of isoelectric focusing and double immunoblotting, and distinguishes between endogenous and rhEpo. However, the adopted monoclonal anti-Epo antibodies are not monospecific. Therefore, the test can occasionally lead to the false-positive detection of rhEpo (epoetin-beta) in post-exercise, protein-rich urine, or in case of contamination of the sample with microorganisms. An improved preanalytical care may counteract a lot of these problems. Adaptation of the criteria may be helpful to further refine direct Epo testing. Indirect tests have the disadvantage that they require blood instead of urine samples, but they can be applied to detect a broader range of performance improving techniques which are illicitly used in sports.

  6. Erythropoietin and diabetes mellitus

    Institute of Scientific and Technical Information of China (English)

    Kenneth; Maiese

    2015-01-01

    Erythropoietin(EPO) is a 30.4 k Da growth factor and cytokine that governs cell proliferation, immune modulation, metabolic homeostasis, vascular function, and cytoprotection. EPO is under investigation for the treatment of variety of diseases, but appears especially suited for the treatment of disorders of metabolism that include diabetes mellitus(DM). DM and the com-plications of this disease impact a significant portion of the global population leading to disability and death with currently limited therapeutic options. In addition to its utility for the treatment of anemia, EPO can improve cardiac function, reduce fatigue, and improve cognition in patients with DM as well as regulate cellular energy metabolism, obesity, tissue repair and regeneration, apoptosis, and autophagy in experimental models of DM. Yet, EPO can have adverse effects that involve the vasculature system and unchecked cellular proliferation. Critical to the cytoprotective capacity and the potential for a positive clinical outcome with EPO are the control of signal transduction pathways that include protein kinase B, the mechanistic target of rapamycin, Wnt signaling, mammalian forkhead transcription factors of the O class, silent mating type information regulation 2 homolog 1(Saccharomyces cerevisiae), and AMP activated protein kinase. Therapeutic strategies that can specifically target and control EPO and its signaling pathways hold great promise for the development of new and effective clinical treatments for DM and the complications of this disorder.

  7. Erythropoietin during hypoglycaemia in type 1 diabetes

    DEFF Research Database (Denmark)

    Kristensen, Peter Lommer; Høi-Hansen, Thomas; Olsen, Niels Vidiendal

    2009-01-01

    AIMS: Preservation of cognitive function during hypoglycaemic episodes is crucial for patients with insulin-treated diabetes to avoid severe hypoglycaemic events. Erythropoietin has neuroprotective potential. However, the role of erythropoietin during hypoglycaemia is unclear. The aim of the stud....... CONCLUSIONS: Hypoglycaemia triggers a rise in plasma erythropoietin in patients with type 1 diabetes. The response is influenced by basal RAS activity. Erythropoietin may carry a neuroprotective potential during hypoglycaemia....... was to explore plasma erythropoietin response to hypoglycaemia and the relationship to basal renin-angiotensin system (RAS) activity and cognitive function. METHODS: We performed a single-blinded, controlled, cross-over study with induced hypoglycaemia or maintained glycaemic level. Nine patients with type 1......AIMS: Preservation of cognitive function during hypoglycaemic episodes is crucial for patients with insulin-treated diabetes to avoid severe hypoglycaemic events. Erythropoietin has neuroprotective potential. However, the role of erythropoietin during hypoglycaemia is unclear. The aim of the study...

  8. Intranasal formulation of erythropoietin (EPO) showed potent protective activity against amyloid toxicity in the Aβ₂₅₋₃₅ non-transgenic mouse model of Alzheimer's disease.

    Science.gov (United States)

    Maurice, Tangui; Mustafa, Muhammad-Hariri; Desrumaux, Catherine; Keller, Emeline; Naert, Gaëlle; de la C García-Barceló, María; Rodríguez Cruz, Yamila; Garcia Rodríguez, Julío César

    2013-11-01

    Erythropoietin (EPO) promotes neurogenesis and neuroprotection. We here compared the protection induced by two EPO formulations in a rodent model of Alzheimer's disease (AD): rHu-EPO and a low sialic form, Neuro-EPO. We used the intracerebroventricular administration of aggregated Aβ₂₅₋₃₅ peptide, a non-transgenic AD model. rHu-EPO was tested at 125-500 µg/kg intraperitoneally and Neuro-EPO at 62-250 µg/kg intranasally (IN). Behavioural procedures included spontaneous alternation, passive avoidance, water-maze and object recognition, to address spatial and non-spatial, short- and long-term memories. Biochemical markers of Aβ₂₅₋₃₅ toxicity in the mouse hippocampus were examined and cell loss in the CA1 layer was determined. rHu-EPO and Neuro-EPO led to a significant prevention of Aβ₂₅₋₃₅-induced learning deficits. Both EPO formulations prevented the induction of lipid peroxidation in the hippocampus, showing an antioxidant activity. rHu-EPO (250 µg/kg) or Neuro-EPO (125 µg/kg) prevented the Aβ₂₅₋₃₅-induced increase in Bax level, TNFα and IL-1β production and decrease in Akt activation. A significant prevention of the Aβ₂₅₋₃₅-induced cell loss in CA1 was also observed. EPO is neuroprotective in the Aβ₂₅₋₃₅ AD model, confirming its potential as an endogenous neuroprotection system that could be boosted for therapeutic efficacy. We here identified a new IN formulation of EPO showing high neuroprotective activity. Considering its efficacy, ease and safety, IN Neuro-EPO is a new promising therapeutic agent in AD.

  9. Carbamylation of Human Lens γ-crystaUins:Relevance to Cataract Formation

    Institute of Scientific and Technical Information of China (English)

    1993-01-01

    Cigarette smoking is a main source of cyanide in human body,which can be taken as a risk factor of cataract formation.In this study,combined gas chromatography and mass spectrum (GC/MS) was used todetermine the amino acid hydantoin after the incubation of soluble humanlens γ-crystallins with cyanate.The carbamylated amino acids obtained bythis procedure are alanine and hlycine,which are N-terminal amino acids ofγ-crystallin,and leucine.The aggregate,which can be observed incarbamylated γ_1-crystallin on...

  10. Biology of erythropoietin.

    Science.gov (United States)

    Lacombe, C; Mayeux, P

    1998-08-01

    Erythropoietin (Epo) controls the proliferation, differentiation and survival of the erythroid progenitors. This cytokine was cloned in 1985 and rapidly became used for treatment of anemia of renal failure, opening the way to the first clinical trials of a hematopoietic growth factor. The clonage of one chain of the Epo receptor followed in 1989, thereby opening the research on intracellular signal transduction induced by Epo. Epo is synthesized mainly by the kidney and the liver and sequences required for tissue-specific expression have been localized in the Epo gene. A 3'enhancer is responsible for hypoxia-inducible Epo gene expression. HIF-1 alpha and beta proteins bind to this enhancer. Gene regulation by hypoxia is widespread in many cells and involves numerous genes in addition to the Epo gene. The Epo receptor belongs to the cytokine receptor family and includes a p66 chain which is dimerized upon Epo activation; two accessory proteins defined by cross-linking remain to be characterized. Epo binding induces the stimulation of Jak2 tyrosine kinase. Jak2 activation leads to the tyrosine phosphorylation of several proteins including the Epo receptor itself. As a result, different intracellular pathways are activated: Ras/MAP kinase, phosphatidylinositol 3-kinase and STAT transcription factors. However, the exact mechanisms by which the proliferation and/or the differentiation of erythroid cells are regulated after Epo stimulation are not known. Furthermore, target disruption of both Epo and Epo receptor showed that Epo was not involved in the commitment of the erythroid lineage and seemed to act mainly as a survival factor.

  11. Protein carbamylation is associated with heart failure and mortality in diabetic patients with end-stage renal disease.

    Science.gov (United States)

    Drechsler, Christiane; Kalim, Sahir; Wenger, Julia B; Suntharalingam, Pirianthini; Hod, Tammy; Thadhani, Ravi I; Karumanchi, S Ananth; Wanner, Christoph; Berg, Anders H

    2015-06-01

    Serum carbamylated albumin (C-Alb) levels are associated with excess mortality in patients with diabetic end-stage renal disease. To gain insight into the pathophysiology of carbamylation, we determined associations between C-Alb and causes of death in patients on chronic hemodialysis. The Die Deutsche Diabetes Dialyse Studie (4D study) was a randomized controlled trial testing the effects of atorvastatin on survival in diabetic patients on dialysis during a median follow-up of 4 years. We stratified 1161 patients by C-Alb to see whether differences in carbamylation altered the effects of atorvastatin on survival. Baseline C-Alb significantly correlated with serum cardiac stress markers troponin T and N-terminal pro-B-type-natriuretic peptide and was associated with a history of heart failure and arrhythmia. C-Alb was strongly associated with 1-year adjusted risk of cardiovascular mortality, sudden cardiac death, and the 4-year risk of death from congestive heart failure (hazard ratios of 3.06, 3.78, and 4.64, respectively) but not with myocardial infarction or stroke. Patients with low C-Alb, treated with atorvastatin, experienced a significant improvement in their 4-year survival (hazard ratio 0.692). High C-Alb levels are associated with ongoing cardiac damage, risk of congestive heart failure, and sudden cardiac death. Thus, carbamylation and uremic cardiomyopathy are associated in patients with diabetes mellitus and kidney disease. In addition, statins were specifically beneficial to hemodialysis patients with low C-Alb.

  12. Regeneration in the nervous system with erythropoietin.

    Science.gov (United States)

    Maiese, Kenneth

    2016-01-01

    Globally, greater than 30 million individuals are afflicted with disorders of the nervous system accompanied by tens of thousands of new cases annually with limited, if any, treatment options. Erythropoietin (EPO) offers an exciting and novel therapeutic strategy to address both acute and chronic neurodegenerative disorders. EPO governs a number of critical protective and regenerative mechanisms that can impact apoptotic and autophagic programmed cell death pathways through protein kinase B (Akt), sirtuins, mammalian forkhead transcription factors, and wingless signaling. Translation of the cytoprotective pathways of EPO into clinically effective treatments for some neurodegenerative disorders has been promising, but additional work is necessary. In particular, development of new treatments with erythropoiesis-stimulating agents such as EPO brings several important challenges that involve detrimental vascular outcomes and tumorigenesis. Future work that can effectively and safely harness the complexity of the signaling pathways of EPO will be vital for the fruitful treatment of disorders of the nervous system.

  13. Antibodies specific for carbamylated proteins precede the onset of clinical symptoms in mice with collagen induced arthritis.

    Directory of Open Access Journals (Sweden)

    Jeroen N Stoop

    Full Text Available OBJECTIVE: The immune response to post-translationally modified antigens is a key characteristic of rheumatoid arthritis. Carbamylation is such a posttranslational modification. Recently, we demonstrated that autoantibodies recognizing carbamylated proteins are present in sera of rheumatoid arthritis. The molecular mechanisms underlying the break of tolerance and hence the induction of anti-CarP antibody responses are unknown as well as their appearance in mouse models for systemic arthritis. Therefore we analyzed their appearance in the mouse collagen-induced arthritis model. METHODS: collagen induced arthritis was induced by immunization with type II collagen in complete Freund's adjuvant. Arthritis severity was monitored by clinical scoring and anti-CarP antibody levels were determined by ELISA. RESULTS: Anti-CarP antibodies were detectable in mice with collagen induced arthritis. We did not detect ACPA in mice with collagen induced arthritis. The specificity of the antibodies for carbamylated proteins was confirmed by inhibition assays and immunoblotting. Injection with complete Freund's adjuvant without type II collagen could also induce anti-CarP antibodies, however, in mice with arthritis, the anti-CarP antibody response was stronger and developed more rapidly. The onset of collagen induced arthritis was preceded by an increase of anti-CarP IgG2a levels in the serum. CONCLUSION: In mice with collagen induced arthritis we did not observe an immune response against citrullinated antigens, but we did observe an immune response against carbamylated antigens. This anti-CarP response already appeared before disease onset, indicating that collagen induced arthritis can be used as an in vivo model to study anti-CarP antibodies. Our data also indicate that the tolerance to carbamylated proteins, in contrast to the response to citrullinated proteins, is easily broken and that arthritis boosts the immune response against these proteins. The anti

  14. Role of Erythropoietin in Renal Anemia Therapy

    African Journals Online (AJOL)

    Keywords: Chronic renal failure, Renal anemia, Erythropoietin resistance. Tropical Journal of ... gastrointestinal reaction, which can increase the iron utilization and improve iron reserves, overcoming the reticuloendothelial system iron.

  15. 重组人促红细胞生成素对脓毒症大鼠肺脏的保护作用%Protective effects of recombinant human erythropoietin on acute lung injury induced by sepsis in rats

    Institute of Scientific and Technical Information of China (English)

    桑珍珍; 许云; 盛英杰; 赵敏

    2013-01-01

    目的 探讨重组人促红细胞生成素(recombinant human erythropoietin,rHuEPO)对内毒素所致大鼠脓毒症急性肺损伤的保护作用.方法 45只雄性SD大鼠随机(随机数字法)分为对照组、模型组、rHuEPO组,每组均15只.经静脉推注脂多糖LPS(6 mg/kg)复制急性肺损伤(ALI)的动物模型,rHuEPO组造模前60 min静脉推注rHuEPO (5000 U/kg),观察12 h后处死.留取颈动脉血及肺组织标本.测定氧和指数(OI)、动脉血氧分压(PaO2)、动脉血二氧化碳分压(PaCO2)、pH值.采用酶联免疫法(ELISA法)测定大鼠血清TNF-α、IL-6、iNOS的水平.在光镜和透射电镜下观察肺组织的病理形态学变化,并取右肺下叶计算肺湿/干质量比(W/D).结果 (1)血气分析:与对照组相比,脓毒症组及rHuEPO组大鼠动脉血PaO2、pH显著降低,PaCO2显著升高;与脓毒症组相比,rHuEPO组PaO2、pH显著升高及PaCO2显著降低,差异具有统计学意义(P<0.05).(2)各组大鼠肺组织湿干质量比(W/D)变化:与对照组相比,脓毒症组及rHuEPO组肺组织W/D显著增加;与脓毒症组相比,rHuEPO组肺组织W/D显著降低,差异具有统计学意义(P<0.05).(3)各组大鼠12 h血清TNF-α、IL-6、iNOS水平的变化:脓毒症组及rHuEPO组上述指标明显高于对照组;与脓毒症组相比,rHuEPO组上述指标明显降低,差异具有统计学意义(P<0.01).(4)光镜及电镜观察脓毒症组病理学改变为急性弥漫性肺损伤,表现为肺泡腔内出血、渗出、炎性细胞浸润,肺微血管内皮细胞、Ⅰ型和Ⅱ型上皮细胞坏死;rHuEPO组急性肺损伤明显轻于脓毒症组,只可见到局灶性肺泡少量炎性细胞浸润.结论 rHuEPO能够降低血清TNF-α、IL-6、iNOS水平进而调节炎症反应,对脓毒症所致急性肺损伤具有一定的保护作用.%Objective To investigate the protective effects of recombinant human erythropoietin (rHuEPO) on acute lung injury (ALI) induced by lipopolysaccharide (LPS

  16. Erythropoietin: from erythropoiesis to cardioprotection

    Directory of Open Access Journals (Sweden)

    Liermis Michael Dita Salabert

    2010-08-01

    Full Text Available Many of the drugs that has shown promise in the treatment of hematologic malignancies and solid tumors, associated with a high potential cardiotoxic. Within this group stand anthracyclines, identified as the type of chemotherapy most likely to cause heart damage, short or long term. With the improvement achieved in the survival of patients with these diseases, this adverse event has become a major concern for the scientific community. Although many agents have been evaluated as potential cardioprotective therapeutic, clinical data are limited and does not suggest that the use of these agents promotes the survival of patients undergoing cardiotoxic treatments. The identification of erythropoietin receptor in hematopoietic tissues, including the heart, as well as its marked cardioprotective effect during ischemia have led to the hypothesis that erythropoietin may be able to prevent anthracycline-induced cardiomyopathy. Addressing this hypothesis is the objective of this work.

  17. Carbamylated low-density lipoprotein induces oxidative stress and accelerated senescence in human endothelial progenitor cells.

    Science.gov (United States)

    Carracedo, Julia; Merino, Ana; Briceño, Carolina; Soriano, Sagrario; Buendía, Paula; Calleros, Laura; Rodriguez, Mariano; Martín-Malo, Alejandro; Aljama, Pedro; Ramírez, Rafael

    2011-04-01

    Carbamylated low-density lipoprotein (cLDL) plays a role in atherosclerosis. In this study we evaluate the effect of uremia on LDL carbamylation and the effect of cLDL and oxidized LDL (oxLDL; 200 μg/ml) on number, function, and genomic stability of endothelial progenitor cells (EPCs) obtained from healthy volunteers. cLDL was generated after incubation of native LDL (nLDL) with uremic serum from patients with chronic kidney disease (CKD) stages 2-4. Oxidative stress was measured by flow cytometry and fluorescent microscopy, mitochondrial depolarization by flow cytometry, senescence by β-galactosidase activity and telomere length, and DNA damage by phosphorylated histone H2AX (γH2AX). The percentage of cLDL by uremic serum was related to the severity of CKD. Compared with nLDL, cLDL induced an increase in oxidative stress (62±5 vs. 8±3%, P<0.001) and cells with mitochondrial depolarization (73±7 vs. 9±5%, P<0.001), and a decrease in EPC proliferation and angiogenesis. cLDL also induced accelerated senescence (73±16 vs. 12±9%, P<0.001), which was associated with a decrease in the expression of γH2AX (62±9 vs. 5±3%, P<0.001). The degree of injury induced by cLDL was comparable to that observed with oxLDL. This study supports the hypothesis that cLDL triggers genomic damage in EPCs, resulting in premature senescence. We can, therefore, hypothesize that EPCs injury by cLDL contributes to an increase in atherosclerotic disease in CKD.

  18. Transplantation of erythropoietin gene-modified neural stem cells improves the repair of injured spinal cord

    Directory of Open Access Journals (Sweden)

    Min-fei Wu

    2015-01-01

    Full Text Available The protective effects of erythropoietin on spinal cord injury have not been well described. Here, the eukaryotic expression plasmid pcDNA3.1 human erythropoietin was transfected into rat neural stem cells cultured in vitro. A rat model of spinal cord injury was established using a free falling object. In the human erythropoietin-neural stem cells group, transfected neural stem cells were injected into the rat subarachnoid cavity, while the neural stem cells group was injected with non-transfected neural stem cells. Dulbecco′s modified Eagle′s medium/F12 medium was injected into the rats in the spinal cord injury group as a control. At 1-4 weeks post injury, the motor function in the rat lower limbs was best in the human erythropoietin-neural stem cells group, followed by the neural stem cells group, and lastly the spinal cord injury group. At 72 hours, compared with the spinal cord injury group, the apoptotic index and Caspase-3 gene and protein expressions were apparently decreased, and the bcl-2 gene and protein expressions were noticeably increased, in the tissues surrounding the injured region in the human erythropoietin-neural stem cells group. At 4 weeks, the cavities were clearly smaller and the motor and somatosensory evoked potential latencies were remarkably shorter in the human erythropoietin-neural stem cells group and neural stem cells group than those in the spinal cord injury group. These differences were particularly obvious in the human erythropoietin-neural stem cells group. More CM-Dil-positive cells and horseradish peroxidase-positive nerve fibers and larger amplitude motor and somatosensory evoked potentials were found in the human erythropoietin-neural stem cells group and neural stem cells group than in the spinal cord injury group. Again, these differences were particularly obvious in the human erythropoietin-neural stem cells group. These data indicate that transplantation of erythropoietin gene-modified neural stem

  19. Transplantation of erythropoietin gene-modified neural stem cells improves the repair of injured spinal cord.

    Science.gov (United States)

    Wu, Min-Fei; Zhang, Shu-Quan; Gu, Rui; Liu, Jia-Bei; Li, Ye; Zhu, Qing-San

    2015-09-01

    The protective effects of erythropoietin on spinal cord injury have not been well described. Here, the eukaryotic expression plasmid pcDNA3.1 human erythropoietin was transfected into rat neural stem cells cultured in vitro. A rat model of spinal cord injury was established using a free falling object. In the human erythropoietin-neural stem cells group, transfected neural stem cells were injected into the rat subarachnoid cavity, while the neural stem cells group was injected with non-transfected neural stem cells. Dulbecco's modified Eagle's medium/F12 medium was injected into the rats in the spinal cord injury group as a control. At 1-4 weeks post injury, the motor function in the rat lower limbs was best in the human erythropoietin-neural stem cells group, followed by the neural stem cells group, and lastly the spinal cord injury group. At 72 hours, compared with the spinal cord injury group, the apoptotic index and Caspase-3 gene and protein expressions were apparently decreased, and the bcl-2 gene and protein expressions were noticeably increased, in the tissues surrounding the injured region in the human erythropoietin-neural stem cells group. At 4 weeks, the cavities were clearly smaller and the motor and somatosensory evoked potential latencies were remarkably shorter in the human erythropoietin-neural stem cells group and neural stem cells group than those in the spinal cord injury group. These differences were particularly obvious in the human erythropoietin-neural stem cells group. More CM-Dil-positive cells and horseradish peroxidase-positive nerve fibers and larger amplitude motor and somatosensory evoked potentials were found in the human erythropoietin-neural stem cells group and neural stem cells group than in the spinal cord injury group. Again, these differences were particularly obvious in the human erythropoietin-neural stem cells group. These data indicate that transplantation of erythropoietin gene-modified neural stem cells into the

  20. Bone marrow mesenchymal stem cells transplantation promotes the release of endogenous erythropoietin after ischemic stroke

    Directory of Open Access Journals (Sweden)

    Wen Lv

    2015-01-01

    Full Text Available This study investigated whether bone marrow mesenchymal stem cell (BMSC transplantation protected ischemic cerebral injury by stimulating endogenous erythropoietin. The model of ischemic stroke was established in rats through transient middle cerebral artery occlusion. Twenty-four hours later, 1 × 10 6 human BMSCs (hBMSCs were injected into the tail vein. Fourteen days later, we found that hBMSCs promoted the release of endogenous erythropoietin in the ischemic region of rats. Simultaneously, 3 μg/d soluble erythropoietin receptor (sEPOR was injected into the lateral ventricle, and on the next 13 consecutive days. sEPOR blocked the release of endogenous erythropoietin. The neurogenesis in the subventricular zone was less in the hBMSCs + sEPOR group than in the hBMSCs + heat-denatured sEPOR group. The adhesive-removal test result and the modified Neurological Severity Scores (mNSS were lower in the hBMSCs + sEPOR group than in the heat-denatured sEPOR group. The adhesive-removal test result and mNSS were similar between the hBMSCs + heat-denatured sEPOR group and the hBMSCs + sEPOR group. These findings confirm that BMSCs contribute to neurogenesis and improve neurological function by promoting the release of endogenous erythropoietin following ischemic stroke.

  1. Bone marrow mesenchymal stem cells transplantation promotes the release of endogenous erythropoietin after ischemic stroke

    Institute of Scientific and Technical Information of China (English)

    Wen Lv; Wen-yu Li; Xiao-yan Xu; Hong Jiang; Oh Yong Bang

    2015-01-01

    This study investigated whether bone marrow mesenchymal stem cell (BMSC) transplantation protected ischemic cerebral injury by stimulating endogenous erythropoietin. The model of isch-emic stroke was established in rats through transient middle cerebral artery occlusion. Twenty-four hours later, 1 × 106 human BMSCs (hBMSCs) were injected into the tail vein. Fourteen days later, we found that hBMSCs promoted the release of endogenous erythropoietin in the ischemic region of rats. Simultaneously, 3 μg/d soluble erythropoietin receptor (sEPOR) was injected into the lateral ventricle, and on the next 13 consecutive days. sEPOR blocked the release of endogenous erythropoietin. The neurogenesis in the subventricular zone was less in the hBMSCs + sEPOR group than in the hBMSCs + heat-denatured sEPOR group. The adhesive-removal test result and the modified Neurological Severity Scores (mNSS) were lower in the hBMSCs + sEPOR group than in the heat-denatured sEPOR group. The adhesive-removal test result and mNSS were similar between the hBMSCs + heat-denatured sEPOR group and the hBMSCs + sEPOR group. These ifndings conifrm that BMSCs contribute to neurogenesis and improve neurological function by promoting the release of endogenous erythropoietin following ischemic stroke.

  2. Erythropoietin and vascular endothelial growth factor as risk markers for severe hypoglycaemia in type 1 diabetes

    DEFF Research Database (Denmark)

    Kristensen, P L; Pedersen-Bjergaard, U; Schalkwijk, C

    2010-01-01

    OBJECTIVE: Circulating erythropoietin (EPO) and vascular endothelial growth factor (VEGF) increase during hypoglycaemia and may represent protective hormonal counter-regulatory responses. We tested the hypothesis that low levels of EPO and VEGF are associated with a higher frequency of severe...... levels to determine future risk of severe hypoglycaemia in people with type 1 diabetes....

  3. Erythropoietin-induced proliferation of gastric mucosal cells

    Institute of Scientific and Technical Information of China (English)

    Kazuro Itoh; Masato Higuchi; Fumio Ishihata; Yushi Sudoh; Soichiro Miura; Yoshio Sawasaki; Kyoko Takeuchi; Shingo Kato; Nobuhiro Imai; Yoichiro Kato; Noriyuki Shibata; Makio Kobayashi; Yoshiyuki Moriguchi

    2006-01-01

    AIM: To analyze the localization of erythropoietin receptor on gastric specimens and characterize the effects of erythropoietin on the normal gastric epithelial proliferation using a porcine gastric epithelial cell culture model.METHODS: Erythropoietin receptor was detected by RT-PCR, Western blotting and immunohistochermistry.Growth stimulation effects of erythropoietin on cultured gastric mucosal cells were determined by ELISA using bromodeoxyuridine (BrdU).RESULTS: Erythropoietin receptor was detected on cultured porcine gastric mucosal epithelial cells.Erythropoietin receptor was also detected histochemically at the base of gastric mucosal epithelium. BrdU assay demonstrated a dose-dependent increase in growth potential of cultured porcine gastric mucosal epithelial cells by administration of erythropoietin, as well as these effects were inhibited by administration of antierythropoietin antibody (P< 0.01).CONCLUSION: These findings indicate that erythropoietin has a potential to proliferate gastric mucosal epithelium via erythropoietin receptor.

  4. Erythropoietin and the effect of oxygen during proliferation and differentiation of human neural progenitor cells

    Directory of Open Access Journals (Sweden)

    Frech Moritz J

    2010-12-01

    Full Text Available Abstract Background Hypoxia plays a critical role in various cellular mechanisms, including proliferation and differentiation of neural stem and progenitor cells. In the present study, we explored the impact of lowered oxygen on the differentiation potential of human neural progenitor cells, and the role of erythropoietin in the differentiation process. Results In this study we demonstrate that differentiation of human fetal neural progenitor cells under hypoxic conditions results in an increased neurogenesis. In addition, expansion and proliferation under lowered oxygen conditions also increased neuronal differentiation, although proliferation rates were not altered compared to normoxic conditions. Erythropoietin partially mimicked these hypoxic effects, as shown by an increase of the metabolic activity during differentiation and protection of differentiated cells from apoptosis. Conclusion These results provide evidence that hypoxia promotes the differentiation of human fetal neural progenitor cells, and identifies the involvement of erythropoietin during differentiation as well as different cellular mechanisms underlying the induction of differentiation mediated by lowered oxygen levels.

  5. The mechanisms of protective effects of erythropoietin (EPO) on sepsis induced myocardial injury in rat%促红细胞生成素对脓毒症大鼠心肌损伤的保护作用

    Institute of Scientific and Technical Information of China (English)

    秦延军; 张新亮; 于悦卿; 卞晓华; 董士民

    2014-01-01

    Objective To investigate the protective effects of erythropoietin (EPO) on myocardium injury after sepsis in rats in order to clarify the mechanisms.Methods The rat models of sepsis were produced by cecal ligation and perforation method (CLP).Ninty-six healthy SD rats were randomly (random number) divided into 3 groups:the sham operation group (Sham group,n =32),the sepsis group (CLP group,n =32),and the EPO treatment group (EPO group,n =32) treated with EPO 1000 IU/kg intraperitoneal injection after the CLP.The observation intervals were set at 3 h,6 h,12 h and 24 h after the surgery.The cardiac hemodynamics of the CLP group were measured.Plasma levels of inflammatory factors and myocardial enzyme indicators were determined by enzyme-linked immunosorbent assay (ELISA) ; Membrane potential levels of chondriosome of myocardial cells,cell apoptosis rates and expressions of nuclear factor-κB p65 of myocardium tissue were detected by flow cytometer; Then the pathological change of myocardium with HE staining was observed under light microscopy.Results (1) Compared with the CLP group,left ventricle systolic pressure (LVSP),left ventricle diastolic end pressure (LVEDP),the maximum rate of left ventricle rise and fall (+ dp/dtmax and-dp/dtmax) in the EPO group improved (P <0.05,P<0.01); (2) Compared with the Sham operation group,plasma levels of tumor necrosis factoralpha (TNF-α),interleukin-6 (IL-6),C-reactive protein (CRP),cardiac troponin-I (cTNI),creatine kinase (CK),lactate dehydrogenase (LDH) and glutamine-oxaloacetic transaminase (GOT) in the CLP group increased at each interval (P < 0.05),and those biomarkers in the EPO group were lower than those in the CLP group (P < 0.05) ; On the contrary,plasma level of anti-inflammatory factor IL-10 in EPO group was higher than that in the CLP group (P < 0.01) ; (3) Compared with the Sham operation group,the cell apoptosis rates in the CLP group increased significantly (P < 0.01),and it decreased obviously in

  6. Recombinant human erythropoietin in sports: a review

    Directory of Open Access Journals (Sweden)

    Rafael Maia de Almeida Bento

    2003-06-01

    Full Text Available Erythropoietin is an endogenous hormone of glicoproteic nature secreted by the kidneys and is the main regulator of the erythropoiesis. An alteration in its production generates a disturbance in the plasmatic concentration giving rise to several types of pathologies related to the hematopoietic system. The recombinant forms of erythropoietin have indiscriminately been used by athletes, mainly in endurance sports, by increasing the erythrocytes concentration, generating a better delivery of oxygen to the muscle tissue. The administration of recombinant erythropoietin was prohibited by the International Olympic Committee and its use considered as doping. This review has the intention to describe the physical, biological and pharmacokinetic properties of the endogenous erythropoietin, as well as its recombinant form, describing also its use in sports and the process of searching methodologies for its detection in doping control.

  7. Erythropoietin in heart failure : effects beyond erythropoiesis

    NARCIS (Netherlands)

    Ruifrok, Willem-Peter Theodoor

    2011-01-01

    Erythropoietin in Heart Failure: Effects beyond Erythropoiesis Hartfalen is een ernstige cardiologische aandoening met een hoge mortaliteit en morbiditeit. Nieuwe behandelmethoden voor hartfalen zijn daarom gewenst. Het doel van dit proefschrift was het onderzoeken van de niet-hematopoietische effec

  8. 21 CFR 864.7250 - Erythropoietin assay.

    Science.gov (United States)

    2010-04-01

    ... erythropoietin (an enzyme that regulates the production of red blood cells) in serum or urine. This assay provides diagnostic information for the evaluation of erythrocytosis (increased total red cell mass)...

  9. Functional Erythropoietin Autocrine Loop in Melanoma

    OpenAIRE

    Kumar, Suresh M; Acs, Geza; Fang, Dong; Herlyn, Meenhard; Elder, David E.; Xu, Xiaowei

    2005-01-01

    Although erythropoietin (Epo) is a known stimulator of erythropoiesis, recent evidence suggests that its biological functions are not confined to hematopoietic cells. To elucidate the role of Epo and erythropoietin receptor (EpoR) in melanoma, we examined the expression and function of these proteins in melanocytes and melanoma cells. We found increased expression of Epo in melanoma cells compared to melanocyte in vitro. EpoR was also strongly expressed in all of the melanoma cell lines and t...

  10. 红细胞生成素对肠缺血再灌注损伤的保护作用及其机制研究%Protective Effect and Potential Mechanism of Erythropoietin on Intestinal Ischemia-reperfusion Injury

    Institute of Scientific and Technical Information of China (English)

    刘启胜; 程正位; 熊建光; 程思; 李湘楚

    2016-01-01

    Background:Inflammation plays an important role in intestinal ischemia-reperfusion injury(IRI),and erythropoietin (EPO)has been reported to have anti-inflammatory activity. Aims:To explore the protective effect of EPO on intestinal IRI and its potential mechanism. Methods:Thirty-two healthy male Sprague-Dawley rats were randomly divided into four groups:sham operation group(sham group),IRI group,EPO group and 740Y-P group. Rats in IRI,EPO and 740Y-P groups were injected intraperitoneally with 0. 9% NaCl,EPO and EPO + 740Y-P,respectively,one hour before the establishment of intestinal IRI model by superior mesenteric artery clamping(45 min)-reperfusion. All rats were sacrificed one hour after reperfusion. Histopathological changes of small intestine were observed;expression of proteins in PI3K/ Akt and NF-κB signaling pathways was measured by Western blotting;expression and secretion of inflammatory cytokines, including interleukin-8(IL-8),tumor necrosis factor-α(TNF-α)and monocyte chemoattractant protein-1(MCP-1)were examined by real-time PCR and ELISA. Results:Compared with sham group,the damage score of small intestine,protein expressions of PI3K,p-Akt and p-NF-κB p65,as well as mRNA expressions and serum levels of IL-8,TNF-α and MCP-1 in IRI group were significantly increased(P < 0. 05). EPO pretreatment could ameliorate the histopathological changes of small intestine in IRI model rats,inhibit PI3K/ Akt and NF-κB signaling activation and down-regulate expression and secretion of inflammatory cytokines. When 740Y-P,a PI3K agonist,was used combinedly,the effect exerted by EPO was diminished. Conclusions:EPO pretreatment can protect against intestinal IRI by inhibiting the activation of PI3K/ Akt/NF-κB signaling and the subsequent inflammatory response.%背景:炎症反应是肠缺血再灌注损伤(IRI)的重要发病机制之一,而红细胞生成素(EPO)具有抗炎活性。目的:探讨 EPO 对肠 IRI 的保护作用

  11. Erythropoietin stimulates patellar tendon healing in rats.

    Science.gov (United States)

    Uslu, Mustafa; Kaya, Ertuğrul; Yaykaşlı, Kürşat Oğuz; Oktay, Murat; Inanmaz, Mustafa Erkan; Işık, Cengiz; Erdem, Havva; Erkan, Melih Engin; Kandiş, Hayati

    2015-12-01

    Erythropoietin (EPO), regulating erythropoiesis, is used to provide protective and regenerative activity in non-haematopoietic tissues. There is insufficient knowledge about the role of EPO activity in tendon healing. Therefore, we investigated the effect of EPO treatment on healing in rat patellar tendons. One hundred and twenty-six, four-month-old male Sprague-Dawley rats were randomly assigned to three experimental groups: 1, no treatment; 2, treatment with isotonic saline (NaCl) and 3, treatment with EPO. Each group was randomly subdivided into two groups for sacrifice at three (1a, 2a, 3a) or six weeks (1b, 2b, 3b). Complete incision of the left patellar tendon from the distal patellar pole was performed. We applied body casts for 20 days after the incised edges of the patellar tendon were brought together with a surgical technique. Both legs were harvested and specimens from each group underwent histological, biomechanical, and protein mRNA expression analyses. There were statistically significant differences in the ultimate breaking force between the EPO group and others at both weeks three and six (prats compared to the control groups biomechanically, histopathologically and with tissue protein mRNA expression. This is the first experimental study to analyze the relationship between EPO treatment and the patellar tendon repair process by biomechanical, histopathological, and tendon tissue mRNA expression methodologies. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. Anti-carbamylated protein antibodies in rheumatoid arthritis patients and their association with rheumatoid factor.

    Science.gov (United States)

    Othman, Maizatul A; Ghazali, Wan Syamimee W; Hamid, Wan Zuraida W A; Wong, Kah K; Yahya, Nurul K

    2017-09-01

    To evaluate levels of anti-carbamylated protein (anti-CarP) antibodies in rheumatoid arthritis (RA) patients and to determine their association with serological parameters and disease activity. Methods: A cross-sectional study involving 105 multiethnic RA patients (48 rheumatoid factor [RF]-positive and 57 RF-negative patients) was conducted at Hospital Universiti Sains Malaysia, Kelantan, Malaysia, from January 2015 to February 2016. Fifty healthy controls (HCs) were included. C-reactive protein (CRP), RF, anti-cyclic citrullinated peptide (anti-CCP) and anti-CarP antibodies were measured. A health assessment questionnaire (HAQ) was administered to the study participants and 28-joint Disease Activity Score (DAS28) were obtained. Results: The level of anti-CarP antibodies was significantly increased in the RA patients compared with HCs (p=0.042). The presence of anti-CarP antibodies was significantly associated with RF (p=0.019) and the HAQ (p=0.010). A significant association between the presence of anti-CarP antibodies and the DAS28 was not found (p=0.632). Conclusion: Our study provides further evidence that the level of anti-CarP antibodies is significantly elevated in RA patients.

  13. Erythropoietin in Brain Development and Beyond

    Directory of Open Access Journals (Sweden)

    Mawadda Alnaeeli

    2012-01-01

    Full Text Available Erythropoietin is known as the requisite cytokine for red blood cell production. Its receptor, expressed at a high level on erythroid progenitor/precursor cells, is also found on endothelial, neural, and other cell types. Erythropoietin and erythropoietin receptor expression in the developing and adult brain suggest their possible involvement in neurodevelopment and neuroprotection. During ischemic stress, erythropoietin, which is hypoxia inducible, can contribute to brain homeostasis by increasing red blood cell production to increase the blood oxygen carrying capacity, stimulate nitric oxide production to modulate blood flow and contribute to the neurovascular response, or act directly on neural cells to provide neuroprotection as demonstrated in culture and animal models. Clinical studies of erythropoietin treatment in stroke and other diseases provide insight on safety and potential adverse effects and underscore the potential pleiotropic activity of erythropoietin. Herein, we summarize the roles of EPO and its receptor in the developing and adult brain during health and disease, providing first a brief overview of the well-established EPO biology and signaling, its hypoxic regulation, and role in erythropoiesis.

  14. Hepatic erythropoietin response in cirrhosis

    DEFF Research Database (Denmark)

    Risør, Louise M; Fenger, Mogens; Olsen, Niels V;

    2016-01-01

    BACKGROUND: Erythropoietin (EPO) is produced in the liver during fetal life, but after birth the production shifts to the kidneys. The liver maintains a production capacity of 10% of the total EPO-production, but can be up-regulated to 100%. Previous studies have demonstrated both elevated...... and reduced concentrations of EPO in cirrhosis. Increased EPO concentrations could be expected due to anemia, hypoxia, renal hypoperfusion, or EPO-mediated hepatoprotective mechanisms. In contrast, poor hepatic production capacity may cause reduced EPO concentrations in cirrhosis. In the present paper we...... aimed to study hepatic and renal venous concentrations of EPO in relation to the severity of the disease. MATERIALS AND METHODS: We included 24 patients with alcoholic cirrhosis and eight age-matched healthy controls. All had a full catheterization performed with the determination of EPO concentrations...

  15. Reduction of pulmonary inflammatory response by erythropoietin in a rat model of endotoxaemia

    Institute of Scientific and Technical Information of China (English)

    SHANG You; JIANG Yuan-xu; XU San-peng; WU Yan; WU Zhou-yang; YUAN Shi-ying; YAO Shang-long

    2009-01-01

    Background Erythropoietin elicits protective effects in lung tissue injury induced by ischaemic reperfusion and hyperoxia.We investigated the protective roles of erythropoietin in pulmonary inflammation and lung injury during acute endotoxaemia.Methods A total of 32 male Sprague-Dawley rats were randomly assigned to four groups:saline group,erythropoietin+saline group,saline+lipopolysaccharide group and erythropoietin+lipopolysaccharide group.Rats were treated with erythropoietin (3000 U/kg,i.p.) or saline,30 minutes prior to lipopolysaccharide administration (6 mg/kg,i.v.).Four hours after lipopolysaccharide injection,samples of pulmonary tissue were collected.Optical microscopy was performed to examine pathological changes in lungs.Wet/dry (W/D) ratios,myeloperoxidase activity,malondialdehyde concentrations and tumour necrosis factor-alpha (TNF-a) as well as interleukin 1 beta (IL-1β) levels in lungs were measured.The pulmonary expression of nuclear factor kappaB (NF-kB) p65 was evaluated by Western blotting.Differences between the different groups were analysed by one-way analysis of variance (ANOVA).Results The lung tissues from the saline+lipopolysaccharide group were significantly damaged,which were less pronounced in the erythropoietin+lipopolysaccharide group.The W/D ratio increased significantly in the saline+lipopolysaccharide group (5.75±0.22) as compared with the saline group (3.85±0.20) (P <0.01),which was significantly reduced in the erythropoietin+lipopolysaccharide group (4.50±0.35) (P <0.01).Myeloperoxidase activity and malondialdehyde levels increased significantly in the saline+lipopolysaccharide group compared with the saline group,which was reduced in the erythropoietin + lipopolysaccharide group.The TNF-a level of pulmonary tissue increased significantly in the saline+lipopolysaccharide group ((9.80±0.82) pg/mg protein) compared with the saline group ((4.20±0.42) pg/mg protein,P <0.01).However,the increase of TNF-a level of

  16. Erythropoietin improves left ventricular function and coronary flow in an experimental model of ischemia-reperfusion injury

    NARCIS (Netherlands)

    van der Meer, P; Lipsic, E; Henning, RH; de Boer, RA; Suurmeijer, AJH; van Veldhuisen, DJ; van Gilst, WH

    2004-01-01

    Recent studies show that erythropoietin (EPO) plays a protective role in brain ischemia. In this condition, administration of EPO protects neurons from ischemic damage. Recently, it has been shown that in patients with chronic heart failure (CHF), EPO treatment improved cardiac function. In the pres

  17. Protein Carbamylation in Chronic Systolic Heart Failure: Relation to Renal Impairment and Adverse Long-Term Outcomes

    Science.gov (United States)

    Wilson Tang, W. H.; Shrestha, Kevin; Wang, Zeneng; Borowski, Allen G.; Troughton, Richard W.; Klein, Allan L.; Hazen, Stanley L.

    2013-01-01

    Background Protein carbamylation, a post-translational modification promoted during uremia and catalyzed by myeloperoxidase (MPO) at sites of inflammation, is linked to altered protein structure, vascular dysfunction, and poor prognosis. We examine the relationship between plasma protein-bound homocitrulline (PBHCit) levels, a marker of protein lysine residue carbamylation, with cardio-renal function and long-term outcomes in chronic systolic heart failure. Methods and Results In 115 patients with chronic systolic HF (LVEF≤35%), we measured plasma PBHCit by quantitative mass spectrometry and performed comprehensive echocardiography with assessment of cardiac structure and performance. Adverse long-term events (death, cardiac transplant) were tracked for 5 years. In our study cohort, the median PBHCit level was 87 [IQR: 59, 128] μmol/mol Lysine. Higher plasma PBHcit levels were associated with poorer renal function (eGFR Spearman’s r= −0.37, p0.10 for each). Furthermore, elevated plasma PBHCit levels were not related to indices of cardiac structure or function (p>0.10 for all examined) except modestly with increased right atrial volume index (RAVi; r=0.31, p=0.002). PBHCit levels predicted adverse long-term events (Hazard ratio [HR]: 1.8, 95% CI 1.3– 2.6, p<0.001), including following adjustment for age, eGFR, MPO and NT-proBNP (HR: 1.9, 95% CI: 1.2–3.1, p=0.006). Conclusions In chronic systolic HF, protein carbamylation is associated with poorer renal but not cardiac function, and portends poorer long-term adverse clinical outcomes even when adjusted for cardio-renal indices of adverse prognosis. PMID:23582087

  18. The relationship of serum erythropoietin level with coronary collateral grade.

    Science.gov (United States)

    Sahinarslan, Asife; Yalcin, Ridvan; Kocaman, Sinan Altan; Ercin, Ugur; Tanalp, Ali Cevat; Topal, Salih; Bukan, Neslihan; Boyaci, Bulent; Cengel, Atiye

    2011-01-01

    Erythropoietin has been shown to induce neovascularization and protect against ischemic vascular injury. We investigated whether a higher serum erythropoietin (EPO) level is related to better coronary collateral vessel grade. Ninety-nine patients with stable angina pectoris who have at least 1 coronary stenosis of equal to or greater than 70% at coronary angiography were prospectively enrolled. Serum EPO and vascular endothelial growth factor (VEGF) levels were studied. Coronary collateral degree was graded according to the Rentrop method. Patients with grade 2-3 collateral degree were included in the good collateral group and formed Group I. The patients with grade 0-1 collateral degree were included in the poor collateral group and formed Group II. The serum EPO level was significantly higher in the good collateral group (17.3 ± 9.3 mU/mL vs 11.7 ± 5.0 mU/mL; P < 0.001). There was also a positive correlation between serum EPO level and Rentrop score (r = 0.39; P < 0.001). In multivariate analysis, serum EPO level (odds ratio [OR] 1.336; 95% confidence interval [CI], 1.120-1.593; P = 0.001), oxygen saturation (OR 0.638; 95% CI, 0.422-0.963; P = 0.033) and presence of chronic total occlusion (CTO) (OR 26.7; 95% CI, 3.874-184.6; P = 0.001) were independently related to well-developed coronary collaterals. Higher serum EPO level is related to better coronary collateral development. Erythropoietin may have a positive effect on the development of collaterals and may provide a new agent for the treatment strategies to enhance coronary collateral vessel development. Copyright © 2011 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

  19. Soluble erythropoietin receptor contributes to erythropoietin resistance in end-stage renal disease.

    Directory of Open Access Journals (Sweden)

    Eliyahu V Khankin

    Full Text Available BACKGROUND: Erythropoietin is a growth factor commonly used to manage anemia in patients with chronic kidney disease. A significant clinical challenge is relative resistance to erythropoietin, which leads to use of successively higher erythropoietin doses, failure to achieve target hemoglobin levels, and increased risk of adverse outcomes. Erythropoietin acts through the erythropoietin receptor (EpoR present in erythroblasts. Alternative mRNA splicing produces a soluble form of EpoR (sEpoR found in human blood, however its role in anemia is not known. METHODS AND FINDINGS: Using archived serum samples obtained from subjects with end stage kidney disease we show that sEpoR is detectable as a 27kDa protein in the serum of dialysis patients, and that higher serum sEpoR levels correlate with increased erythropoietin requirements. Soluble EpoR inhibits erythropoietin mediated signal transducer and activator of transcription 5 (Stat5 phosphorylation in cell lines expressing EpoR. Importantly, we demonstrate that serum from patients with elevated sEpoR levels blocks this phosphorylation in ex vivo studies. Finally, we show that sEpoR is increased in the supernatant of a human erythroleukaemia cell line when stimulated by inflammatory mediators such as interleukin-6 and tumor necrosis factor alpha implying a link between inflammation and erythropoietin resistance. CONCLUSIONS: These observations suggest that sEpoR levels may contribute to erythropoietin resistance in end stage renal disease, and that sEpoR production may be mediated by pro-inflammatory cytokines.

  20. Specific activities of poetam preparation (superlow-doses of antibodies to erythropoietin) and recombinant erythropoietin.

    Science.gov (United States)

    Dygai, A M; Zhdanov, V V; Udut, E V; Simanina, E V; Gur'yantseva, L A; Khrichkova, T Yu; Epshtein, O I; Sergeeva, S A

    2006-09-01

    We compared the capacity of superlow-dose of antibodies to erythropoietin (Poetam) and recombinant erythropoietin (Recormon) to stimulate the recovery of adriamycin-suppressed erythropoiesis in mice. Both preparations exhibited high erythron activation capacity and considerably increased the content of erythrocytes and reticulocytes in the peripheral blood and content of erythrokaryocytes and erythroid precursors in the hemopoietic tissue of experimental animals. The effect of Recormon manifested immediately after injection, while the effect of Poetam was somewhat delayed, but more lasting (due to activation of host erythropoietin system).

  1. Changes in lymphocyte properties after employment of the combination of carbamylation and oxidative stress, an in vitro study.

    Science.gov (United States)

    Pieniazek, Anna; Gwozdzinski, Krzysztof

    2016-08-01

    It is well known that oxidative stress and carbamylation alter macromolecule properties and functions. We evaluated the influence of sodium cyanate (NaOCN) and the combination of cyanate and hydrogen peroxide (H2O2) on nonenzymatic antioxidant capacity (NEAC), total thiols, reduced glutathione (GSH) and hydroperoxide level in mononuclear blood cells (MNCs). We also examined plasma membrane properties of MNCs using the spin labeling method in EPR spectroscopy (electron paramagnetic resonance spectroscopy). We showed that MNCs are resistant to cyanate treatment up to a concentration of 2mM (survival test). On the other hand, a significant loss of antioxidant defense of cells, e.g. NEAC upon NaOCN, H2O2 and the combination of cyanate and hydrogen peroxide was observed. Carbamylation slightly decreased GSH and the free thiol level, but H2O2 and its combination with NaOCN lead to a decrease in their amounts. A markedly higher level of hydroperoxides was only observed in the cells treated with H2O2. We found a significant decrease in lipid membrane fluidity at the depth of 12th and 16th carbon atoms of fatty acids in lymphocytes treated with cyanate or H2O2. The combination of both substances acted synergistically and induced profound changes in comparison to cyanate and hydrogen peroxide used alone.

  2. Prognostic significance of erythropoietin and erythropoietin receptor in gastric adenocarcinoma

    Institute of Scientific and Technical Information of China (English)

    Lin Wang; Hai-Gang Li; Zhong-Sheng Xia; Jian-Ming Wen; Jun Lv

    2011-01-01

    AIM: To investigate the expression of Erythropoietin (Epo) and its receptor (EpoR) in gastric adenocarcinoma (GAC) and the correlation with angiogenesis and clinicopathological features. METHODS: The expressions of Epo, EpoR and vascular endothelial growth factor (VEGF), as well as microvessel density were evaluated in 172 GAC biopsies by immunohistochemical staining. The correlations between these parameters and patient's clinicopathological features were analyzed statistically. RESULTS: The proportion of Epo and EpoR alterations in GAC was higher than that in adjacent normal mucosa (P = 0.035 and 0.030). Epo high-expression was associated with EpoR high-expression, Lauren type, extensive lymph node metastasis and advanced stage of GAC (P = 0.018, 0.018, 0.004 and 0), while EpoR expression was linked with older age, World Health Organization type, extensive lymph node metastasis and advanced stage (P = 0.001, 0.013, 0.008 and 0.001). VEGF high expression was significantly correlated with EpoR low-expression, Lauren type, extensive lymph node metastasis and advanced stage (P = 0.001, 0.001, 0.001 and 0.007). The expression of Epo or EpoR was associated with microvessel density (P = 0.004 and 0.046). On multivariate analysis, only lymph node metastasis, abnormal Epo expression and tumor nodes metastases stage were independently associated with survival. In addition, a strong association with the immunohistochemical expression of EpoR and the angiogenic protein, VEGF, was noted. CONCLUSION: Increased expression of Epo and EpoR may play a significant role in the carcinogenesis, angiogenesis and progression of GAC. Epo may be an independent prognostic factor.

  3. Disease Activity and Conversion into Multiple Sclerosis after Optic Neuritis Is Treated with Erythropoietin

    Directory of Open Access Journals (Sweden)

    Kurt-Wolfram Sühs

    2016-09-01

    Full Text Available Changes in cerebral lesion load by magnetic resonance imaging (MRI in patients from a double-blind, placebo-controlled, phase II study on erythropoietin in clinically isolated optic neuritis (ClinicalTrials.gov, NCT00355095 were analyzed. Therefore, patients with acute optic neuritis were assigned to receive either 33,000 IU of recombinant human erythropoietin (IV daily for three days, or a placebo, as an add-on to methylprednisolone. Of 35 patients, we investigated changes in cerebral lesion load in MRIs obtained at baseline and at weeks 4, 8, and 16. In 5 of the 35 patients, we found conversion into multiple sclerosis (MS based on MRI progression only. These five patients had received the placebo. Another five patients showed MRI progression together with relapses. Three of these patients had received erythropoietin, and two the placebo. Yet, analyzing the change in absolute numbers of periventricular, juxtacortical, and infratentorial lesions including gadolinium-enhancing lesions, there were no significant differences between the groups. Although effective in terms of retinal nerve fiber layer protection, erythropoietin treatment of acute isolated optic neuritis did not influence further evolution of MRI lesions in the brain when comparing absolute numbers. However, early conversion from clinically isolated syndrome to MS assessed by MRI activity seemed to occur more frequently in the placebo-treated group.

  4. Disease Activity and Conversion into Multiple Sclerosis after Optic Neuritis Is Treated with Erythropoietin

    Science.gov (United States)

    Sühs, Kurt-Wolfram; Papanagiotou, Panagiotis; Hein, Katharina; Pul, Refik; Scholz, Kerstin; Heesen, Christoph; Diem, Ricarda

    2016-01-01

    Changes in cerebral lesion load by magnetic resonance imaging (MRI) in patients from a double-blind, placebo-controlled, phase II study on erythropoietin in clinically isolated optic neuritis (ClinicalTrials.gov, NCT00355095) were analyzed. Therefore, patients with acute optic neuritis were assigned to receive either 33,000 IU of recombinant human erythropoietin (IV) daily for three days, or a placebo, as an add-on to methylprednisolone. Of 35 patients, we investigated changes in cerebral lesion load in MRIs obtained at baseline and at weeks 4, 8, and 16. In 5 of the 35 patients, we found conversion into multiple sclerosis (MS) based on MRI progression only. These five patients had received the placebo. Another five patients showed MRI progression together with relapses. Three of these patients had received erythropoietin, and two the placebo. Yet, analyzing the change in absolute numbers of periventricular, juxtacortical, and infratentorial lesions including gadolinium-enhancing lesions, there were no significant differences between the groups. Although effective in terms of retinal nerve fiber layer protection, erythropoietin treatment of acute isolated optic neuritis did not influence further evolution of MRI lesions in the brain when comparing absolute numbers. However, early conversion from clinically isolated syndrome to MS assessed by MRI activity seemed to occur more frequently in the placebo-treated group. PMID:27706045

  5. Symmetric signaling by an asymmetric 1 erythropoietin: 2 erythropoietin receptor complex.

    Science.gov (United States)

    Zhang, Yingxin L; Radhakrishnan, Mala L; Lu, Xiaohui; Gross, Alec W; Tidor, Bruce; Lodish, Harvey F

    2009-01-30

    Via sites 1 and 2, erythropoietin binds asymmetrically to two identical receptor monomers, although it is unclear how asymmetry affects receptor activation and signaling. Here we report the design and validation of two mutant erythropoietin receptors that probe the role of individual members of the receptor dimer by selectively binding either site 1 or site 2 on erythropoietin. Ba/F3 cells expressing either mutant receptor do not respond to erythropoietin, but cells co-expressing both receptors respond to erythropoietin by proliferation and activation of the JAK2-Stat5 pathway. A truncated receptor with only one cytosolic tyrosine (Y343) is sufficient for signaling in response to erythropoietin, regardless of the monomer on which it is located. Similarly, only one receptor in the dimer needs a juxtamembrane hydrophobic L253 or W258 residue, essential for JAK2 activation. We conclude that despite asymmetry in the ligand-receptor interaction, both sides are competent for signaling, and appear to signal equally.

  6. Effects of type II collagen epitope carbamylation and citrullination in human leucocyte antigen (HLA)-DR4(+) monozygotic twins discordant for rheumatoid arthritis.

    Science.gov (United States)

    De Santis, M; Ceribelli, A; Cavaciocchi, F; Generali, E; Massarotti, M; Isailovic, N; Crotti, C; Scherer, H U; Montecucco, C; Selmi, C

    2016-09-01

    The aim of this study is to investigate the effect of the native, citrullinated or carbamylated type II human collagen T cell- and B cell-epitopes on the adaptive immune response in rheumatoid arthritis (RA). Peripheral blood T and B cells obtained from a human leucocyte D4-related (antigen DR4(-) HLA-DR4)(+) woman with early RA, her healthy monozygotic twin and an unrelated HLA-DR3(+) woman with early RA were analysed for activation (CD154/CD69), apoptosis (annexin/7-aminoactinomycin), cytokine production [interferon (IFN)γ/interleukin (IL)-17/IL-4/IL-10/IL-6] and functional phenotype (CD45Ra/CCR7) after stimulation with the collagen native T cell epitope (T261-273), the K264 carbamylated T cell epitope (carT261-273), the native B cell epitope (B359-369) or the R360 citrullinated B cell epitope (citB359-369), and the combinations of these. The T cell memory compartment was activated by T cell epitopes in both discordant DR4(+) twins, but not in the DR3(+) RA. The collagen-specific activation of CD4(+) T cells was induced with both the native and carbamylated T cell epitopes only in the RA twin. Both T cell epitopes also induced IL-17 production in the RA twin, but a greater IL-4 and IL-10 response in the healthy twin. The citrullinated B cell epitope, particularly when combined with the carbamylated T cell epitope, induced B cell activation and an increased IL-6/IL-10 ratio in the RA twin compared to a greater IL-10 production in the healthy twin. Our data suggest that circulating collagen-specific T and B cells are found in HLA-DR4(+) subjects, but only RA activated cells express co-stimulatory molecules and produce proinflammatory cytokines. Carbamylation and citrullination further modulate the activation and cytokine polarization of T and B cells.

  7. CNS hypoxia is more pronounced in murine cerebral than noncerebral malaria and is reversed by erythropoietin

    DEFF Research Database (Denmark)

    Hempel, Casper; Combes, Valery; Hunt, Nicholas Henry;

    2011-01-01

    -ribose) polymerase-1 (PARP-1) gene knockout mice. The effect of erythropoietin, an oxygen-sensitive cytokine that mediates protection against CM, on cerebral hypoxia was studied in C57BL/6 mice. Numerous hypoxic foci of neurons and glial cells were observed in mice with CM. Substantially fewer and smaller foci were...... observed in mice without CM, and hypoxia seemed to be confined to neuronal cell somas. PARP-1-deficient mice were not protected against CM, which argues against a role for cytopathic hypoxia. Erythropoietin therapy reversed the development of CM and substantially reduced the degree of neural hypoxia......Cerebral malaria (CM) is associated with high mortality and risk of sequelae, and development of adjunct therapies is hampered by limited knowledge of its pathogenesis. To assess the role of cerebral hypoxia, we used two experimental models of CM, Plasmodium berghei ANKA in CBA and C57BL/6 mice...

  8. Development of a new radioimmunoassay for erythropoietin using recombinant erythropoietin

    Energy Technology Data Exchange (ETDEWEB)

    Mason-Garcia, M.; Beckman, B.S.; Brookins, J.W.; Powell, J.S.; Lanham, W.; Blaisdell, S.; Keay, L.; Li, S.C.; Fisher, J.W. (Tulane Univ. School of Medicine, New Orleans, LA (USA))

    1990-11-01

    The development of a 24 hour radioimmunoassay for erythropoietin (EPO) using EPO derived from recombinant DNA as both immunogen and ligand is described in the present paper. Mixed breed rabbits immunized with 10 micrograms/kg of EPO derived from a stably transfected cell line (MD) produced antibodies to EPO with high titer (up to 1:896,000 final dilution in the tube), high affinity (8.4 x 10(11) liter/M), and good specificity. Purified EPO from the above source or from AmGen Biologicals (AG) were successfully radioiodinated with the chloramine-T method and used as ligand in the radioimmunoassay. Standard dose-response curves prepared with EPO from both commercial sources were not significantly different and showed a sensitivity of 0.75 to 0.96 mU/tube. The dose-response curves in both systems also showed parallelism with serially diluted serum from a patient with aplastic anemia. Within-assay and between-assay precision were determined by assaying multiple replicates of a serum pool. Recovery of exogenous EPO added to a serum pool averaged 97% for both systems. The range of normal human serum EPO was determined by assaying the sera of 153 hematologically-normal adult subjects and was found to be 1.1 to 27.3 mU/ml for MD EPO and 0.5 to 16.7 mU/ml for AG EPO. Sera from several patients with hematologic abnormalities were also assayed, including those of 36 patients with anemia of end-stage renal disease (mean +/- SEM, 29.5 +/- 4.0 mU/ml; P less than 0.01). In conclusion, this new, more rapid and sensitive radioimmunoassay system can be used to measure EPO levels in sera from normal human subjects and patients with several types of anemia, and should also be very useful in therapeutic drug monitoring of patients receiving EPO from various commercial sources.

  9. The Effect of Erythropoietin on S100 Protein Expression in Cochlea After Acoustic Overstimulation: An Experimental Study

    Directory of Open Access Journals (Sweden)

    Gulsen Gurgen

    2014-03-01

    Full Text Available Aim: To investigate the effect of Erythropoietin on acoustically overstimulated rat spiral ganglion neurons (SGNs using S100 protein immunostaining.Material and Method: Twenty-two Wistar albino rats were divided into three groups: healthy control group (n=7, Saline solution (n=7 and Erythropoietin injection groups (n=8. Saline solution and Erythropoietin injection groups received white noise (100 dB SPL for 3 hours. Cochlear sections were stained by silver staining technique and immunostained by S100 antibody. Results: Histochemical analysis of silver staining sections revealed normal structure and a weak staining in SGNs of healthy control group. However, dark-black cytoplasmic staining, cellular shrinkage and degeneration were detected in saline injection group. On the other hand, a few weakly stained neurons were observed in erythropoietin injection group. S100 staining demonstrated strong reaction in Schwann cells and myelin sheaths of SGNs in healthy control group (p<0.05. In saline solution injection group, Schwann cells showed moderate S100 reaction and other regions of SGNs showed weak reaction (p<0.05. In erythropoietin injection group, strong S100 expression almost similar to the healthy control group was determined, although there was an occasional decrease. Discussion: Erythropoetin may prevent noise induced SGN degeneration via protecting the Schwann cells in rat cochlea.

  10. Erythropoietin: ready for prime-time cardioprotection.

    NARCIS (Netherlands)

    Riksen, N.P.; Hausenloy, D.J.; Yellon, D.M.

    2008-01-01

    To improve clinical outcomes in patients presenting with an acute myocardial infarction, new strategies to limit infarct size and postinfarct remodelling are warranted. Recent animal studies have revealed that erythropoietin has the potential to achieve both these goals. Even more intriguing is the

  11. Erythropoietin receptor signaling is membrane raft dependent

    NARCIS (Netherlands)

    K.L. McGraw (Kathy); G.M. Fuhler (Gwenny); J.O. Johnson (Joseph); J.A. Clark (Justine); G.C. Caceres (Gisela); L. Sokol (Lubomir); A.F. List (Alan)

    2012-01-01

    textabstractUpon erythropoietin (Epo) engagement, Epo-receptor (R) homodimerizes to activate JAK2 and Lyn, which phosphorylate STAT5. Although recent investigations have identified key negative regulators of Epo-R signaling, little is known about the role of membrane localization in controlling rece

  12. Transplantation of erythropoietin gene-modiifed neural stem cells improves the repair of injured spinal cord

    Institute of Scientific and Technical Information of China (English)

    Min-fei Wu; Shu-quan Zhang; Rui Gu; Jia-bei Liu; Ye Li; Qing-san Zhu

    2015-01-01

    The protective effects of erythropoietin on spinal cord injury have not been well described. Here, the eukaryotic expression plasmid pcDNA3.1 human erythropoietin was transfected into rat neural stem cells culturedin vitro. A rat model of spinal cord injury was established using a free falling object. In the human erythropoietin-neural stem cells group, transfected neural stem cells were injected into the rat subarachnoid cavity, while the neural stem cells group was inject-ed with non-transfected neural stem cells. Dulbecco’s modified Eagle’s medium/F12 medium was injected into the rats in the spinal cord injury group as a control. At 1–4 weeks post injury, the motor function in the rat lower limbs was best in the human erythropoietin-neural stem cells group, followed by the neural stem cells group, and lastly the spinal cord injury group. At 72 hours, compared with the spinal cord injury group, the apoptotic index and Caspase-3 gene and protein expressions were apparently decreased, and the bcl-2 gene and protein expressions were noticeably increased, in the tissues surrounding the injured region in the human erythro-poietin-neural stem cells group. At 4 weeks, the cavities were clearly smaller and the motor and somatosensory evoked potential latencies were remarkably shorter in the human erythropoi-etin-neural stem cells group and neural stem cells group than those in the spinal cord injury group. These differences were particularly obvious in the human erythropoietin-neural stem cells group. More CM-Dil-positive cells and horseradish peroxidase-positive nerve fibers and larger amplitude motor and somatosensory evoked potentials were found in the human erythro-poietin-neural stem cells group and neural stem cells group than in the spinal cord injury group. Again, these differences were particularly obvious in the human erythropoietin-neural stem cells group. These data indicate that transplantation of erythropoietin gene-modified neural stem cells into the

  13. A quest for erythropoietin over nine decades.

    Science.gov (United States)

    Fisher, J W

    1998-01-01

    The major research accomplishments of the author are described from the time of his PhD thesis work on the mechanism of cobalt polycythemia to the present day. His early work on the quest for the cell that produces erythropoietin (Epo) to his current work on oxygen sensing and signal transduction pathways involved in erythropoietin gene expression are reported. He describes his main research interest in the mechanism of cobalt polycythemia between 1954 and 1962 and his research on how hormones such as the glucocorticoids function in the regulation of erythropoiesis (1956-1962). His major findings during this period were the discovery that hydrocortisone and corticosterone stimulated erythropoiesis (1958) and that cobalt increased erythropoietin production in the isolated perfused dog kidney (1961). He describes how he was led astray in some of his early studies on the cells in the kidney that produce erythropoietin, because of the less-developed technology available to him at that time; and how in situ hybridization and other molecular biology techniques enabled him to confirm some of the earlier work in mice by other investigators that interstitial cells in the kidney were the site of production of erythropoietin in the primate. His work in the controversial area of the mechanism of the anemia of end-stage renal disease is described in detail, as it pertains to Epo deficiency and suppressed erythroid progenitor cell response to Epo. He also discusses his recent work on signal transduction pathways (hypoxia, nitric oxide, adenosine, and C kinase) in oxygen sensing and Epo gene expression.

  14. [The role of erythropoietin in improvement of wound healing].

    Science.gov (United States)

    Sorg, H; Kuhbier, J W; Menger, B; Reimers, K; Harder, Y; Vogt, P M

    2010-11-01

    Pleiotropic substances are characterized by their versatile and complex range of actions which makes them potential new active agents for the therapy of wounds. Besides its known effect to increase red blood cell production, the glycoprotein hormone erythropoietin (EPO) has been found to demonstrate a tissue protective effect in several other organs. The administration of EPO during skin wound healing is most likely essentially based on its cytopotective, proangiogenic, antiapoptotic and antiinflammatory effects. Herein EPO stimulates a coordinated interaction of different types of cells at a low or only a single dose. This review article aims to present the advantages and disadvantages of EPO administration in different experimental models to study the healing and regeneration processes of the skin and discusses possible clinical applications.

  15. Hepatic erythropoietin response in cirrhosis. A contemporary review

    DEFF Research Database (Denmark)

    Risør, Louise M; Fenger, Mogens; Olsen, Niels Vidiendal;

    2016-01-01

    The main function of erythropoietin (EPO) is to maintain red blood cell mass, but in recent years, increasing evidence has suggested a wider biological role not solely related to erythropoiesis, e.g. angiogenesis and tissue protection. EPO is produced in the liver during fetal life, but the main...... production shifts to the kidney after birth. The liver maintains a production capacity of up to 10% of the total EPO synthesis in healthy controls, but can be up-regulated to 90-100%. However, the hepatic EPO synthesis has been shown not to be adequate for correction of anemia in the absence of renal......-derived EPO. Elevated circulating EPO has been reported in a number of diseases, but data from cirrhotic patients are sparse and the level of plasma EPO in patients with cirrhosis is controversial. Cirrhosis is characterized by liver fibrosis, hepatic dysfunction and the release of proinflammatory cytokines...

  16. Use of Recombinant Human Erythropoietin in Renal Anemia in Children

    Directory of Open Access Journals (Sweden)

    Habibur Rahman

    2009-11-01

    Full Text Available Erythropoietin is a hormone highly effective as like as natural erythropoietin to maintain target hemoglobin and hematocrit level in renal anemia. Its advantage over blood transfusion has been proved by improving the quality of life and decreasing morbidity and mortality in ESRD patients. Effectiveness of r-erythropoietin depends on absences of infection, inflammation and vitamin deficiency and iron status. Iron supplementation is needed before r-erythropoietin administration and sub-cutaneous rout is better in renal anemia because of slow and sustained releases of r-erythropoietin from the site of administration. Target hemoglobin level is 11-12.5 gm/dl and hematocrit is 33% which can be achieved by this hormone therapy. Key words- Recombinant erythropoietin, renal anemia, end stage renal disease.DOI: 10.3329/bsmmuj.v2i1.3713 BSMMU J 2009; 2(1: 50-53  

  17. Anti-carbamylated Protein Antibody Levels Correlate with Anti-Sa (Citrullinated Vimentin) Antibody Levels in Rheumatoid Arthritis.

    Science.gov (United States)

    Challener, Gregory J; Jones, Jonathan D; Pelzek, Adam J; Hamilton, B JoNell; Boire, Gilles; de Brum-Fernandes, Artur José; Masetto, Ariel; Carrier, Nathalie; Ménard, Henri A; Silverman, Gregg J; Rigby, William F C

    2016-02-01

    The presence of anticitrullinated protein antibodies (ACPA) in rheumatoid arthritis (RA) indicates a breach in immune tolerance. Recent studies indicate that this breach extends to homocitrullination of lysines with the formation of anti-carbamylated protein (anti-CarP) antibodies. We analyzed the clinical and serologic relationships of anti-CarP in 2 RA cohorts. Circulating levels of immunoglobulin G anti-CarP antibodies were determined by ELISA in established (Dartmouth-Hitchcock Medical Center) and early (Sherbrooke University Hospital Center) cohorts and evaluated for anticyclic citrullinated peptide antibodies (anti-CCP), specific ACPA, and rheumatoid factor (RF) levels using the Student t test and correlation analysis. We identified elevated anti-CarP antibodies titers in 47.0% of seropositive patients (Dartmouth, n = 164), with relationships to anti-CCP (p elevated anti-CarP antibodies; titers correlated to anti-CCP (p = 0.01) but not IgM-RF (p = 0.09). A strong correlation with anti-Sa was observed: 47.9% anti-Sa+ patients were anti-CarP antibodies+ versus only 25.4% anti-Sa- in the Sherbrooke cohort (p = 0.0002), and 62.6% anti-Sa+ patients versus 26.9% anti-Sa- were anti-CarP antibodies+ in Dartmouth (p anti-CarP antibody positivity. We also describe a surprising and unexpected association of anti-CarP with anti-Sa antibodies that could not be explained by cross-reactivity. Further, considerable heterogeneity exists between anti-CarP reactivity and other citrullinated peptide reactivity, raising the question of how the pathogenesis of antibody responses for carbamylated proteins and citrullinated proteins may be linked in vivo.

  18. Antierythropoietin Antibodies in Hemodialysis Patients Treated with Recombinant Erythropoietin

    OpenAIRE

    Savaş ÖZTÜRK; Alper GÜMÜŞ; Vecihi MEMİLİ; Muhammet Emin DÜZ; Egemen CEBECİ; Macit KOLDAŞ; Rümeyza KAZANCIOĞLU

    2014-01-01

    OBJECTIVE: Erythropoietin resistance is a serious problem in patients treated with recombinant erythropoietin. Antierythropoietin antibodies are considered to be one of the causes of this resistance. MATERIAL and ME THODS: We investigated antierythropoietin antibodies in chronic hemodialysis patients and compared the results with healthy controls by means of establishing an ELISA method. A total of 121 chronic hemodialysis patients receiving recombinant erythropoietin were included in the ...

  19. The Role of Erythropoietin Signaling in Human Cancer

    Science.gov (United States)

    2004-01-01

    human central nervous system. Pediatr Res, 1998; 43: 40-49. 16. Ruscher K, Freyer D, Karsch M, Isaev N, Megow D, Sawitzki B, Priller J, Dirnagl...Erythropoietin and erythropoietin receptor in the developing human central nervous system. Pediatr Res, 1998; 43: 40-49. 14. Ruscher K, Freyer D, Karsch M...38. Ruscher K, Freyer D, Karsch M, Isaev N, Megow D, Sawitzki B, Priller J, Dirnagl U, and Meisel A. Erythropoietin is a paracrine mediator of

  20. Antierythropoietin Antibodies in Hemodialysis Patients Treated with Recombinant Erythropoietin

    Directory of Open Access Journals (Sweden)

    Savaş ÖZTÜRK

    2014-05-01

    Full Text Available OBJECTIVE: Erythropoietin resistance is a serious problem in patients treated with recombinant erythropoietin. Antierythropoietin antibodies are considered to be one of the causes of this resistance. MATERIAL and ME THODS: We investigated antierythropoietin antibodies in chronic hemodialysis patients and compared the results with healthy controls by means of establishing an ELISA method. A total of 121 chronic hemodialysis patients receiving recombinant erythropoietin were included in the study. The patients were subdivided according to the type of recombinant erythropoietin (erythropoietin-α or erythropoietin-β they had been treated with in the last six months. RESULTS: The absorbance values of patients were compared with the absorbance values of the control group by a specific and reproducible method. LOD (limit of detection and LOQ (limit of quantitation values were also calculated. The difference in the absorbance values between the therapy and control groups was statistically significant. CONCLUSION: Both erythropoietin-α and erythropoietin-β induce production of antibodies against erythropoietin. Anti rh-EPO antibodies may play a role in EPO resistance.

  1. Erythropoietin: physiology and pharmacology update.

    Science.gov (United States)

    Fisher, James W

    2003-01-01

    This minireview is an update of a 1997 review on erythropoietin (EPO) in this journal. EPO is a 30,400-dalton glycoprotein that regulates red cell production. In the human, EPO is produced by peritubular cells in the kidneys of the adult and in hepatocytes in the fetus. Small amounts of extra-renal EPO are produced by the liver in adult human subjects. EPO binds to an erythroid progenitor cell surface receptor that includes a p66 chain, and, when activated, the p66 protein becomes dimerized. EPO receptor activation induces a JAK2 tyrosine kinase, which leads to tyrosine phosphorylation of the EPO receptor and several proteins. EPO receptor binding leads to intracellular activation of the Ras/mitogen-activated kinase pathway, which is involved with cell proliferation, phosphatidylinositol 3-kinase, and STATS 1, 3, 5A, and 5B transcriptional factors. EPO acts primarily to rescue erythroid cells from apoptosis (programmed cell death) to increase their survival. EPO acts synergistically with several growth factors (SCF, GM-CSF, 1L-3, and IGF-1) to cause maturation and proliferation of erythroid progenitor cells (primarily colony-forming unit-E). Oxygen-dependent regulation of EPO gene expression is postulated to be controlled by a hypoxia-inducible transcription factor (HIF-1alpha). Hypoxia-inducible EPO production is controlled by a 50-bp hypoxia-inducible enhancer that is approximately 120 bp 3' to the polyadenylation site. Hypoxia signal transduction pathways involve kinases A and C, phospholipase A(2), and transcription factors ATF-1 and CREB-1. A model has been proposed for adenosine activation of EPO production that involves protein kinases A and C and the phospholipase A(2) pathway. Other effects of EPO include a hematocrit-independent, vasoconstriction-dependent hypertension, increased endothelin production, upregulation of tissue renin, change in vascular tissue prostaglandins production, stimulation of angiogenesis, and stimulation of endothelial and vascular

  2. 促红细胞生成素改善ob/ob小鼠肝脏脂质沉积%Protective effects of erythropoietin on lipid metabolism in the liver of ob/ob mice

    Institute of Scientific and Technical Information of China (English)

    洪汀; 毕艳; 葛智娟; 汤孙寅焱; 汤文娟; 朱大龙

    2016-01-01

    目的:研究促红细胞生成素(EPO)对肝脏脂质沉积的影响及可能的分子机制。方法12只雄性8周龄遗传型肥胖小鼠(ob/ob)随机数字表法分为2组:一组腹腔注射EPO(3000 U/kg),即EPO组(ob/ob+EPO,n=6);另一组注射等量磷酸盐缓冲液(PBS),即PBS组(ob/ob+PBS,n=6);同窝野生型C57BL/6小鼠作为正常对照组(C57BL/6,n=6),药物干预5周。以棕榈酸(PA,0.5 mmol/L)及不同浓度EPO处理人肝癌细胞株HepG2,分为对照组(不处理)、PA组、PA+EPO (5 U/ml)组及PA+EPO (10 U/ml)组。油红O染色观察各组小鼠肝组织及HepG2细胞内脂质沉积。Western blotting法检测各组小鼠肝脏及HepG2细胞中EPO受体(EPOR)、固醇调节元件结合蛋白1c(SREBP-1c)、脂肪酸合酶(FAS)、乙酰辅酶A羧化酶(ACC)及肉毒碱棕榈酰基转移酶1a(CPT-1a)的蛋白表达。多组间数据比较采用单因素方差分析,两两比较采用最小显著差异法。结果油红O染色显示EPO干预的小鼠肝脏组织及HepG2细胞内脂质沉积均较各自对照组减少。与PBS组相比,EPO组小鼠肝脏SREBP-1c、FAS、ACC蛋白水平显著下降(分别为0.78±0.08比1.23±0.03、1.03±0.08比1.16±0.01、1.10±0.33比1.69±0.02,t=-6.906、-2.756、-8.794,均P<0.05),EPOR和CPT-1a蛋白水平明显升高(分别为1.28±0.14比0.97±0.06、0.77±0.06比0.60±0.12,t=2.749、2.655,均P<0.05)。在HepG2细胞中,与PA组相比,PA+EPO(10 U/ml)组中SREBP-1c、FAS、ACC蛋白水平显著下降(t=-10.731、-2.760、-9.618,均P<0.05), EPOR和CPT-1a蛋白水平升高(t=7.556、2.674,均P<0.05)。结论 EPO可能通过抑制肝脏脂质合成,促进脂肪酸氧化,从而减少肝脏脂质过度沉积。%Objective To investigate the effects of erythropoietin (EPO) on hepatic lipid metabolism and explore the underlying mechanism. Methods Twelve eight-week female ob/ob mice were randomly divided

  3. Effects of Erythropoietin on the Bone Microenvironment

    OpenAIRE

    McGee, SJ; Havens, AM; Shiozawa, Y; Y. Jung; Taichman, RS

    2011-01-01

    It has well been established that blood and bone share a unique, regulatory relationship with one another, though the specifics of this relationship still remain unanswered. Erythropoietin (Epo) is known primarily for its role as a hematopoietic hormone. However, after the discovery of Epo receptor (Epo-R) outside the hematopoietic tissues, Epo has been avidly studied for its possible non-hematopoietic effects. It has been proposed that Epo interacts with bone both directly, by activating bon...

  4. Erythropoietin stimulates hepatocyte regeneration after liver resection

    OpenAIRE

    Schön, Michael R.; Hogrebe, Esther; Hengstler, Jan Georg; Donaubauer, Bernd; Faber, Sonya C.; Bauer, Alexander; Pietsch, Uta-Carolin; Jelkmann, Wolfgang; Thiery, Joachim; Hauss, Johann Peter; Tannapfel, Andrea

    2008-01-01

    The increased relevance of liver surgery and transplantation as a therapeutic modality over the last two decades mandates the development of novel strategies to improve liver regeneration. Here we studied whether erythropoietin (EPO) improves liver regeneration after hepatectomy in pigs. Eighteen female pigs underwent laparoscopic left lateral liver resection and were allocated randomly into three groups. No EPO was administered to the control group (group 1, n=6). Group 2 (...

  5. Procedures for monitoring recombinant erythropoietin and analogs in doping.

    Science.gov (United States)

    Lamon, Séverine; Robinson, Neil; Saugy, Martial

    2010-03-01

    Hemoglobin concentration is one of the principal factors of aerobic power and, consequently, of performance in many types of physical activities. The use of recombinant human erythropoietin is, therefore, particularly powerful for improving the physical performances of patients, and, more generally, improving their quality of life. This article discusses procedures for monitoring recombinant erythropoietin and its analogues in doping for athletic performance.

  6. Paraneoplastic Erythrocytosis of Colon Cancer, with Serum Erythropoietin within the Normal Reference Range

    OpenAIRE

    Kitayama, Hiromitsu; Kondo, Tomohiro; SUGIYAMA, Junko; Hirayama, Michiaki; Oyamada, Yumiko; Tsuji, Yasushi

    2016-01-01

    Patient: Female, 75 Final Diagnosis: Erythropoietin-secreting colon cancer Symptoms: None Medication: — Clinical Procedure: Immunohistochemistry Specialty: Hematology Objective: Rare disease Background: Paraneoplastic erythrocytosis can be brought on by ectopic erythropoietin production usually in kidney, brain, and liver tumor with increase of serum erythropoietin level. We report here a paraneoplastic erythrocytosis of colon cancer with serum erythropoietin within the normal reference, whic...

  7. Hypoxia and the initiation of erythropoietin production. [Rats

    Energy Technology Data Exchange (ETDEWEB)

    Schooley, J.C.; Mahlmann, L.J.

    1975-01-01

    The initiation of erythropoietin production in rats by hypoxia is dependent upon the magnitude of the hypoxic exposure, the position of the oxygen dissociation curve at the time of the hypoxic exposure, and the animal's endocrine status. Normal male rats produce more erythropoietin and elevate their intraerythrocytic 2,3-DPG levels more than female rats exposed to the same degree of hypoxia. Hypophysectomized rats produce erythropoietin following severe hypoxic exposure, but do not elevate their 2,3-DPG levels above control values. Respiratory acidosis in rats produced by breathing 10 percent CO/sub 2/ or by the injection of acetazolamide inhibits the initiation of erythropoietin production by hypoxic environments, but this inhibition is minimal in animals with metabolic acidosis produced by ureterligation. Changes in serum erythropoietin levels and the in vitro P/sub 50/ appear to be two separate but interrelated physiological events which occur during the adaptation of animals to hypoxic environments.

  8. Umbilical Cord Serum Erythropoietin Levels and Maternal Smoking in Pregnancy

    Directory of Open Access Journals (Sweden)

    Soner Sazak

    2012-01-01

    Full Text Available Objective. To evaluate the effect of maternal smoking during pregnancy on levels of umbilical cord erythropoietin. Methods. Erythropoietin levels were measured in umbilical cord sera of 60 newborns who were delivered vaginally at term. There were 20 (33% smoking and 40 (67% nonsmoking mothers. Results. Mean cord serum erythropoietin levels were significantly lower in the nonsmokers (nonsmokers, 24 ± 9 IU/L; smokers, 61 ± 46 IU/L; P<.001. There was a significant positive correlation between the number of cigarettes smoked per day and cord serum erythropoietin levels (r, 0.58; P≤.05. Conclusions. Smoking during pregnancy is associated with increased levels of umbilical cord erythropoietin at birth. This may indicate a risk of fetal hypoxia and growth restriction. Education and encouragement of cessation of smoking during pregnancy are important to avoid associated fetal and maternal morbidity and mortality.

  9. Recombinant erythropoietin in humans has a prolonged effect on circulating erythropoietin isoform distribution

    DEFF Research Database (Denmark)

    Aachmann-Andersen, Niels Jacob; Just Christensen, Søren; Lisbjerg, Kristian

    2014-01-01

    The membrane-assisted isoform immunoassay (MAIIA) quantitates erythropoietin (EPO) isoforms as percentages of migrated isoforms (PMI). We evaluated the effect of recombinant human EPO (rhEPO) on the distribution of EPO isoforms in plasma in a randomized, placebo-controlled, double-blinded, cross...

  10. Isoforms of the Erythropoietin receptor in dopaminergic neurons of the Substantia Nigra.

    Science.gov (United States)

    Marcuzzi, Federica; Zucchelli, Silvia; Bertuzzi, Maria; Santoro, Claudio; Tell, Gianluca; Carninci, Piero; Gustincich, Stefano

    2016-11-01

    Erythropoietin receptor (EpoR) regulates erythrocytes differentiation in blood. In the brain, EpoR has been shown to protect several neuronal cell types from cell death, including the A9 dopaminergic neurons (DA) of the Substantia Nigra (SN). These cells form the nigrostriatal pathway and are devoted to the control of postural reflexes and voluntary movements. Selective degeneration of A9 DA neurons leads to Parkinson's disease. By the use of nanoCAGE, a technology that allows the identification of Transcription Start Sites (TSSs) at a genome-wide level, we have described the promoter-level expression atlas of mouse A9 DA neurons purified with Laser Capture Microdissection (LCM). Here, we identify mRNA variants of the Erythropoietin Receptor (DA-EpoR) transcribed from alternative TSSs. Experimental validation and full-length cDNA cloning is integrated with gene expression analysis in the FANTOM5 database. In DA neurons, the EpoR gene encodes for a N-terminal truncated receptor. Based on STAT5 phosphorylation assays, we show that the new variant of N-terminally truncated EpoR acts as decoy when co-expressed with the full-length form. A similar isoform is also found in human. This work highlights new complexities in the regulation of Erythropoietin (EPO) signaling in the brain.

  11. Does erythropoietin augment noise induced hearing loss?

    DEFF Research Database (Denmark)

    Frederiksen, Birgitte Lidegaard; Cayé-Thomasen, Per; Lund, Søren Peter

    2007-01-01

    of EPO upon damage to the central nervous system and the retina. This paper reports three separate trials, conducted to investigate the hypothesis that noise-induced hearing loss is prevented or reduced by erythropoietin. The trials employed three different modes of drug application, different...... administration time windows and different rodent species. In trial 1, guinea pigs were exposed to 110dB SPL, 4-20kHz wide band noise (WBN) for 8h. EPO was administered to the round window membrane 24h after noise exposure, either sustained by pump for a week or by single dose middle ear instillation. In trial 2...

  12. Erythropoietin-induced iritis-like reaction.

    Science.gov (United States)

    Beiran, I; Krasnitz, I; Mezer, E; Meyer, E; Miller, B

    1996-01-01

    The present report describes an iritis-like reaction found in 13 patients treated with recombinant human erythropoietin (Eprex), a drug given to hemodialysis patients for their chronic anemia. Among 120 patients being treated by hemodialysis in two centers affiliated with our medical center, ten out of 30 Eprex-treated patients but none of 90 not being treated with Eprex developed this reaction. The observations described support a causal relation between Eprex treatment and the iritis-like reaction. Further investigative effort is needed to establish the mechanism.

  13. Early treatment of a child with NAGS deficiency using N-carbamyl glutamate results in a normal neurological outcome.

    Science.gov (United States)

    Van Leynseele, Anouk; Jansen, Anna; Goyens, Philippe; Martens, Geert; Peeters, Stefaan; Jonckheere, An; De Meirleir, Linda

    2014-12-01

    Acute hyperammonemia has a variety of etiologies and clinical manifestations. If not treated early in neonates, it leads to irreversible brain damage or death. We present a 7-day-old female patient who was brought to the emergency department with drownsiness and vomiting. Metabolic work-up revealed a blood ammonia level of 290 μmol/L (normal carbamylglutamate (NCG) was added resulting in a rapid normalisation of ammonemia. Feedings were progressively reintroduced, the ammonia levels remained low. The results of the metabolic work-up were compatible with carbamyl phosphate synthase 1 (CPS1) or N-acetyl glutamate synthase (NAGS) deficiency. Genetic analysis confirmed the latter diagnosis with a homozygous mutation c. 1450T > C (p.W484R) in exon 6 of the NAGS gene in the patient and a carrier state in both parents. At the age of 9 months, the child is growing well with normal neurological development, under treatment with NCG 100 mg/kg/day and a normal diet. Conclusion: This case highlights the importance of keeping a high index of suspicion and early testing for ammonia levels in neonates/children with unexplained encephalopathy. In neonates with congenital hyperammonemia, NCG should always be started together with the standard management of hyperammonemia until all laboratory investigations are complete or indicate another disease.

  14. In vivo metabolism of recombinant human erythropoietin in the rat

    Energy Technology Data Exchange (ETDEWEB)

    Spivak, J.L.; Hogans, B.B.

    1989-01-01

    We compared the in vivo plasma clearance and organ accumulation in anesthetized rats of 125I-labeled, recombinant human erythropoietin and 125I-labeled, desialylated recombinant erythropoietin. The immediate volume of distribution of 125I-labeled, recombinant erythropoietin approximated that of the plasma volume. Its plasma clearance was multiexponential, with an initial rapid distribution phase (t1/2 = 53 minutes) and a slower elimination phase (t1/2 = 180 minutes). Organ accumulation of labeled recombinant erythropoietin, as compared with 125I-labeled human albumin, was negligible until 30 minutes after injection when small amounts appeared in the kidneys and bone marrow. Only 24% of the 125I-labeled, desialylated recombinant erythropoietin was recovered immediately after injection, and 96% of the hormone was cleared from the plasma with a t1/2 of 2.0 minutes. The bulk of the desialylated hormone accumulated in the liver where it was rapidly catabolized and its breakdown products released back into the plasma. Significantly, in contrast to unmodified erythropoietin, there was also early accumulation of desialylated hormone in the kidneys, marrow, and spleen. Desialylated orosomucoid but not orosomucoid, yeast mannan, or dextran sulfate 500 inhibited the rapid plasma clearance and hepatic accumulation of desialylated erythropoietin. Oxidation of the desialylated hormone restored its plasma recovery and clearance to normal but rendered it biologically inactive, and accumulation in organs other than the kidney was negligible.

  15. Statistical analysis plan for the Erythropoietin in Traumatic Brain Injury trial: a randomised controlled trial of erythropoietin versus placebo in moderate and severe traumatic brain injury.

    LENUS (Irish Health Repository)

    Presneill, Jeffrey

    2014-01-01

    The Erythropoietin in Traumatic Brain Injury (EPO-TBI) trial aims to determine whether the administration of erythropoietin to patients with moderate or severe traumatic brain injury improves patient-centred outcomes.

  16. Role of erythropoietin in anemia after heart transplantation.

    Science.gov (United States)

    Gleissner, Christian A; Klingenberg, Roland; Staritz, Peter; Koch, Achim; Ehlermann, Philipp; Wiggenhauser, Alfred; Dengler, Thomas J

    2006-10-10

    Anemia after heart transplantation is common; however, there are scant data on etiology and treatment. This study evaluates type of anemia and the effects of erythropoietin therapy. In 37 anemic heart transplant recipients (31 male/59.1+/-10.3 years/hemoglobin anemia work-up was performed including erythropoietin determination. For three months, 12 anemic patients with renal failure (9 male/64.1+/-13.6 years) were treated with 1-3x4000 IU of epoietin beta/week; treatment endpoints were hemoglobin levels and quality of life as determined by questionnaire. In 31 patients no other cause of anemia than renal insufficiency (mean creatinine 1.9+/-0.9 mg/dl, mean calculated GFR 50.8+/-21.5 ml/min, no hemodialysis) was found; in 93.5% of these patients with renal insufficiency, measured erythropoietin levels were markedly lower than predicted [Beguin Y, Clemons GK, Pootrakul P, Fillet G. Quantitative assessment of erythropoiesis and functional classification of anemia based on measurements of serum transferrin receptor and erythropoietin. Blood 1993; 81(4):1067-1076.]. There was an inverse correlation of hemoglobin levels with serum creatinine/creatinine clearance and a strong trend for inverse correlation of erythropoietin levels. All 12 patients treated with erythropoietin showed a significant increase in hemoglobin levels after three months returning to pre-treatment values within 3 months of cessation of therapy (before study 10.8+/-1.1 g/dl, end of study 14.1+/-1.7 g/dl, three months after end of study 11.6+/-2.1 g/dl; pAnemia after heart transplantation is associated with moderate renal failure and low erythropoietin levels in most patients. Erythropoietin therapy resulted in increased hemoglobin levels in all and improved quality of life in 75% of patients. Erythropoietin may be a superior marker of functional renal impairment after heart transplantation; its therapeutic substitution allows effective anemia management and improves quality of life.

  17. Erythropoietin and the use of a transgenic model of erythropoietin-deficient mice

    Directory of Open Access Journals (Sweden)

    Pichon A

    2016-04-01

    Full Text Available Aurélien Pichon,1–3 Florine Jeton,1,2 Raja El Hasnaoui-Saadani,4 Luciana Hagström,5 Thierry Launay,6 Michèle Beaudry,1 Dominique Marchant,1 Patricia Quidu,1 Jose-Luis Macarlupu,7 Fabrice Favret,8 Jean-Paul Richalet,1,2 Nicolas Voituron1,2 1Laboratory “Hypoxia and Lung” EA 2363, University Paris 13, Sorbonne Paris Cité, Bobigny Cedex, 2Laboratory of Excellence GR-Ex, Paris, 3Laboratory MOVE EA 6314, FSS, Poitiers University, Poitiers, France; 4Research Unit, College of Medicine, Princess Noura University, Riyadh, Saudi Arabia; 5Laboratório Interdisciplinar de Biociências, Universidade de Brasília, Brasília, Brazil; 6Unité de Biologie Intégrative des Adaptations à l'Exercice, University Paris Saclay and Genopole®, University Sorbonne-Paris-Cité, Paris, France; 7High Altitude Unit, Laboratories for Research and Development, Universidad Peruana Cayetano Heredia, Lima, Peru; 8Laboratory “Mitochondrie, Stress Oxydant et Protection Musculaire” EA 3072, University of Strasbourg, Strasbourg, France Abstract: Despite its well-known role in red blood cell production, it is now accepted that erythropoietin (Epo has other physiological functions. Epo and its receptors are expressed in many tissues, such as the brain and heart. The presence of Epo/Epo receptors in these organs suggests other roles than those usually assigned to this protein. Thus, the aim of this review is to describe the effects of Epo deficiency on adaptation to normoxic and hypoxic environments and to suggest a key role of Epo on main physiological adaptive functions. Our original model of Epo-deficient (Epo-TAgh mice allowed us to improve our knowledge of the possible role of Epo in O2 homeostasis. The use of anemic transgenic mice revealed Epo as a crucial component of adaptation to hypoxia. Epo-TAgh mice survive well in hypoxic conditions despite low hematocrit. Furthermore, Epo plays a key role in neural control of ventilatory acclimatization and response to

  18. Scanning electron microscopy of erythropoietin-stimulated bone marrow

    Energy Technology Data Exchange (ETDEWEB)

    Leblond, P.F. (Hospital of St. Sacrement, Quebec); Chamberlain, J.K.; Weed, R.I.

    1975-01-01

    This work describes and illustrates the scanning electron microscopic modifications observed in the femoral bone marrow of normal mice 72 hours after a single injection of partly purified sheep erythropoietin and of mice afflicted with a chronic congenital hemolytic anemia analogous to the disease Hereditary Spherocytosis in man. In acordance with previous transmission electron microscopic studies, the observations are consistent with an effect of erythropoietin both on the frequency of cell migration across the normally intact marrow sinus endothelium and on the morphology of sinus adventitial cells. It is suggested that these ultrastructural modifications may be responsible for the greater patency of the marrow-blood barrier under erythropoietin stimulation.

  19. Polycythemia, increased erythropoietin levels in a patient with renal lymphoma

    Directory of Open Access Journals (Sweden)

    Riyaz Ahmad Bhat

    2014-01-01

    Full Text Available A young male presented to our clinic with 3 months history of shortness of breathness and progressive distension of abdomen. On investigations, patient had renal failure, polycythemia and nephromegaly. A diagnosis of non-Hodgkin′s lymphoma was made on renal and lymph node biopsy. Serum erythropoietin concentrations were physiologically inappropriate. - Erythropoietin immunohistochemistry on renal tissue samples demonstrated positive staining for tumor cells. This patient was managed as a case of infiltrative lymphoproliferative disorder with kidney involvement having polycythemia owing to paraneoplastic Erythropoietin production and possibly local hypoxia produced by tumor cells. With maximum efforts, we could not find such an association in the literature.

  20. Die Auswirkungen von Erythropoietin auf die Ischämie/Reperfusionsschäden der Fettleber nach orthotoper Lebertransplantation am Rattenmodell

    OpenAIRE

    Rademacher, Sebastian

    2011-01-01

    The scarcity of appropriate donor organs represents one of the main problems in the present transplantation surgery. This circumstance forces the surgeon to accept so-called marginal organs more often. These qualitatively limited grafts are associated with higher rates of primary nonfunction or dysfunction and reduced recipient survival. Investigations in animals demonstrated positive effects of recombinant human Erythropoietin (rhEPO) in various organ systems already. The protective influenc...

  1. Erythropoietin and erythropoietin receptor in hepatocellular carcinoma: correlation with vasculogenic mimicry and poor prognosis.

    Science.gov (United States)

    Yang, Zhihong; Sun, Baocun; Zhao, Xiulan; Shao, Bing; An, Jindan; Gu, Qiang; Wang, Yong; Dong, Xueyi; Zhang, Yanhui; Qiu, Zhiqiang

    2015-01-01

    To evaluate erythropoietin (Epo) and erythropoietin receptor (EpoR) expression, its relationship with vasculogenic mimicry (VM) and its prognostic value in human hepatocellular carcinoma (HCC), we examined Epo/EpoR expression and VM formation using immunohistochemistry and CD31/PAS (periodic acid-Schiff) double staining on 92 HCC specimens. The correlation between Epo/EpoR expression and VM formation was analyzed using two-tailed Chi-square test and Spearman correlation analysis. Survival curves were generated using Kaplan-Meier method. Multivariate analysis was performed using Cox regression model to assess the prognostic values. Results showed positive correlation between Epo/EpoR expression and VM formation (P age, Epo and EpoR were independent prognostic factors related to OS. These results will provide evidence for further research on HCC microcirculation patterns and also will provide new possible targets for HCC diagnosis and treatment.

  2. Erythropoietin and erythropoietin receptor expression in the guinea pig inner ear

    DEFF Research Database (Denmark)

    Cayé-Thomasen, Per; Wagner, Niels; Lidegaard Frederiksen, Birgitte

    2005-01-01

    The erythropoietin receptor (EPOR) is expressed in the brain and erythropoietin (EPO) has been shown to have neurotrophic and neuroprotective functions in the central nervous system and in the retina. These findings may be applied to the inner ear, pending EPO receptor presence. Accordingly......, this study determines expression of EPO and EPOR in the inner ear of the guinea pig. Normal guinea pig inner ears were processed for immunohistochemistry, using poly-clonal antibodies against EPO and the EPO receptor. EPO expression was exclusively found in most, but not all spiral ganglion neurons...... expressed by several cell types within the guinea pig cochlea. We hypothesize on the existence of a local paracrine system and that EPO treatment may be feasible following inner ear damage....

  3. Erythropoietin overrides the triggering effect of DNA platination products in a mouse model of Cisplatin-induced neuropathy

    Directory of Open Access Journals (Sweden)

    Egensperger Rupert

    2009-07-01

    Full Text Available Abstract Background Cisplatin mediates its antineoplastic activity by formation of distinct DNA intrastrand cross links. The clinical efficacy and desirable dose escalations of cisplatin are restricted by the accumulation of DNA lesions in dorsal root ganglion (DRG cells leading to sensory polyneuropathy (PNP. We investigated in a mouse model by which mechanism recombinant erythropoietin (rhEPO protects the peripheral nervous system from structural and functional damage caused by cisplatin treatment with special emphasis on DNA damage burden. Results A cumulative dose of 16 mg cisplatin/kg resulted in clear electrophysiological signs of neuropathy, which were significantly attenuated by concomitant erythropoietin (cisplatin 32,48 m/s ± 1,68 m/s; cisplatin + rhEPO 49,66 m/s ± 1,26 m/s; control 55,01 m/s ± 1,88 m/s; p Conclusion The protective effect of recombinant erythropoietin is not mediated by reducing the burden of DNA platination in the target cells, but it is likely to be due to a higher resistance of the target cells to the adverse effect of DNA damage. The increased frequency of intact mitochondria might also contribute to this protective role.

  4. Recombinant human erythropoietin to target cognitive dysfunction in bipolar disorder

    DEFF Research Database (Denmark)

    Miskowiak, Kamilla Woznica; Ehrenreich, Hannelore; Christensen, Ellen M

    2014-01-01

    OBJECTIVE: Available drug treatments for bipolar disorder fail to reverse patients' cognitive deficits. Erythropoietin has neurotrophic actions and aids neurocognitive function. The aim of the study was to investigate the potential of erythropoietin to treat cognitive dysfunction in bipolar......; secondary outcomes were sustained attention and facial expression recognition; and tertiary outcomes were attention, executive function, subjective cognitive function, and mood. Analysis was by intention to treat, using repeated-measures analysis of covariance adjusted for stratification variables and mood...... in erythropoietin versus saline groups (P = .10). However, erythropoietin enhanced sustained attention (P = .001), recognition of happy faces (P = .03), and speed of complex information processing across learning, attention, and executive function (P = .01). These effects occurred in absence of changes in simple...

  5. Known players, new interplay in atherogenesis: Chronic shear stress and carbamylated-LDL induce and modulate expression of atherogenic LR11 in human coronary artery endothelium.

    Science.gov (United States)

    Bajari, Tarek M; Winnicki, Wolfgang; Gensberger, Eva-Theres; Scharrer, Susanna I; Regele, Heinz; Aumayr, Klaus; Kopecky, Chantal; Gmeiner, Bernhard M; Hermann, Marcela; Zeillinger, Robert; Sengölge, Gürkan

    2014-02-01

    In this study we examined whether low-density lipoprotein (LDL) receptor family members represent a link between blood flow characteristics and modified low-density lipoproteins involved in endothelial injury, a pivotal factor in atherogenesis. We demonstrated the expression of pro-atherogenic LDL receptor relative (LR11) for the first time in human coronary artery endothelial cells (HCAEC) in vitro and in vivo. Next, LR11 expression and regulation were explored in HCAEC cultured conventionally or on the inner surface of hollow fiber capillaries under exposure to shear stress for 10 days in the presence or absence of LDL. There was no LR11 expression under static conditions. When exposed to chronic low shear stress (2.5 dynes/cm²) transmembrane and soluble endothelial-LR11 were detected in high levels irrespective of the type of LDL added (carbamylated or native). In contrast, chronic high shear stress (25 dynes/cm²) inhibited the LR11-inducing effect of LDL such that transmembrane and soluble LR11 expression became non-detectable with native LDL. Carbamylated LDL significantly counteracted this atheroprotective effect of high shear stress as shown by lower, yet sustained expression of soluble and transmembrane LR11. Oxidised LDL showed similar effects compared to carbamylated LDL but caused significantly lower LR11 expression under chronic high shear stress. Medium from HCAEC under LR11-inducing conditions enhanced vascular smooth muscle cell migration, which was abrogated by the anti-LR11 antibody. Expression of LR11 depended entirely on p38MAPK phosphorylation. We conclude that coronary endothelial LR11 expression modulated by LDL and chronic shear stress contributes to atherogenesis. LR11 and p38MAPK are potential targets for prevention of atherosclerosis.

  6. Biotinylated recombinant human erythropoietins: Bioactivity and utility as receptor ligand

    Energy Technology Data Exchange (ETDEWEB)

    Wojchowski, D.M.; Caslake, L. (Pennsylvania State Univ., University Park (USA))

    1989-08-15

    Recombinant human erythropoietin labeled covalently with biotin at sialic acid moieties has been prepared, and has been shown to possess high biological activity plus utility as a receptor ligand. Initially, the effects on biological activity of covalently attaching biotin to erythropoietin alternatively at carboxylate, amino, or sialic acid groups were compared. Biotinylation of erythropoietin at carboxylate groups using biotin-amidocaproyl hydrazide plus 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide led to substantial biological inactivation, although biotinylated molecules retained detectable activity when prepared at low stoichiometries. Biotinylation at amino groups using sulfosuccinimidyl 6-(biotinamido) hexanoate resulted in a high level of biological inactivation with little, if any, retention of biological activity, regardless of labeling stoichiometries. Biotinylation at sialic acid moieties using periodate and biotinamidocaproyl hydrazide proceeded efficiently (greater than 95% and 80% labeling efficiencies for human urinary and recombinant erythropoietin, respectively) and yielded stably biotinylated erythropoietin molecules possessing comparably high biological activity (ie, 45% of the activity of unmodified hormone). Utility of recombinant biotin-(sialyl)-erythropoietin (in combination with 125I-streptavidin) in the assay of cell surface receptors was demonstrated using two distinct murine erythroleukemia cell lines, Friend 745 and Rauscher Red 1. The densities and affinities of specific hormone binding sites were 116 +/- 4 sites, 3.3 +/- 0.4 nmol/L kd and 164 +/- 5 sites, 2.7 +/- 0.4 nmol/L kd, respectively. It is predicted that the present development of biotin-(sialyl)-erythropoietin as a chemically and biologically stable, bioactive ligand will assist in advancing an understanding of the regulated expression and physicochemistry of the human and murine erythropoietin receptors.

  7. Effects of erythropoietin in skin wound healing are dose related.

    Science.gov (United States)

    Sorg, Heiko; Krueger, Christian; Schulz, Torsten; Menger, Michael D; Schmitz, Frank; Vollmar, Brigitte

    2009-09-01

    The hematopoietic growth factor erythropoietin (EPO) attracts attention due to its all-tissue-protective pleiotropic properties. We studied the effect of EPO on dermal regeneration using intravital microscopy in a model of full dermal thickness wounds in the skin-fold chamber of hairless mice. Animals received repetitive low doses or high doses of EPO (RLD-EPO or RHD-EPO) or a single high dose of EPO (SHD-EPO). SHD-EPO accelerated wound epithelialization, reduced wound cellularity, and induced maturation of newly formed microvascular networks. In contrast, RHD-EPO impaired the healing process, as indicated by delayed epithelialization, high wound cellularity, and lack of maturation of microvascular networks. Also, RHD-EPO caused an excessive erythrocyte mass and rheological malfunction, further deteriorating vessel and tissue maturation. Moreover, RHD-EPO altered fibroblast and keratinocyte migration in vitro, while both cell types exposed to RLD-EPO, and, in particular, to SHD-EPO showed accelerated wound scratch closure. In summary, our data show that a single application of a high dose of EPO accelerates and improves skin wound healing.

  8. Low dose erythropoietin stimulates bone healing in mice.

    Science.gov (United States)

    Garcia, P; Speidel, V; Scheuer, C; Laschke, M W; Holstein, J H; Histing, T; Pohlemann, T; Menger, M D

    2011-02-01

    Beyond its classical role in regulation of erythropoiesis, erythropoietin (EPO) has been shown to exert protective and regenerative actions in a variety of non-hematopoietic tissues. However, little is known about potential actions in bone regeneration. To analyze fracture healing in mice, a femoral 0.25 mm osteotomy gap was stabilized with a pin-clip technique. Animals were treated with 500 U EPO/kg bw per day or with vehicle only. After 2 and 5 weeks, fracture healing was analyzed biomechanically, radiologically and histologically. Expression of PCNA and NFκB was examined by Western blot analysis. Vascularization was analyzed by immunohistochemical staining of PECAM-1. Circulating endothelial progenitor cells were measured by flow-cytometry. Herein, we demonstrate that EPO-treatment significantly accelerates bone healing in mice. This is indicated by a significantly greater biomechanical stiffness and a higher radiological density of the periosteal callus at 2 and 5 weeks after fracture and stabilization. Histological analysis demonstrated significantly more bone and less cartilage and fibrous tissue in the periosteal callus. Endosteal vascularization was significantly increased in EPO-treated animals when compared to controls. The number of circulating endothelial progenitor cells was significantly greater in EPO-treated animals. The herein shown acceleration of healing by EPO may represent a promising novel treatment strategy for fractures with delayed healing and non-union formation.

  9. Plant recombinant erythropoietin attenuates inflammatory kidney cell injury.

    Science.gov (United States)

    Conley, Andrew J; Mohib, Kanishka; Jevnikar, Anthony M; Brandle, Jim E

    2009-02-01

    Human erythropoietin (EPO) is a pleiotropic cytokine with remarkable tissue-protective activities in addition to its well-established role in red blood cell production. Unfortunately, conventional mammalian cell cultures are unlikely to meet the anticipated market demands for recombinant EPO because of limited capacity and high production costs. Plant expression systems may address these limitations to enable practical, cost-effective delivery of EPO in tissue injury prevention therapeutics. In this study, we produced human EPO in tobacco and demonstrated that plant-derived EPO had tissue-protective activity. Our results indicated that targeting to the endoplasmic reticulum (ER) provided the highest accumulation levels of EPO, with a yield approaching 0.05% of total soluble protein in tobacco leaves. The codon optimization of the human EPO gene for plant expression had no clear advantage; furthermore, the human EPO signal peptide performed better than a tobacco signal peptide. In addition, we found that glycosylation was essential for the stability of plant recombinant EPO, whereas the presence of an elastin-like polypeptide fusion had a limited positive impact on the level of EPO accumulation. Confocal microscopy showed that apoplast and ER-targeted EPO were correctly localized, and N-glycan analysis demonstrated that complex plant glycans existed on apoplast-targeted EPO, but not on ER-targeted EPO. Importantly, plant-derived EPO had enhanced receptor-binding affinity and was able to protect kidney epithelial cells from cytokine-induced death in vitro. These findings demonstrate that tobacco plants may be an attractive alternative for the production of large amounts of biologically active EPO.

  10. Erythropoietin Levels in Elderly Patients with Anemia of Unknown Etiology.

    Directory of Open Access Journals (Sweden)

    Zachary Gowanlock

    Full Text Available In many elderly patients with anemia, a specific cause cannot be identified. This study investigates whether erythropoietin levels are inappropriately low in these cases of "anemia of unknown etiology" and whether this trend persists after accounting for confounders.This study includes all anemic patients over 60 years old who had erythropoietin measured between 2005 and 2013 at a single center. Three independent reviewers used defined criteria to assign each patient's anemia to one of ten etiologies: chronic kidney disease, iron deficiency, chronic disease, confirmed myelodysplastic syndrome (MDS, suspected MDS, vitamin B12 deficiency, folate deficiency, anemia of unknown etiology, other etiology, or multifactorial etiology. Iron deficiency anemia served as the comparison group in all analyses. We used linear regression to model the relationship between erythropoietin and the presence of each etiology, sequentially adding terms to the model to account for the hemoglobin concentration, estimated glomerular filtration rate (eGFR and Charlson Comorbidity Index.A total of 570 patients met the inclusion criteria. Linear regression analysis showed that erythropoietin levels in chronic kidney disease, anemia of chronic disease and anemia of unknown etiology were lower by 48%, 46% and 27%, respectively, compared to iron deficiency anemia even after adjusting for hemoglobin, eGFR and comorbidities.We have shown that erythropoietin levels are inappropriately low in anemia of unknown etiology, even after adjusting for confounders. This suggests that decreased erythropoietin production may play a key role in the pathogenesis of anemia of unknown etiology.

  11. Novel uses for recombinant erythropoietin therapy in unlicensed indications.

    Science.gov (United States)

    Macartney, Christine A; Adgey, A A Jennifer; Jones, Frank G C; Morris, Treen C M; McMullin, Mary-Frances

    2004-01-01

    Clinical uses for recombinant human erythropoietin (rHuEPO) therapy continue to expand. Initial use was in anaemia associated with end-stage renal disease, but more recently there have been many reports of the benefits of erythropoietin in other clinical situations such as cancer-related anaemia. Recombinant erythropoietin reduces the need for blood transfusion and hence exposure to donor blood products as well as improving quality of life. We report four patients who were transfusion dependent, none of whom had licensed indications for the use of recombinant erythropoietin. Two patients had microangiopathic haemolytic anaemia secondary to mechanical valve haemolysis and were unsuitable for any further cardiac intervention. One patient had anaemia of chronic disease and anti-Vel red cell antibodies, making compatible blood transfusions difficult to obtain. The fourth patient had primary thrombocythaemia and developed transfusion-dependent anaemia secondary to myelosuppressive agents. All four patients had a relative deficiency in endogenous erythropoietin levels ranging between 7 and 41 IU/l. After commencing recombinant erythropoietin therapy, all had a response in haemoglobin of at least 1 g/dl with an overall improvement in their quality of life. We conclude that rHuEPO is a very convenient and useful form of treatment in transfusion-dependent anaemia and in some cases beyond the licensed indications.

  12. Effects of Recombinant Erythropoietin on Breast Cancer-Initiating Cells

    Directory of Open Access Journals (Sweden)

    Tiffany M. Phillips

    2007-12-01

    Full Text Available BACKGROUND: Cancer anemia causes fatigue and correlates with poor treatment outcome. Erythropoietin has been introduced in an attempt to correct these defects. However, five recent clinical trials reported a negative impact of erythropoietin on survival and/or tumor control, indicating that experimental evaluation of a possible direct effect of erythropoietin on cancer cells is required. Cancer recurrence is thought to rely on the proliferation of cancer initiating cells (CICs. In breast cancer, CICs can be identified by phenotypic markers and their fate is controlled by the Notch pathway. METHODS: In this study, we investigated the effect of erythropoietin on CICs in breast cancer cell lines. Levels of erythropoietin receptor (EpoR, CD24, CD44, Jagged-1 expression, activation of Notch-1 were assessed by flow cytometry. Self-renewing capacity of CICs was investigated in sphere formation assays. RESULTS: EpoR expression was found on the surface of CICs. Recombinant human Epo (rhEpo increased the numbers of CICs and self-renewing capacity in a Notch-dependent fashion by induction of Jagged-1. Inhibitors of the Notch pathway and P13-kinase blocked both effects. CONCLUSIONS: Erythropoietin functionally affects CICs directly. Our observation may explain the negative impact of recombinant Epo on local control and survival of cancer patients with EpoR-positive tumors.

  13. Recombinant human erythropoietin for repair of white matter damage

    Institute of Scientific and Technical Information of China (English)

    Wei Zhou; Xiao Rong; Li Tao; Weineng Lu

    2011-01-01

    Erythropoietin has been shown to exhibit neuroprotective effects in animal models. A neonatal rat model of hypoxic-ischemic white matter damage was established via bilateral carotid artery ligation in 4-day-old Sprague-Dawley rats. The rats were subsequently treated with recombinant human erythropoietin to observe pathological changes in the brain and long-term neurobehavioral functions before and after intervention. Results showed that the number of myelin basic protein-positive cells, which reflected myelin/oligodendrocyte damage, significantly increased, although the number of amyloid precursor protein-positive cells, which reflected axonal injury, significantly decreased in periventricular white matter at 72 hours and 7 days following erythropoietin intervention. The number of glial fibrillary acidic protein-positive cells, indicating astrocytic damage, significantly decreased in periventricular white matter of erythropoietin-treated rats at 48 hours, 72 hours, 7 days, and 26 days. Following erythropoietin intervention in the 30-day-old rats, head-turning time in the slope test was shortened and open-field test scores increased. These results suggested that erythropoietin promoted repair of white matter damage, as well as improved neurobehavioral functions in a rat model of hypoxic-ischemic injury.

  14. Erythropoietin in bone - Controversies and consensus.

    Science.gov (United States)

    Hiram-Bab, Sahar; Neumann, Drorit; Gabet, Yankel

    2017-01-01

    Erythropoietin (Epo) is the main hormone that regulates the production of red blood cells (hematopoiesis), by stimulating their progenitors. Beyond this vital function, several emerging roles have been noted for Epo in other tissues, including neurons, heart and retina. The skeletal system is also affected by Epo, however, its actions on bone are, as yet, controversial. Here, we review the seemingly contradicting evidence regarding Epo effects on bone remodeling. We also discuss the evidence pointing to a direct versus indirect effect of Epo on the osteoblastic and osteoclastic cell lineages. The current controversy may derive from a context-dependent mode of action of Epo, namely opposite skeletal actions during bone regeneration and steady-state bone remodeling. Differences in conclusions from the published in-vitro studies may thus relate to the different experimental conditions. Taken together, these studies indicate a complexity of Epo functions in bone cells.

  15. [Treatment of renal anemia with erythropoietin].

    Science.gov (United States)

    Spustova, V; Kovac, A

    1999-08-01

    During the last decade, a considerable amount of new information has accumulated regarding therapy optimalization of renal anaemia with recombinant human erythropoietin (EPO). Key question involved is EPO hyporesponsiveness caused by absolute or functional iron deficiency. Most controversial issue in the treatment of renal anaemia in patients with chronic renal insufficiency is the definition of optimal target haemoglobin. Many questions about optimizing EPO therapy were considered at the 2nd European Epoetin Symposium which was held in April 1998 on Crete. Discussion was devoted also to revision of a draft version of the European Best Practice Guidelines for the Management of Anaemia in Patients with Chronic Renal Failure. The presented review is on summary of new insights presented at the symposium. (Ref. 85.)

  16. Infantile pyknocytosis: effectiveness of erythropoietin treatment

    Directory of Open Access Journals (Sweden)

    Eleonora Buzzi

    2013-04-01

    Full Text Available Infantile pyknocytosis is a rare form of neonatal haemolytic anaemia with unusual red cell morphology. Anaemia is mostly severe and red blood cells transfusion is often needed. In this report, we have described a male child aged 10 days, born at 37 weeks + 3 days, who presented neonatal jaundice and severe anaemia. After a careful peripheral blood smear examination, infantile pyknocytosis was diagnosed. A treatment with recombinant subcutaneous erythropoietin (1,000 UI/prokg/week in conjunction with iron supplementation (6 mg/kg/day was started. The therapy was reduced 6 weeks after the beginning and discontinued 4 weeks after the reaching of a steady state of the haemoglobin values. After 12 months of follow up, the patient showed no anaemia and pyknocytosis.

  17. 外源性促红细胞生成素对大鼠视网膜脱离光感受器细胞的保护作用%Protective effects of recombinant erythropoietin on photoreceptor cells in rat with retinal detachment

    Institute of Scientific and Technical Information of China (English)

    解正高; 宫媛媛; 宋毅; 李彩红; 吴星伟

    2010-01-01

    Objective To investigate the protective effect of recombinant erythropoietin (EPO) on the photoreceptor cells in rat with retinal detachment (RD). Methods One hundred and sixty-two normal male rats were randomly divided into normal control (NC) group, RD model group, RD+phosphate buffer solution (RD+PBS) group, RD+EPO 100 ng group, RD+EPO 200 ng group and RD+EPO 400 ng group. Three days after RD, activated caspase-3 and bcl-XL were detected by Western blot and/or immunofluorescence, and apoptosis were measured by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate digoxigenin nick-end labeling(TUNEL). Fourteen and 28 days and two months after RD, the outer nuclear layer (ONL) thickness was measured by histopathologic method. Results Western bolt indicated that the protein level of activated caspase-3 and bcl-XL between six groups were statistically significant(F= 35. 96, 30. 75;P<0. 01). The number of TUNEL positive cells and activated caspase-3 positive cells are consistent with each other in different groups. Fourteen days and two months after RD, the differences of ONL thickness between six groups were statistically significant (F= 21. 52, 96. 25;P<0. 01). Conclusion Supplement of EPO after RD can alleviate apoptosis by inhibiting of the caspase-3 activity and increasing the expression of bcl-XL, thus exerts protective effect on photoreceptor cells.%目的 观察外源性促红细胞生成素(EPO)对大鼠视网膜脱离(RD)状态下光感受器细胞的保护作用.方法 采用计算机产生随机数字的方法将162只正常雄性SD大鼠分为正常对照组(NC组)、RD组、RD+磷酸盐缓冲液(PBS)组、RD+EPO 100、200、400 ng组.RD后3 d,采用蛋白免疫印迹(Western blot)检测半胱氨酸蛋白酶3(caspase-3)活性和B细胞淋巴瘤/白血病-XL(bcl-XL)的表达,免疫荧光检测caspase-3活性,脱氧核糖核苷酸末端转移酶介导的缺口末端标记法(TUNEL)检测光感受器细胞凋亡情况.RD后14、28 d,2个

  18. Anemia induces accumulation of erythropoietin mRNA in the kidney and liver.

    OpenAIRE

    Bondurant, M C; Koury, M J

    1986-01-01

    Regulation of the production of erythropoietin occurs in the kidney and liver largely through control of accumulation of erythropoietin mRNA. Erythropoietin mRNA was first detected in kidneys at 1.5 h postanemia and reached a plateau value at least 200-fold above the control value by 4 to 8 h. A 20-base sequence immediately upstream from the reported erythropoietin mRNA initiation site is complementary to a hypervariable sequence in 18S rRNA.

  19. Erythropoietin blockade inhibits the induction of tumor angiogenesis and progression.

    Directory of Open Access Journals (Sweden)

    Matthew E Hardee

    Full Text Available BACKGROUND: The induction of tumor angiogenesis, a pathologic process critical for tumor progression, is mediated by multiple regulatory factors released by tumor and host cells. We investigated the role of the hematopoietic cytokine erythropoietin as an angiogenic factor that modulates tumor progression. METHODOLOGY/PRINCIPAL FINDINGS: Fluorescently-labeled rodent mammary carcinoma cells were injected into dorsal skin-fold window chambers in mice, an angiogenesis model that allows direct, non-invasive, serial visualization and real-time assessment of tumor cells and neovascularization simultaneously using intravital microscopy and computerized image analysis during the initial stages of tumorigenesis. Erythropoietin or its antagonist proteins were co-injected with tumor cells into window chambers. In vivo growth of cells engineered to stably express a constitutively active erythropoietin receptor EPOR-R129C or the erythropoietin antagonist R103A-EPO were analyzed in window chambers and in the mammary fat pads of athymic nude mice. Co-injection of erythropoietin with tumor cells or expression of EPOR-R129C in tumor cells significantly stimulated tumor neovascularization and growth in window chambers. Co-injection of erythropoietin antagonist proteins (soluble EPOR or anti-EPO antibody with tumor cells or stable expression of antagonist R103A-EPO protein secreted from tumor cells inhibited angiogenesis and impaired tumor growth. In orthotopic tumor xenograft studies, EPOR-R129C expression significantly promoted tumor growth associated with increased expression of Ki67 proliferation antigen, enhanced microvessel density, decreased tumor hypoxia, and increased phosphorylation of extracellular-regulated kinases ERK1/2. R103A-EPO antagonist expression in mammary carcinoma cells was associated with near-complete disruption of primary tumor formation in the mammary fat pad. CONCLUSIONS/SIGNIFICANCE: These data indicate that erythropoietin is an

  20. The isotype and IgG subclass distribution of anti-carbamylated protein antibodies in rheumatoid arthritis patients.

    Science.gov (United States)

    van Delft, Myrthe A M; Verheul, Marije K; Burgers, Leonie E; Derksen, Veerle F A M; van der Helm-van Mil, Annette H M; van der Woude, Diane; Huizinga, Tom W J; Toes, René E M; Trouw, Leendert A

    2017-08-15

    Anti-carbamylated protein (anti-CarP) antibodies have recently been reported to occur in around 45% of rheumatoid arthritis (RA) patients and to have prognostic and diagnostic properties. At present, the breadth and molecular make-up of the anti-CarP antibody response is ill defined. To understand the anti-CarP antibody immune response and potential immune effector mechanisms it can recruit, we determined the anti-CarP antibody isotype and IgG-subclass usage in RA patients. Anti-CarP antibody IgM, IgA, and IgG or IgG subclasses were detected by enzyme-linked immunosorbent assay (ELISA) in sera from 373 unselected RA patients and 196 healthy controls. An additional 114 anti-citrullinated protein antibody (ACPA) and anti-CarP IgG double-positive patients were selected to study the concomitant presence of both antibody systems. Anti-CarP IgG was present in around 45% of the patients and comprised all anti-CarP IgG subclasses. The presence of anti-CarP IgG1 particularly associates with radiological damage. Anti-CarP IgM was detected in 16% of RA patients, even in anti-CarP IgG-positive individuals, and is indicative of an actively ongoing immune response. Around 45% of the patients were positive for IgA which included ACPA-positive cases but also 24% of the ACPA-negative cases. In ACPA and anti-CarP double-positive patients, the distribution and number of isotypes and IgG subclasses was similar for both autoantibodies at the group level, but substantial variation was observed within individual patient samples. In RA, the anti-CarP antibody response uses a broad spectrum of isotypes and seems to be an actively ongoing immune reaction. Furthermore, the anti-CarP and ACPA autoantibody responses seems to be differentially regulated.

  1. 促红细胞生成素对大鼠肾脏缺血再灌注损伤的抗炎保护作用及其机制%Protective effect of erythropoietin on inflammation of renal ischemia-reperfusion injury in rats

    Institute of Scientific and Technical Information of China (English)

    汪悠悠; 贾宁; 彭莉; 张慧涛; 朱晔; 郑晶; 朱伟平; 张桦

    2013-01-01

    目的:探讨促红细胞生成素(EPO)对大鼠肾脏缺血再灌注损伤(IRI)的抗炎保护作用及其机制。方法36只雄性SD大鼠随机分为假手术(SOR)组、IRI组和EPO组,每组12只。于再灌注2 h、6 h、12 h、24 h各时相点观察肾脏病理改变,检测血尿素氮(BUN)和肌酐(Scr)水平,ELISA法检测肾组织匀浆肿瘤坏死因子-α(TNF-α)含量,Western印迹法检测磷酸化p38丝裂原活化蛋白激酶(p-p38MAPK)蛋白表达。结果 IRI组血BUN、Scr水平和肾组织匀浆TNF-α含量显著升高,并出现明显的肾脏病理改变;肾组织p-p38MAPK蛋白表达明显增强,于再灌注12 h达到峰值,24 h表达减弱。而在EPO组,BUN、Scr和 TNF-α水平显著低于 IRI 组(P<0.05),在各时相点的肾脏病理改变与同期 IRI 组比较明显减轻, p-p38MAPK表达在各时相点较IRI组明显减弱。结论 EPO可显著改善IRI造成的肾脏病理和肾功能异常,其肾脏保护作用可能与抑制p38MAPK活化、降低TNF-α水平、减轻炎性损伤有关。%Objective To investigate protective effects and mechanisms of erythropoietin (EPO) on inflammation induced by renal ischemia-reperfusion injury (IRI) in rats. Methods A total of 36 male Sprague-Dawley rats were randomly divided into 3 groups of Sham operation (SOR), IRI and EPO pretreatment (n=12 in each group). Renal IRI model was created by clamping the bilateral renal pedicle for 45 min and then released. 3000 IU/kg of EPO was administered in EPO group via the abdominal cavity 24 hours before clamping. Blood samples and the kidney were obtained at 2, 6, 12 and 24 h after reperfusion. The serous concentrations of blood urea nitrogen and serum creatinine were measured.The levels of tumor necrosis factorα(TNF-α) in the renal tissues were detected by ELISA, and the expression of phosphorylating-p38 mitogen-activated protein kinase (p-p38MAPK) in the renal tissues were assessed by western

  2. 促红细胞生成素对大鼠脊髓运动神经元缺氧性损伤的保护作用%Protective Effect of Erythropoietin on Anoxia of Motoneurons after Spinal Cord Injury in Rats

    Institute of Scientific and Technical Information of China (English)

    胡杨; 秦文; 廉凯

    2014-01-01

    Objective To observe the protective effect of erythropoietin (EPO) on anoxia of motoneurons after spinal cord injury in rats. Methods The motoneuron was dissociated from neonate Wistar rats and cultivated in vitro with deprivation of oxygen in the medium. The changes of morphology were observed by phase-contrast microscopy, and the expression of EPO receptor (EPOR) was detected with West-ern blotting. The survival rate of motoneuron was measured with methyl thiazolyl tetrazolium (MTT) assay, and the level of lactate dehydro-genase (LDH) was observed. Results Compared with the control group, the expression of EPOR and the level of LDH increased (P<0.01), and the survival rate of motoneuron decreased (P<0.01) in the anoxia group. Compared with the anoxia group, the expression of EPOR and the level of LDH decreased (P<0.05), and the survival rate of motoneuron increased (P<0.01) in the EPO group, which was related with the level of EPO. Conclusion EPO could relieve the damage of motoneuron caused by anoxia, especially by upregulating EPOR.%目的:观察重组红细胞生成素(EPO)对大鼠脊髓运动神经元细胞缺氧性损伤的保护作用。方法对Wistar乳鼠脊髓运动神经元细胞进行原代分离培养,通过去除培养液中氧气来模拟脊髓缺氧。倒置显微镜下观察细胞形态变化,Western blotting检测EPO受体(EPOR)蛋白的表达,噻唑蓝(MTT)比色法及乳酸盐脱氢酶(LDH)活力测定观察加入不同浓度EPO对神经元细胞的保护作用。结果与正常对照组比较,缺氧组脊髓运动神经元缺氧后EPOR表达及LDH浓度明显增加(P<0.01),细胞存活率明显降低(P<0.01);与缺氧组比较, EPO组EPOR表达及LDH浓度降低(P<0.05),细胞存活率明显增强(P<0.01),且与浓度相关。结论EPO可减轻缺氧对运动神经元的损害,而EPOR表达上调可能是EPO发挥其对缺氧神经元保护作用的重要途径之一。

  3. Mystery Story about Erythropoietin (Epo) and Erythropoietin Receptor (EpoR) are Disguised?

    Science.gov (United States)

    Cubranić, Aleksandar; Redzovic, Arnela; Dobrila-Dintinjana, Renata; Vukelić, Jelena; Dintinjana, Marijan

    2015-05-01

    In this review we would like to focus our attention upon very controversial reports on Erythropoietin (Epo) and Erythropoietin Receptor (EpoR) expression in cancer patients. The effects of Epo on cancerous tissues are poorly understood. Hypoxia results in an increase in the level of the production of both Epo and EpoR via activation of the hypoxia-inducible factor 1 (HIF-1) pathway. HIF-1α, promotes the expression of vascular endothelial growth factor (VEGF). The signaling through VEGF in both a paracrine and an autocrine manner is required for the homeostasis of adult vessels. Macrophages stimulate vessel sprouting via a soluble factor other than VEGF, rather than through direct contact with endothelial cells. The intriguing questions are set about many researches to link Epo/EpoR expression and function in order to establish one of the mechanisms of tumor growth, disease progression of cancer patient. However, it is uncertain role in tumour angiogenesis as promoter and stimulator of tumour growth which should need to be furtherly validated.

  4. Neuroprotective properties of a novel, non-haematopoietic agonist of the erythropoietin receptor

    DEFF Research Database (Denmark)

    Pankratova, Stanislava; Kiryushko, Dar'Ya; Sonn, Katrin

    2010-01-01

    designed a peptide, termed Epotris, corresponding to the C alpha-helix region (amino-acid residues 92-111) of human erythropoietin. The peptide specifically bound to the erythropoietin receptor and promoted neurite outgrowth and survival of primary neurons with the same efficiency as erythropoietin......, but with 10(3)-fold lower potency. Knockdown of the erythropoietin receptor or interference with its downstream signalling inhibited the Epotris-induced neuritogenic and pro-survival effect. Similarly to erythropoietin, Epotris penetrated the blood-brain barrier. Moreover, treatment with the peptide...

  5. EPO's alter ego: erythropoietin has multiple actions.

    Science.gov (United States)

    Lappin, Terence R; Maxwell, A Peter; Johnston, Patrick G

    2002-01-01

    Many cancer patients suffer from anemia, which has a major detrimental effect on their quality of life. Recombinant human erythropoietin (rHuEPO) is now widely used in cancer patients, as it improves hematocrit, lowers blood transfusion requirements, and improves quality of life. Recent research indicates that EPO has pleiotropic effects on the body well beyond the maintenance of red cell mass, but the mechanisms involved in relieving fatigue and improving quality of life in cancer patients are poorly understood. EPO receptors (EPO-Rs) have been detected in many different cells and tissues, providing evidence for autocrine, paracrine, and endocrine functions of EPO. Apart from its endocrine function, EPO may have a generalized role as an antiapoptotic agent that is associated with enhancement of muscle tone, mucosal status, and gonadal and cognitive function. The recent discovery of EPO-Rs in breast tumor vasculature, while raising important questions about the possible effects of pharmacological doses of rHuEPO on tumor cells, also suggests that the receptors could provide a useful target for drugs attached to EPO.

  6. Erythropoietin receptor signaling is membrane raft dependent.

    Directory of Open Access Journals (Sweden)

    Kathy L McGraw

    Full Text Available Upon erythropoietin (Epo engagement, Epo-receptor (R homodimerizes to activate JAK2 and Lyn, which phosphorylate STAT5. Although recent investigations have identified key negative regulators of Epo-R signaling, little is known about the role of membrane localization in controlling receptor signal fidelity. Here we show a critical role for membrane raft (MR microdomains in creation of discrete signaling platforms essential for Epo-R signaling. Treatment of UT7 cells with Epo induced MR assembly and coalescence. Confocal microscopy showed that raft aggregates significantly increased after Epo stimulation (mean, 4.3±1.4(SE vs. 25.6±3.2 aggregates/cell; p≤0.001, accompanied by a >3-fold increase in cluster size (p≤0.001. Raft fraction immunoblotting showed Epo-R translocation to MR after Epo stimulation and was confirmed by fluorescence microscopy in Epo stimulated UT7 cells and primary erythroid bursts. Receptor recruitment into MR was accompanied by incorporation of JAK2, Lyn, and STAT5 and their activated forms. Raft disruption by cholesterol depletion extinguished Epo induced Jak2, STAT5, Akt and MAPK phosphorylation in UT7 cells and erythroid progenitors. Furthermore, inhibition of the Rho GTPases Rac1 or RhoA blocked receptor recruitment into raft fractions, indicating a role for these GTPases in receptor trafficking. These data establish a critical role for MR in recruitment and assembly of Epo-R and signal intermediates into discrete membrane signaling units.

  7. Erythropoietin couples hematopoiesis with bone formation.

    Directory of Open Access Journals (Sweden)

    Yusuke Shiozawa

    Full Text Available BACKGROUND: It is well established that bleeding activates the hematopoietic system to regenerate the loss of mature blood elements. We have shown that hematopoietic stem cells (HSCs isolated from animals challenged with an acute bleed regulate osteoblast differentiation from marrow stromal cells. This suggests that HSCs participate in bone formation where the molecular basis for this activity is the production of BMP2 and BMP6 by HSCs. Yet, what stimulates HSCs to produce BMPs is unclear. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we demonstrate that erythropoietin (Epo activates Jak-Stat signaling pathways in HSCs which leads to the production of BMPs. Critically, Epo also directly activates mesenchymal cells to form osteoblasts in vitro, which in vivo leads to bone formation. Importantly, Epo first activates osteoclastogenesis which is later followed by osteoblastogenesis that is induced by either Epo directly or the expression of BMPs by HSCs to form bone. CONCLUSIONS/SIGNIFICANCE: These data for the first time demonstrate that Epo regulates the formation of bone by both direct and indirect pathways, and further demonstrates the exquisite coupling between hematopoiesis and osteopoiesis in the marrow.

  8. Blood doping : infusions, erythropoietin and artificial blood.

    Science.gov (United States)

    Eichner, E Randy

    2007-01-01

    As science marches on, athletes and coaches march close behind. Researchers have long been interested in how red cell mass and blood volume affect exercise capacity. Interest in blood doping soared after the 1968 Mexico City Olympics. Studies in the 1970s and 1980s suggested that transfusing red cells could speed endurance performance. Diverse athletes of the time were accused of blood doping. In the late 1980s, recombinant human erythropoietin (EPO) began to supplant transfusion for doping. EPO use is a suspect in nearly 20 deaths in 4 years in European cyclists. In the 1998 Tour de France, a team was ejected for using EPO and six other teams quit the race. The beat goes on; in recent years, diverse endurance and sprint athletes have been caught or accused of using EPO. Tests to detect EPO are improving but are not yet foolproof. As EPO tests improve, blood transfusion is back in vogue and some athletes may have infused artificial blood. Tests for detecting artificial blood also exist, but it seems it will take widespread, year-round, unannounced, out-of-competition testing and stern penalties to deter blood doping.

  9. Pretreatment with erythropoietin reduces hepatic ischemia-reperfusion injury

    Institute of Scientific and Technical Information of China (English)

    Yu-Hong Luo; Zheng-Dong Li; Li-Xin Liu; Gao-Hong Dong

    2009-01-01

    BACKGROUND: During hepatectomy, a period of ischemia and restoration of the blood supply can result in hepatic ischemia-reperfusion injury (IRI). Current research indicates that erythropoietin (EPO) has a protective effect in animal models of cerebral ischemia, myocardial infarction, and renal IRI. However there is lack of research into the role of EPO in hepatic IRI. This study aimed to explore the role of EPO in hepatic IRI and its possible mechanism of action. METHODS: Thirty male Sprague-Dawley rats were divided into three groups: (1) ten rats in the experimental group were given 1000 IU/kg EPO one day before the operation; (2) ten rats in a control group were given normal saline preoperatively as a placebo; and (3) ten rats served as a sham-operated group. Hepatic IRI was induced by occluding the hepatic arteries of the three cephalad hepatic segments and the portal vein for about 45 minutes, while in the sham-operated group only laparotomy was performed. The levels of ALT and AST were tested 24 hours pre- and post-operation. All rats were sacriifced 24 hours after the operation to assess the pathologic changes in the liver and measure the expression of heme oxygenase-1 (HO-1) through Western blotting and RT-PCR. RESULTS: Hepatic IRI was markedly mitigated in the experimental group as compared with the control group. Moreover, the expression of HO-1 at the level of both transcription and protein increased prominently (P<0.05) in the experimental group. CONCLUSION: These results demonstrate that EPO can up-regulate HO-1 in liver tissues and accordingly decrease hepatic injury through its anti-inlfammatory property.

  10. AMPK is Involved in Mediation of Erythropoietin Influence on Metabolic Activity and Reactive Oxygen Species Production in White Adipocytes

    OpenAIRE

    Wang, Li; Di, Lijun; Noguchi, Constance Tom

    2014-01-01

    Erythropoietin, discovered for its indispensable role during erythropoiesis, has been used in the therapy for selected red blood cell disorders in erythropoietin-deficient patients. The biological activities of erythropoietin have been found to extend to non-erythroid tissues due to the expression of erythropoietin receptor. We previously demonstrated that erythropoietin promotes metabolic activity and white adipocytes browning to increase mitochondrial function and energy expenditure via per...

  11. Garlic accelerates red blood cell turnover and splenic erythropoietic gene expression in mice: evidence for erythropoietin-independent erythropoiesis.

    Directory of Open Access Journals (Sweden)

    Bünyamin Akgül

    Full Text Available Garlic (Allium sativum has been valued in many cultures both for its health effects and as a culinary flavor enhancer. Garlic's chemical complexity is widely thought to be the source of its many health benefits, which include, but are not limited to, anti-platelet, procirculatory, anti-inflammatory, anti-apoptotic, neuro-protective, and anti-cancer effects. While a growing body of scientific evidence strongly upholds the herb's broad and potent capacity to influence health, the common mechanisms underlying these diverse effects remain disjointed and relatively poorly understood. We adopted a phenotype-driven approach to investigate the effects of garlic in a mouse model. We examined RBC indices and morphologies, spleen histochemistry, RBC half-lives and gene expression profiles, followed up by qPCR and immunoblot validation. The RBCs of garlic-fed mice register shorter half-lives than the control. But they have normal blood chemistry and RBC indices. Their spleens manifest increased heme oxygenase 1, higher levels of iron and bilirubin, and presumably higher CO, a pleiotropic gasotransmitter. Heat shock genes and those critical for erythropoiesis are elevated in spleens but not in bone marrow. The garlic-fed mice have lower plasma erythropoietin than the controls, however. Chronic exposure to CO of mice on garlic-free diet was sufficient to cause increased RBC indices but again with a lower plasma erythropoietin level than air-treated controls. Furthermore, dietary garlic supplementation and CO treatment showed additive effects on reducing plasma erythropoietin levels in mice. Thus, garlic consumption not only causes increased energy demand from the faster RBC turnover but also increases the production of CO, which in turn stimulates splenic erythropoiesis by an erythropoietin-independent mechanism, thus completing the sequence of feedback regulation for RBC metabolism. Being a pleiotropic gasotransmitter, CO may be a second messenger for garlic

  12. Central nervous system frontiers for the use of erythropoietin

    DEFF Research Database (Denmark)

    Olsen, Niels Vidiendal

    2003-01-01

    Recombinant human erythropoietin (r-HuEPO; epoetin alfa) is well established as safe and effective for the treatment of anemia. In addition to the erythropoietic effects of endogenous erythropoietin (EPO), recent evidence suggests that it may elicit a neuroprotective effect in the central nervous...... system (CNS). Preclinical studies have demonstrated the presence of EPO receptors in the brain that are up-regulated under hypoxic or ischemic conditions. Intracerebral and systemic administration of epoetin alfa have been demonstrated to elicit marked neuroprotective effects in multiple preclinical...

  13. Effects of Erythropoietin Administration on Adrenal Glands of Landrace/Large White Pigs after Ventricular Fibrillation.

    Science.gov (United States)

    Faa, Armando; Faa, Gavino; Papalois, Apostolos; Obinu, Eleonora; Locci, Giorgia; Pais, Maria Elena; Lelovas, Pavlos; Barouxis, Dimitrios; Pantazopoulos, Charalampos; Vasileiou, Panagiotis V; Iacovidou, Nicoletta; Xanthos, Theodoros

    2016-01-01

    Aim. To evaluate the effects of erythropoietin administration on the adrenal glands in a swine model of ventricular fibrillation and resuscitation. Methods. Ventricular fibrillation was induced via pacing wire forwarded into the right ventricle in 20 female Landrace/Large White pigs, allocated into 2 groups: experimental group treated with bolus dose of erythropoietin (EPO) and control group which received normal saline. Cardiopulmonary resuscitation (CPR) was performed immediately after drug administration as per the 2010 European Resuscitation Council (ERC) guidelines for Advanced Life Support (ALS) until return of spontaneous circulation (ROSC) or death. Animals who achieved ROSC were monitored, mechanically ventilated, extubated, observed, and euthanized. At necroscopy, adrenal glands samples were formalin-fixed, paraffin-embedded, and routinely processed. Sections were stained with hematoxylin-eosin. Results. Oedema and apoptosis were the most frequent histological changes and were detected in all animals in the adrenal cortex and in the medulla. Mild and focal endothelial lesions were also detected. A marked interindividual variability in the degree of the intensity of apoptosis and oedema at cortical and medullary level was observed within groups. Comparing the two groups, higher levels of pathological changes were detected in the control group. No significant difference between the two groups was observed regarding the endothelial changes. Conclusions. In animals exposed to ventricular fibrillation, EPO treatment has protective effects on the adrenal gland.

  14. Effects of Erythropoietin Administration on Adrenal Glands of Landrace/Large White Pigs after Ventricular Fibrillation

    Directory of Open Access Journals (Sweden)

    Armando Faa

    2016-01-01

    Full Text Available Aim. To evaluate the effects of erythropoietin administration on the adrenal glands in a swine model of ventricular fibrillation and resuscitation. Methods. Ventricular fibrillation was induced via pacing wire forwarded into the right ventricle in 20 female Landrace/Large White pigs, allocated into 2 groups: experimental group treated with bolus dose of erythropoietin (EPO and control group which received normal saline. Cardiopulmonary resuscitation (CPR was performed immediately after drug administration as per the 2010 European Resuscitation Council (ERC guidelines for Advanced Life Support (ALS until return of spontaneous circulation (ROSC or death. Animals who achieved ROSC were monitored, mechanically ventilated, extubated, observed, and euthanized. At necroscopy, adrenal glands samples were formalin-fixed, paraffin-embedded, and routinely processed. Sections were stained with hematoxylin-eosin. Results. Oedema and apoptosis were the most frequent histological changes and were detected in all animals in the adrenal cortex and in the medulla. Mild and focal endothelial lesions were also detected. A marked interindividual variability in the degree of the intensity of apoptosis and oedema at cortical and medullary level was observed within groups. Comparing the two groups, higher levels of pathological changes were detected in the control group. No significant difference between the two groups was observed regarding the endothelial changes. Conclusions. In animals exposed to ventricular fibrillation, EPO treatment has protective effects on the adrenal gland.

  15. Erythropoietin against cisplatin-induced peripheral neurotoxicity in rats.

    Science.gov (United States)

    Orhan, Bulent; Yalcin, Suayib; Nurlu, Gulay; Zeybek, Dilara; Muftuoglu, Sevda

    2004-01-01

    Cisplatin (CDDP) is a potent anticancer drug, and neurotoxicity is one of its most important dose-limiting toxicities. In this study we investigated the role of recombinant human erythropoietin (rhuEPO) for protection against CDDP-induced neurotoxicity. All experiments were conducted on female Wistar-albino rats. Animals were randomly assigned to three groups. Group A received only CDDP, group B received CDDP plus rhuEPO, and group C received only rhuEPO. Electroneurography (ENG) was done in the beginning and at the end of 7 wk, then the rats were sacrificed and the sciatic nerve was removed for histopathological examination. The mean initial latency was 2.7438 ms in group A, 2.4875 ms in group B, and 2.62 ms in group C. After 7 wk of treatment, the latency was 2.4938, 2.6313, and 2.3900 ms, respectively. The difference in latencies was not statistically significant. The amplitude of compound muscle action potential (CMAP) was 12.8125 mV, 14.3875 mV, and 14.5600 mV before the treatment and 8.4875, 12.8250, and, 13.0800 mV after treatment, respectively. Amplitude of CMAP was significantly greater in rhuEPO-treated groups (groups B and C) compared to cisplatin only Group A. The mean area of CMAP was 12.2625, 12.3500, and, 12.2800 mV s before the treatment and 5.7125, 10.6463, and 9.1600 mV s after the treatment, respectively. The area of CMAP was significantly larger in rhuEPO-treated groups. In histopathological studies thick, thin, and total number of nerve fibers were 4053, 5050, and 9103, in group A, 5100, 8231, and 13331, in group B, and 5264, 6010, and 11274, in group C respectively. In the microscopic examination active myelinization process was observed in rhuEPO-treated groups. We concluded that at the given dose and schedule CDDP-induced motor neuropathy and rhuEPO prevented this neuropathy by sparing the number of normal nerve fibers and by protecting the amplitude and area of CMAP. We concluded that rhuEPO may also play a role in active myelinization and

  16. Acute normobaric hypoxia stimulates erythropoietin release.

    Science.gov (United States)

    Mackenzie, Richard W A; Watt, Peter W; Maxwell, Neil S

    2008-01-01

    Investigations studying the secretion of EPO (erythropoietin) in response to acute hypoxia have produced mixed results. Further, the errors associated with the various methods used to determine EPO are not well documented. The purpose of the current study was to determine the EPO response of 17 trained male subjects to either an acute bout of normobaric hypoxia (Hy; n = 10) or normoxia (Con; n = 7). A secondary aim was to determine the error associated with the measurement of EPO. After baseline tests, the treatment group (Hy) underwent a single bout of hypoxic exposure (F(I(O(2))) approximately 0.148; 3100 m) consisting of a 90-min rest period followed by a 30-min exercise phase (50% V(O)(2max)). Venous blood samples were drawn pre (0 min) and post (120 min) each test to assess changes in plasma EPO (DeltaEPO). The control (Con) group was subjected to the same general experimental design, but placed in a normoxic environment (F(I(O(2))) approximately 0.2093). The Hy group demonstrated a mean increase in EPO [19.3 (4.4) vs. 24.1 (5.1) mU/mL], p < 0.04, post 120 min of normobaric hypoxia. The calculated technical error of measurement for EPO was 2.1 mU/mL (9.8%). It was concluded that an acute bout of hypoxia, has the capacity to elevate plasma EPO. This study also demonstrates that the increase in EPO accumulation was 2 times greater than the calculated measurement of error.

  17. Increased Serum Levels of Anti-Carbamylated 78-kDa Glucose-Regulated Protein Antibody in Patients with Rheumatoid Arthritis

    Directory of Open Access Journals (Sweden)

    Hui-Chun Yu

    2016-09-01

    Full Text Available The objective of this study was to investigate the presence and titer of anti-carbamylated 78-kDa glucose-regulated protein (anti-CarGRP78 antibody in serum from controls, and patients with rheumatoid arthritis (RA, systemic lupus erythematosus (SLE and primary Sjögren syndrome (pSS. Thirty-three RA patients, 20 SLE patients, 20 pSS patients, and 20 controls were enrolled from our outpatient clinic. GRP78 was cloned and carbamylated. Serum titers of anti- cyclic citrullinated peptides (anti-CCP, anti-GRP78, and anti-CarGRP78 were measured with an enzyme-linked immunosorbent assay. No differences in serum titers of anti-GRP78 antibody in patients with RA, SLE, or pSS compared with the controls were observed. Serum levels of anti-carGRP78 antibody in patients with RA, but not SLE or pSS, were significantly higher compared with the controls (OD405 0.15 ± 0.08 versus 0.11 ± 0.03, p = 0.033. There was a positive correlation between the serum levels of anti-GRP78 antibody, but not anti-CarGRP78 antibody, with the levels of anti-CCP antibody in patients with RA. Both anti-GRP78 and anti-carGRP78 antibodies failed to correlate with C-reactive protein levels in patients with RA. In conclusion, we demonstrated the presence of anti-CarGRP78 antibody in patients with RA. In addition, the serum titer of anti-CarGRP78 antibody was significantly elevated in patients with RA compared with the controls. Anti-CarGRP78 antibody could also be detected in patients with SLE or pSS.

  18. Increased Serum Levels of Anti-Carbamylated 78-kDa Glucose-Regulated Protein Antibody in Patients with Rheumatoid Arthritis.

    Science.gov (United States)

    Yu, Hui-Chun; Lai, Pei-Hsuan; Lai, Ning-Sheng; Huang, Hsien-Bin; Koo, Malcolm; Lu, Ming-Chi

    2016-09-08

    The objective of this study was to investigate the presence and titer of anti-carbamylated 78-kDa glucose-regulated protein (anti-CarGRP78) antibody in serum from controls, and patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and primary Sjögren syndrome (pSS). Thirty-three RA patients, 20 SLE patients, 20 pSS patients, and 20 controls were enrolled from our outpatient clinic. GRP78 was cloned and carbamylated. Serum titers of anti- cyclic citrullinated peptides (anti-CCP), anti-GRP78, and anti-CarGRP78 were measured with an enzyme-linked immunosorbent assay. No differences in serum titers of anti-GRP78 antibody in patients with RA, SLE, or pSS compared with the controls were observed. Serum levels of anti-carGRP78 antibody in patients with RA, but not SLE or pSS, were significantly higher compared with the controls (OD405 0.15 ± 0.08 versus 0.11 ± 0.03, p = 0.033). There was a positive correlation between the serum levels of anti-GRP78 antibody, but not anti-CarGRP78 antibody, with the levels of anti-CCP antibody in patients with RA. Both anti-GRP78 and anti-carGRP78 antibodies failed to correlate with C-reactive protein levels in patients with RA. In conclusion, we demonstrated the presence of anti-CarGRP78 antibody in patients with RA. In addition, the serum titer of anti-CarGRP78 antibody was significantly elevated in patients with RA compared with the controls. Anti-CarGRP78 antibody could also be detected in patients with SLE or pSS.

  19. The role of thyroid hormone in the regulation of hepatic carbamyl phosphate synthetase activity in Rana catesbeiana.

    Science.gov (United States)

    Galton, V A; Morganelli, C M; Schneider, M J; Yee, K

    1991-11-01

    Both spontaneous and thyroid hormone (TH)-induced metamorphosis of Rana catesbeiana are accompanied by a marked increase in the activity of the urea cycle enzyme carbamyl phosphate synthetase (CPS). The increase induced by exogenous TH is de novo synthesis of enzyme and appears to be secondary to an increase in the CPS mRNA level resulting from the elevated plasma TH. Since endogenous TH levels rise sharply during spontaneous metamorphosis, a similar sequence of events would be anticipated. However, after midclimax, CPS activity continues to increase, while plasma TH levels steadily decline, suggesting that other factors are involved. To obtain insight into this problem, the changes in CPS mRNA level during spontaneous development were determined using a mammalian CPS cDNA probe and correlated with changes in CPS activity and plasma T3 concentration. CPS mRNA level and CPS activity were barely detectable until midprometamorphosis, but both increased rapidly during the latter half of this phase. CPS activity continued to rise, reaching a maximum in the adult frog. The CPS mRNA level, however, was highest during the first half of climax, but declined after midclimax and was relatively low in the adult frog. Studies were also performed in which the rise and fall in the plasma T3 concentration typical of metamorphic climax were induced by exposure of premetamorphic tadpoles to T3, followed by its withdrawal. Both CPS activity and CPS mRNA level were induced by T3, but when plasma T3 levels fell after removal of the exogenous T3, CPS mRNA level, but not CPS activity, also decreased. Additional studies indicated that the TH-induced increase in CPS mRNA was evident within 24 h, could be prevented by simultaneous injection of actinomycin-D, and could not be induced in tadpoles undergoing climax; in this phase the T3 receptors are fully occupied with endogenous TH. When premetamorphic tadpoles were immersed in T3-containing water (0-500 nM) for 6 days, CPS mRNA, CPS

  20. Intravitreal injection of erythropoietin sustained-release microspheres protects damaged retinal ganglion cells in rats%促红细胞生成素缓释微球玻璃体腔注射对视网膜神经节细胞的保护作用

    Institute of Scientific and Technical Information of China (English)

    荣先芳; 莫晓芬; 任甜甜; 袁伟恩; 王艳; 王鑫

    2010-01-01

    目的 探讨乳酸/羟基乙酸共聚物(PLGA)装载的促红细胞生成素(EPO)缓释微球(EPO-PLGA微球)经玻璃体腔注射对大鼠视神经挫伤模型中受损视网膜神经节细胞(RGC)的保护作用.方法 选取成年SD大鼠,建立视神经挫伤模型.建模后分别经玻璃体腔内注射含10 IU EPO的PLGA微球(EPO-PLGA组)、10 IU EPO(EPO组)、5 μl空白PLGA(PLGA组)、5 μl PBS(PBS组),另设未治疗组不予玻璃体腔注药.术后5 d和2周,做视网膜切片,对各组RGC凋亡情况行TUNEL检测;术后23 d,DiI上丘逆标RGC,并于术后4周处死大鼠,视网膜铺片观察各组RGC存活情况;每组各个时间点分别处死6只SD大鼠.采用方差分析对结果进行比较.结果 TUNEL检测显示,术后5 d和2周,各组均可见TUNEL阳性细胞,其中EPO-PLGA组和EPO组TUNEL阳性细胞显著减少,其细胞凋亡率明显少于PLGA组、PBS组及未治疗组.术后4周,视网膜铺片RGC计数显示,正常SD大鼠RGC密度为(2387.7±164.9)个/mm2,未治疗组为(748.3±58.8)个/mm2,EPO-PLGA组为(1296.7±157.6)个/mm2,EPO组为(1418.5±154.9)个/mm2,PLGA组为(821.7±52.1)个/mm2,PBS组为(804.4±86.4)个/mm2;可见EPO-PLGA组和EPO组较未治疗组细胞密度显著增高,具有明显的RGC保护作用(P均<0.01),而EPO-PLGA组和EPO组间差异无统计学意义(P=0.065).结论 EPO-PLGA缓释微球与EPO具有等效的RGC保护作用,这为进一步观察EPO-PLGA缓释微球的长效神经保护作用奠定了基础.%Objective To investigate the protective effect of erythropoietin (EPO) encapsulated in poly (L-lactic-co-glycolic acid) (PLGA) microspheres on damaged retinal ganglion cell (RGC) by intravitreal injection after optic nerve crush. Methods Adult SD rats were selected to establish an optic nerve crush model. Immediately after the crush, the animals received intravitreal doses of 10 IU EPO of EPO-PLGA microspheres (EPO-PLGA group), 10 IU EPO (EPO group), blank PLGA microshperes (PLGA group), and PBS (PBS

  1. Neuroprotective effects of erythropoietin posttreatment against kainate-induced excitotoxicity in mixed spinal cultures.

    Science.gov (United States)

    Yoo, Jong Yoon; Won, You Jin; Lee, Jong Hwan; Kim, Jong Uk; Sung, In Young; Hwang, Seung Jun; Kim, Mi Jung; Hong, Hea Nam

    2009-01-01

    Although the neuroprotective effects of erythropoietin (EPO) preconditioning are well known, the potential of postapplied EPO to protect neurons against excitotoxic injury has not been clearly established. Here we show that kainate (KA)-induced excitotoxicity, which plays a key role in secondary spinal cord injury, decreased neuron survival, inhibited neurite extension, and significantly reduced the expression of erythropoietin receptors (EpoR) in cultured spinal neurons. Posttreatment with EPO for 48 hr protected neurons against KA-induced injury, opposing KA-induced apoptosis and promoting regrowth of motoneuron neurites. These neuroprotective effects were paralleled by a restoration of EpoR expression. The importance of the EpoR signaling pathway was demonstrated using an EpoR blocking antibody, which neutralized the neuroprotective action of EPO posttreatment and prevented EPO-induced increases in EpoR expression. We also found that up-regulated EpoR stimulated the Janus kinase 2 (JAK2) pathway, which is known to facilitate neuronal growth and neurite regeneration. Although EPO posttreatment modestly attenuated KA-induced reactive gliosis in mixed neuron-glial cultures, blocking EpoR activity did not alter glial fibrillary acidic protein expression or astrocyte proliferation. In conclusion, 48 hr treatment with EPO following KA exposure induced EpoR-dependent protection against excitotoxic injury, demonstrating that preconditioning is not a prerequisite for neuroprotection by EPO. The neuroprotective effects of EPO posttreatment were mediated by an EpoR-dependent signaling pathway that possibly involves JAK2. The neuroprotective effect of EPO posttreatment against KA excitotoxicity appears to reflect direct effects on neurons and not indirect effects mediated by astrocytes.

  2. High-dose erythropoietin in patients with progressive multiple sclerosis

    DEFF Research Database (Denmark)

    Schreiber, Karen; Magyari, Melinda; Sellebjerg, Finn

    2017-01-01

    BACKGROUND: Erythropoietin (EPO) is a part of an endogenous neuroprotective system in the brain and may address pathophysiological mechanisms in progressive multiple sclerosis (MS). OBJECTIVE: To evaluate a treatment effect of EPO on progressive MS. METHODS: This was a single-center, randomized...

  3. Treatment of anemia of nephrotic syndrome with recombinant erythropoietin

    NARCIS (Netherlands)

    Gansevoort, RT; Vaziri, ND; deJong, PE

    Nephrotic syndrome has been recently shown to cause erythropoietin (EPO) deficiency in humans and experimental models. However, efficacy and safety of recombinant EPO (rEPO) in the treatment of the associated anemia has not been previously investigated. We report a patient with nephrotic syndrome

  4. Regulation of plasma erythropoietin in chronic liver disease

    Institute of Scientific and Technical Information of China (English)

    Frank Tacke; Tom Luedde; Michael P.Manns; Christian Trautwein

    2004-01-01

    @@ To the Editor: In a May-issue of the World Journal of Gastroenterology, there is a very interesting study by Bruno et al. on erythropoietin(EPO) levels in patients with chronic liver disease[1]. We have very recently reported a similar, but much larger study by Tacke et al.[2] on the role of EPO in chronic liver disease.

  5. The anemia of prematurity. Factors governing the erythropoietin response.

    Science.gov (United States)

    Stockman, J A; Garcia, J F; Oski, F A

    1977-03-24

    We performed sequential studies in 45 premature infants (birth weights less than 1500 g) from 7 to 120 days of age to determine factors governing the erythropoietin response to a declining hemoglobin concentration. The hemoglobin level and the plasma erythropoietin showed a significant inverse correlation (r = 0.50, P less than 0.001), as did, even more strikingly, the plasma erythropoietin response and the infants' oxygen-unloading capacity (r = 0.55, P less than 0.001). In infants with "right-shifted" oxygen-hemoglobin dissociation curves (hemoglobin F less than 30 per cent) hemoglobin levels fell 2 to 3 g per deciliter lower than those in infants with "left-shifted" curves (hemoglobin F greater than 60 per cent) before comparable erythropoietin responses occurred. It appears that premature infants respond appropriately to alterations in oxygen unloading capacity and that the position of the oxygen-hemoglobin dissociation curve and not the hemoglobin concentration alone has a major role in modulated erythropoiesis.

  6. Recombinant Human Erythropoietin in the Treatment of Acute Ischemic Stroke

    NARCIS (Netherlands)

    Ehrenreich, Hannelore; Weissenborn, Karin; Prange, Hilmar; Schneider, Dietmar; Weimar, Christian; Wartenberg, Katja; Schellinger, Peter D.; Bohn, Matthias; Becker, Harald; Wegrzyn, Martin; Jaehnig, Peter; Herrmann, Manfred; Knauth, Michael; Baehr, Mathias; Heide, Wolfgang; Wagner, Armin; Schwab, Stefan; Reichmann, Heinz; Schwendemann, Guenther; Dengler, Reinhard; Kastrup, Andreas; Bartels, Claudia

    2009-01-01

    Background and Purpose-Numerous preclinical findings and a clinical pilot study suggest that recombinant human erythropoietin (EPO) provides neuroprotection that may be beneficial for the treatment of patients with ischemic stroke. Although EPO has been considered to be a safe and well-tolerated dru

  7. Production and analysis of a biosimilar erythropoietin in Egypt

    Directory of Open Access Journals (Sweden)

    Ebied WM

    2014-05-01

    Full Text Available Wael M Ebied,1 Hytham M Ahmed,2 Fawzy A Elbarbry31SEDICO Pharmaceuticals, Merck & Co External Partner, 6th of October City, Cairo, 2Pharmaceutical Analysis Department, Faculty of Pharmacy, Damanhour University, Damanhour, Egypt; 3Pharmaceutical Sciences, School of Pharmacy, Pacific University Oregon, Hillsboro, OR, USAAbstract: Although management of chronic diseases has been a major challenge for health care systems in developed and developing countries, biopharmaceuticals have been successful in treating many life-threatening conditions. However, the high cost of these agents restricts their availability to countries where patients and/or health care systems are able to afford them. Licensing these biopharmaceuticals as biosimilars after expiration of their patents might increase access to such medicines at an affordable price in developing countries. South Egypt Drug Industries Company (SEDICO is an Egyptian pharmaceutical company that has had the opportunity to manufacture some of these drugs. SEDICO biotechnology products, such as insulin, erythropoietin, streptokinase, angiokinase, follicle-stimulating hormone, aprotinin, filgrastim, and somatropin, have been available on the Egyptian market for more than 6 years. For this paper, erythropoietin, which has been investigated over a number of years, was chosen as a representative example of SEDICO biotechnology products. Our findings confirm that SEDICO erythropoietin can compete with the originator epoetins on the Egyptian market with high quality and at a lower cost.Keywords: biosimilars, developing countries, insulin, human growth hormone, erythropoietin, epoetin, Egypt

  8. Recombinant erythropoietin found in seized blood bags from sportsmen.

    Science.gov (United States)

    Mallorquí, Joaquim; Segura, Jordi; de Bolòs, Carme; Gutiérrez-Gallego, Ricardo; Pascual, Jose A

    2008-02-01

    During an anti-doping investigation, the Spanish Guardia Civil confiscated blood bags from elite sportsmen. A novel immuno-purification method demonstrated that plasma samples with elevated erythropoietin (EPO) contained recombinant material (rEPO). This shows that rEPO is used before autologous blood transfusions and that rEPO analysis in plasma can be reliably addressed.

  9. Treatment of anemia of nephrotic syndrome with recombinant erythropoietin

    NARCIS (Netherlands)

    Gansevoort, RT; Vaziri, ND; deJong, PE

    1996-01-01

    Nephrotic syndrome has been recently shown to cause erythropoietin (EPO) deficiency in humans and experimental models. However, efficacy and safety of recombinant EPO (rEPO) in the treatment of the associated anemia has not been previously investigated. We report a patient with nephrotic syndrome an

  10. Erythropoietin--en ny terapi ved cerebral iskaemi?

    DEFF Research Database (Denmark)

    Kalialis, Louise Vennegaard; Olsen, Niels Vidiendal

    2003-01-01

    Erythropoietin (EPO) is a cytokine which is commonly associated with its central role in erythropoiesis. The clinical applications of the recombinant hormone are currently restricted to the treatment of anemia in renal failure and cancer. Recent studies, however, have suggested a new role for EPO...

  11. Effects of erythropoietin on advanced pulmonary vascular remodelling

    NARCIS (Netherlands)

    van Albada, M. E.; Sarvaas, G. J. du Marchie; Koster, J.; Houwertjes, M. C.; Berger, R. M. F.; Schoemaker, R. G.

    2008-01-01

    Erythropoietin (EPO) mobilises endothelial progenitor cells and promotes neovascularisation in heart failure. The present authors studied the effects of EPO on pulmonary vascular and cardiac remodelling in a model for flow-associated pulmonary arterial hypertension (PAH). PAH was induced in adult ma

  12. Erythropoietin Pretreatment of Transplanted Endothelial Colony-Forming Cells Enhances Recovery in a Cerebral Ischemia Model by Increasing Their Homing Ability: A SPECT/CT Study.

    Science.gov (United States)

    Garrigue, Philippe; Hache, Guillaume; Bennis, Youssef; Brige, Pauline; Stalin, Jimmy; Pellegrini, Lionel; Velly, Lionel; Orlandi, Francesca; Castaldi, Elena; Dignat-George, Françoise; Sabatier, Florence; Guillet, Benjamin

    2016-11-01

    Endothelial colony-forming cells (ECFCs) are promising candidates for cell therapy of ischemic diseases, as less than 10% of patients with an ischemic stroke are eligible for thrombolysis. We previously reported that erythropoietin priming of ECFCs increased their in vitro and in vivo angiogenic properties in mice with hindlimb ischemia. The present study used SPECT/CT to evaluate whether priming of ECFCs with erythropoietin could enhance their homing to the ischemic site after transient middle cerebral artery occlusion (MCAO) followed by reperfusion in rats and potentiate their protective or regenerative effect on blood-brain barrier (BBB) disruption, cerebral apoptosis, and cerebral blood flow (CBF). Rats underwent a 1-h MCAO followed by reperfusion and then 1 d after MCAO received an intravenous injection of either PBS (control, n = 10), PBS-primed ECFCs (ECFCPBS, n = 13), or erythropoietin-primed ECFCs (ECFCEPO, n = 10). ECFC homing and the effect on BBB disruption, cerebral apoptosis, and CBF were evaluated by SPECT/CT up to 14 d after MCAO. The results were expressed as median ± interquartile range for ipsilateral-to-contralateral ratio of the activity in middle cerebral artery-vascularized territories in each hemisphere. Histologic evaluation of neuronal survival and astrocytic proliferation was performed on day 14. Erythropoietin priming increased homing of ECFCs to the ischemic hemisphere (ECFCPBS, 111.0% ± 16.0%; ECFCEPO, 146.5% ± 13.3%). BBB disruption was significantly reduced (control, 387% ± 153%; ECFCPBS, 151% ± 46% [P < 0.05]; ECFCEPO, 112% ± 9% [P < 0.001]) and correlated negatively with ECFC homing (Pearson r = -0.6930, P = 0.0002). Cerebral apoptosis was significantly reduced (control, 161% ± 10%; ECFCPBS, 141% ± 9% [P < 0.05]; ECFCEPO,118% ± 5% [P < 0.001]) and correlated negatively with ECFC homing (r = -0.7251, P < 0.0001). CBF was significantly restored with ECFCs and almost totally so with erythropoietin priming (control, 72% ± 2

  13. Effects of systemic domestic recombinant human erythropoietin on HIF-1α expression in the retina in a rabbit model of acute high intraocular pressure

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Objective To observe the expression of hypoxia inducible factor-1α (HIF-1α) in the retina of rabbits with acute high intraocular pressure and to investigate the mechanism of systemic domestic recombinant human erythropoietin (rhEPO) protecting the retina from ischemia-reperfusion injury. Methods First,control group and model group were established in rabbit eyes. The acute high intraocular pressure model was established by saline perfusion into anterior chamber,and then hypodermic injection of domestic rhEP...

  14. Multiple Doses of Erythropoietin Impair Liver Regeneration by Increasing TNF-α, the Bax to Bcl-xL Ratio and Apoptotic Cell Death

    OpenAIRE

    Katja Klemm; Christian Eipel; Daniel Cantré; Kerstin Abshagen; Menger, Michael D.; Brigitte Vollmar

    2008-01-01

    BACKGROUND: Liver resection and the use of small-for-size grafts are restricted by the necessity to provide a sufficient amount of functional liver mass. Only few promising strategies to maximize liver regeneration are available. Apart from its erythropoiesis-stimulating effect, erythropoietin (EPO) has meanwhile been recognized as mitogenic, tissue-protective, and anti-apoptotic pleiotropic cytokine. Thus, EPO may support regeneration of hepatic tissue. METHODOLOGY: Rats undergoing 68% hepat...

  15. Contemporary uses of erythropoietin in pregnancy: a literature review.

    Science.gov (United States)

    Sienas, Laura; Wong, Tienne; Collins, Rebecca; Smith, James

    2013-08-01

    The objectives of this study were to survey the current research and provide an update on the uses and benefits of erythropoietin (EPO) in pregnancy and the postpartum period. A review of MEDLINE (1947 to present) was performed. Search terms included "erythropoietin," "pregnan*," with subheadings of "administration & dosage," "pharmacokinetics," "therapeutic use," "fetus," "fertility." We reviewed relevant articles published from 2002 to 2012. Case reports, observational studies, case-control studies, randomized controlled trials, retrospective analyses, animal studies, and review articles were included. Articles were selected if they discussed a use of EPO in pregnancy or the immediate postpartum period, as well as use of EPO in the neonate. Authors independently reviewed and extracted data. Of the 65 articles reviewed, 45 were included. Erythropoietin was used in the treatment of maternal anemia. Because of the molecule's large size, recombinant EPO does not appear to cross the placenta. No fetal morbidity or mortality was noted. Therefore, this is a safe therapy that can be used in pregnancy. Use of EPO may be especially important for women who decline blood products. Neonatal uses of EPO show benefit in the treatment of anemia due to blood type incompatibility. Erythropoietin is gaining popularity as a therapeutic option during pregnancy and the postpartum period. Further investigation is needed to establish a standard dosage and dosing interval. New studies reviewing its use in the neonate for perinatal-hypoxic injury and anemia due to blood type incompatibility provide exciting opportunities for further therapeutic use. Obstetricians and gynecologists, family physicians. After completing this CME activity, physicians should be better able to treat anemia in pregnancy, including causes and interventions; assess renal disease in pregnancy, targets of hemoglobin, precautions, and treatment considerations; and evaluate erythropoietin use in neonates and fetuses

  16. Prognostic significance of erythropoietin in pancreatic adenocarcinoma.

    Directory of Open Access Journals (Sweden)

    Thilo Welsch

    Full Text Available BACKGROUND: Erythropoietin (Epo administration has been reported to have tumor-promoting effects in anemic cancer patients. We investigated the prognostic impact of endogenous Epo in patients with pancreatic ductal adenocarcinoma (PDAC. METHODOLOGY: The clinico-pathological relevance of hemoglobin (Hb, n = 150, serum Epo (sEpo, n = 87 and tissue expression of Epo/Epo receptor (EpoR, n = 104 was analyzed in patients with PDAC. Epo/EpoR expression, signaling, growth, invasion and chemoresistance were studied in Epo-exposed PDAC cell lines. RESULTS: Compared to donors, median preoperative Hb levels were reduced by 15% in both chronic pancreatitis (CP, p<0.05 and PDAC (p<0.001, reaching anemic grade in one third of patients. While inversely correlating to Hb (r = -0.46, 95% of sEPO values lay within the normal range. The individual levels of compensation were adequate in CP (observed to predicted ratio, O/P = 0.99 but not in PDAC (O/P = 0.85. Strikingly, lower sEPO values yielding inadequate Epo responses were prominent in non-metastatic M0-patients, whereas these parameters were restored in metastatic M1-group (8 vs. 13 mU/mL; O/P = 0.82 vs. 0.96; p<0.01--although Hb levels and the prevalence of anemia were comparable. Higher sEpo values (upper quartile ≥ 16 mU/ml were not significantly different in M0 (20% and M1 (30% groups, but were an independent prognostic factor for shorter survival (HR 2.20, 10 vs. 17 months, p<0.05. The pattern of Epo expression in pancreas and liver suggested ectopic release of Epo by capillaries/vasa vasorum and hepatocytes, regulated by but not emanating from tumor cells. Epo could initiate PI3K/Akt signaling via EpoR in PDAC cells but failed to alter their functions, probably due to co-expression of the soluble EpoR isoform, known to antagonize Epo. CONCLUSION/SIGNIFICANCE: Higher sEPO levels counteract anemia but worsen outcome in PDAC patients. Further trials are required to clarify how overcoming a sEPO threshold

  17. Prognostic significance of erythropoietin in pancreatic adenocarcinoma.

    Science.gov (United States)

    Welsch, Thilo; Zschäbitz, Stefanie; Becker, Verena; Giese, Thomas; Bergmann, Frank; Hinz, Ulf; Keleg, Shereen; Heller, Anette; Sipos, Bence; Klingmüller, Ursula; Büchler, Markus W; Werner, Jens; Giese, Nathalia A

    2011-01-01

    Erythropoietin (Epo) administration has been reported to have tumor-promoting effects in anemic cancer patients. We investigated the prognostic impact of endogenous Epo in patients with pancreatic ductal adenocarcinoma (PDAC). The clinico-pathological relevance of hemoglobin (Hb, n = 150), serum Epo (sEpo, n = 87) and tissue expression of Epo/Epo receptor (EpoR, n = 104) was analyzed in patients with PDAC. Epo/EpoR expression, signaling, growth, invasion and chemoresistance were studied in Epo-exposed PDAC cell lines. Compared to donors, median preoperative Hb levels were reduced by 15% in both chronic pancreatitis (CP, p<0.05) and PDAC (p<0.001), reaching anemic grade in one third of patients. While inversely correlating to Hb (r = -0.46), 95% of sEPO values lay within the normal range. The individual levels of compensation were adequate in CP (observed to predicted ratio, O/P = 0.99) but not in PDAC (O/P = 0.85). Strikingly, lower sEPO values yielding inadequate Epo responses were prominent in non-metastatic M0-patients, whereas these parameters were restored in metastatic M1-group (8 vs. 13 mU/mL; O/P = 0.82 vs. 0.96; p<0.01)--although Hb levels and the prevalence of anemia were comparable. Higher sEpo values (upper quartile ≥ 16 mU/ml) were not significantly different in M0 (20%) and M1 (30%) groups, but were an independent prognostic factor for shorter survival (HR 2.20, 10 vs. 17 months, p<0.05). The pattern of Epo expression in pancreas and liver suggested ectopic release of Epo by capillaries/vasa vasorum and hepatocytes, regulated by but not emanating from tumor cells. Epo could initiate PI3K/Akt signaling via EpoR in PDAC cells but failed to alter their functions, probably due to co-expression of the soluble EpoR isoform, known to antagonize Epo. Higher sEPO levels counteract anemia but worsen outcome in PDAC patients. Further trials are required to clarify how overcoming a sEPO threshold ≥16 mU/ml by endogenous or exogenous means may predispose to or

  18. The protective effect of erythropoietin on renal function after releasing of bilateral ureter obstruction in young rat%促红细胞生成素对双侧输尿管梗阻-解除梗阻后幼鼠肾功能的保护作用

    Institute of Scientific and Technical Information of China (English)

    王焱; 任川川; 吕宇涛; 王庆伟; 谢佳丰; 崔林刚; 朱文; 文建国

    2016-01-01

    (147.3±4.9)、(141.5±5.7)、(136.7 ±4.3)mmol/L,组间差异有统计学意义(P<0.05).结论 EPO可促进BUO-R幼鼠肾功能及水盐处理功能的恢复,发挥肾脏保护作用.%Objective To investigate the protective effect of erythropoietin (EPO) on renal function after releasing of bilateral ureters obstruction (BUO-R) in young SD rats.Methods From October 2015 to June 2016,forty young SD rats were bought and equally divided into 4 groups randomly (BUO group,BUO-R group,BUO-R+ EPO group and Sham group;n =10) according to random number table.The BUO model was built by bilateral ureteral ligation.EPO (500 U/kg) was given to BUO-R + EPO rats immediately after releasing of BUO,and then repeated 2d,4d and 6d thereafter and the same volume of normal saline was simultaneously given to BUO-R rats.The Sham group was prepared in parallel by laparotomy and free dissection of bilateral ureters but not ligated.The urine samples were collected by metabolic cage 24h before death and then blood samples (1 ml) were collected from inferior vena cava.Results The urine osmolarity of Sham group was the highest [(1 794 ± 103) mOsm/kg],BUO-R + EPO group was (1 257 ± 82) mOsm/ kg,and BUO-R group was the lowest [(756 ±69) mOsm/kg];Whereas the urine output of Sham group was the lowest [(26 ± 5) μl/(min · kg)],BUO-R + EPO group was (48 ± 7) μl (min · kg),and BUO-R group was the highest [(71 ± 9) μl/(min · kg)];P < 0.05.The concentrations of urinary K +,Na + andcreatinine in BUO-R + EPO group were [(133.8 ± 5.8) mmol/L,(134.7 ± 4.9) mmol/L and (3 549 ±482) μmol/L] lower than those in Sham group [(154.7 ± 6.5) mmol/L,(149.3 ± 7.8) mmol/L and(4 537 ± 624) μmol/L],but higher than those in BUO-R group [(112.4 ± 7.2) mmol/L,(106.5 ± 6.3)mmol/L and (2 612 ±536) μmol/L],P <0.05.The concentrations of hematal K+,urea and creatinine inthree experimental groups were all higher than those in Sham group;of which the hematal K +,urea andcreatinine in BUO group were the

  19. Erythropoietin augments the cytokine response to acute endotoxin-induced inflammation in humans

    DEFF Research Database (Denmark)

    Hojman, Pernille; Taudorf, Sarah; Lundby, Carsten;

    2009-01-01

    Recent studies have shown that erythropoietin (EPO) offers protection against ischemia, hemorrhagic shock and systemic inflammation in many tissues and it has been suggested that EPO has anti-inflammatory effects. With the aim of investigating the potential acute anti-inflammatory effects of EPO...... receiving either (1) LPS alone, (2) EPO alone (15,000 IE of rHuEPO) or (3) EPO and LPS. Endotoxin administration alone induced a 3-, 12- and 5-fold increase in plasma concentrations of TNF-alpha, IL-6 and IL-10, respectively, 3h after LPS challenge. When EPO was given prior to a bolus injection...... with endotoxin, the levels of TNF-alpha and IL-6 were enhanced by 5- and 40-fold, respectively, whereas the endotoxin-induced increase in IL-10 response was not influenced by EPO. In contrast to our hypothesis, we find that EPO augments the acute inflammatory effect....

  20. Plasma immunoreactive erythropoietin in normal women studied sequentially during and after pregnancy.

    Science.gov (United States)

    Widness, J A; Clemons, G K; Garcia, J F; Schwartz, R

    1984-07-15

    Six healthy, nonanemic women with uncomplicated singleton pregnancies were sequentially studied for plasma immunoreactive erythropoietin levels, hematologic indices, and human placental lactogen. Mean group levels of erythropoietin as well as human placental lactogen were significantly increased (p less than 0.01) after 18 weeks' gestation compared to nonpregnant values (20 to 30 weeks post partum). However, individual responses of erythropoietin during pregnancy were found to be highly variable. There was a direct correlation of both maternal plasma erythropoietin and human placental lactogen with gestational age (p less than 0.001) but no detectable relation of erythropoietin with human placental lactogen levels. We speculate that the increase in erythropoietin levels during pregnancy acts as a trophic stimulus for effecting an increase in maternal red blood cell mass presumably to meet the increased metabolic (oxygen) demands of pregnancy.

  1. Anti-Erythropoietin Antibody Associated Pure Red Cell Aplasia Resolved after Liver Transplantation

    Directory of Open Access Journals (Sweden)

    Annie K. Hung

    2015-01-01

    Full Text Available Patients undergoing antiviral therapy for chronic hepatitis C often develop anemia secondary to ribavirin and interferon. Recombinant erythropoietin has been used to improve anemia associated with antiviral therapy and to minimize dose reductions, which are associated with decreased rates of sustained virologic response. A rare potential side effect of recombinant erythropoietin is anti-erythropoietin antibody associated pure red cell aplasia. In chronic kidney disease patients with this entity, there have been good outcomes associated with renal transplant and subsequent immunosuppression. In this case, a chronic liver disease patient developed anti-erythropoietin associated pure red cell aplasia and recovered after liver transplantation and immunosuppression. It is unclear whether it is the transplanted organ, the subsequent immunosuppression, or the combination that contributed to the response. In conclusion, anti-erythropoietin associated pure red cell aplasia is a serious complication of erythropoietin therapy, but this entity should not be considered a contraindication for solid organ transplantation.

  2. Cytoprotective effect of recombinant human erythropoietin produced in transgenic tobacco plants.

    Directory of Open Access Journals (Sweden)

    Farooqahmed S Kittur

    Full Text Available Asialo-erythropoietin, a desialylated form of human erythropoietin (EPO lacking hematopoietic activity, is receiving increased attention because of its broader protective effects in preclinical models of tissue injury. However, attempts to translate its protective effects into clinical practice is hampered by unavailability of suitable expression system and its costly and limit production from expensive mammalian cell-made EPO (rhuEPO(M by enzymatic desialylation. In the current study, we took advantage of a plant-based expression system lacking sialylating capacity but possessing an ability to synthesize complex N-glycans to produce cytoprotective recombinant human asialo-rhuEPO. Transgenic tobacco plants expressing asialo-rhuEPO were generated by stably co-expressing human EPO and β1,4-galactosyltransferase (GalT genes under the control of double CaMV 35S and glyceraldehyde-3-phosphate gene (GapC promoters, respectively. Plant-produced asialo-rhuEPO (asialo-rhuEPO(P was purified by immunoaffinity chromatography. Detailed N-glycan analysis using NSI-FTMS and MS/MS revealed that asialo-rhuEPO(P bears paucimannosidic, high mannose-type and complex N-glycans. In vitro cytoprotection assays showed that the asialo-rhuEPO(P (20 U/ml provides 2-fold better cytoprotection (44% to neuronal-like mouse neuroblastoma cells from staurosporine-induced cell death than rhuEPO(M (21%. The cytoprotective effect of the asialo-rhuEPO(P was found to be mediated by receptor-initiated phosphorylation of Janus kinase 2 (JAK2 and suppression of caspase 3 activation. Altogether, these findings demonstrate that plants are a suitable host for producing cytoprotective rhuEPO derivative. In addition, the general advantages of plant-based expression system can be exploited to address the cost and scalability issues related to its production.

  3. Synthesis of new series of N-3-[-{2-(substituted phenyl-4-oxo-5-(substituted benzylidene)-1,3-thiazolidine}-carbamyl]-propyl-2-aminothiazole and their biological importance

    Indian Academy of Sciences (India)

    Pushkal Samadhiya; Ritu Sharma; Santosh K Srivastava; Savitri D Srivastava

    2011-09-01

    Synthesis of new series of N-3-[-{2-(substituted phenyl-4-oxo-5-(substituted benzylidene)-1,3-thiazolidine}-carbamyl]-propyl-2-aminothiazole, 5(a-s) have been developed. The cycloaddition reaction of thioglycolic acid with N-{3-(substituted benzylidine-carbamyl)-propyl}-2-aminothiazole, 3(a-s) in the presence of anhydrous ZnCl2 afforded new heterocyclic compounds N1-3-[-{2-(substituted phenyl-4-oxo-1,3-thiazolidine}-carbamyl]-propyl-2-aminothiazole 4(a-s). The latter product on treatment with several selected substituted aromatic aldehydes in the presence of C2H5ONa undergoes Knoevenagel reaction to yield 5(a-s). The structure of compounds 1, 2, 3(a-s), 4(a-s) and 5(a-s) were confirmed by IR, 1H NMR, 13C NMR, FAB mass and chemical analysis. All final compounds were screened for their antimicrobial activity against some selected bacteria and fungi and antituberculosis study against M. tuberculosis, gave acceptable activity.

  4. Expression and analysis of the glycosylation properties of recombinant human erythropoietin expressed in Pichia pastoris

    OpenAIRE

    Ser Huy Teh; Mun Yik Fong; Zulqarnain Mohamed

    2011-01-01

    The Pichia pastoris expression system was used to produce recombinant human erythropoietin, a protein synthesized by the adult kidney and responsible for the regulation of red blood cell production. The entire recombinant human erythropoietin (rhEPO) gene was constructed using the Splicing by Overlap Extension by PCR (SOE-PCR) technique, cloned and expressed through the secretory pathway of the Pichia expression system. Recombinant erythropoietin was successfully expressed in P. pastoris. The...

  5. High glucose stimulates the expression of erythropoietin in rat glomerular epithelial cells

    OpenAIRE

    Lim, Seul Ki; Park, Soo Hyun

    2011-01-01

    It has been reported that the levels of erythropoietin are associated with diabetes mellitus. Glomerular epithelial cells, located in the renal cortex, play an important role in the regulation of kidney function and hyperglycemia-induced cell loss of glomerular epithelial cells is implicated in the onset of diabetic nephropathy. This study investigated the effect of high glucose on erythropoietin and erythropoietin receptor expression in rat glomerular epithelial cells. We found that 25 mM D-...

  6. Systemic administration of erythropoietin inhibits retinopathy in RCS rats.

    Directory of Open Access Journals (Sweden)

    Weiyong Shen

    Full Text Available OBJECTIVE: Royal College of Surgeons (RCS rats develop vasculopathy as photoreceptors degenerate. The aim of this study was to examine the effect of erythropoietin (EPO on retinopathy in RCS rats. METHODS: Fluorescein angiography was used to monitor retinal vascular changes over time. Changes in retinal glia and vasculature were studied by immunostaining. To study the effects of EPO on retinal pathology, EPO (5000 IU/kg was injected intraperitoneally in 14 week old normal and RCS rats twice a week for 4 weeks. Changes in the retinal vasculature, glia and microglia, photoreceptor apoptosis, differential expression of p75 neurotrophin receptor (p75NTR, pro-neurotrophin 3 (pro-NT3, tumour necrosis factor-α (TNFα, pigment epithelium derived factor (PEDF and vascular endothelial growth factor-A (VEGF-A, the production of CD34(+ cells and mobilization of CD34(+/VEGF-R2(+ cells as well as recruitment of CD34(+ cells into the retina were examined after EPO treatment. RESULTS: RCS rats developed progressive capillary dropout and subretinal neovascularization which were accompanied by retinal gliosis. Systemic administration of EPO stabilized the retinal vasculature and inhibited the development of focal vascular lesions. Further studies showed that EPO modulated retinal gliosis, attenuated photoreceptor apoptosis and p75NTR and pro-NT3 upregulation, promoted the infiltration of ramified microglia and stimulated VEGF-A expression but had little effect on TNFα and PEDF expression. EPO stimulated the production of red and white blood cells and CD34(+ cells along with effective mobilization of CD34(+/VEGF-R2(+ cells. Immunofluorescence study demonstrated that EPO enhanced the recruitment of CD34+ cells into the retina. CONCLUSIONS: Our results suggest that EPO has therapeutic potentials in treatment of neuronal and vascular pathology in retinal disease. The protective effects of EPO on photoreceptors and the retinal vasculature may involve multiple

  7. Effects of continuous erythropoietin receptor activator in sepsis-induced acute kidney injury and multi-organ dysfunction.

    Directory of Open Access Journals (Sweden)

    Camila E Rodrigues

    Full Text Available BACKGROUND: Despite advances in supportive care, sepsis-related mortality remains high, especially in patients with acute kidney injury (AKI. Erythropoietin can protect organs against ischemia and sepsis. This effect has been linked to activation of intracellular survival pathways, although the mechanism remains unclear. Continuous erythropoietin receptor activator (CERA is an erythropoietin with a unique pharmacologic profile and long half-life. We hypothesized that pretreatment with CERA would be renoprotective in the cecal ligation and puncture (CLP model of sepsis-induced AKI. METHODS: RATS WERE RANDOMIZED INTO THREE GROUPS: control; CLP; and CLP+CERA (5 µg/kg body weight, i.p. administered 24 h before CLP. At 24 hours after CLP, we measured creatinine clearance, biochemical variables, and hemodynamic parameters. In kidney tissue, we performed immunoblotting--to quantify expression of the Na-K-2Cl cotransporter (NKCC2, aquaporin 2 (AQP2, Toll-like receptor 4 (TLR4, erythropoietin receptor (EpoR, and nuclear factor kappa B (NF-κB--and immunohistochemical staining for CD68 (macrophage infiltration. Plasma interleukin (IL-2, IL-1β, IL-6, IL-10, interferon gamma, and tumor necrosis factor alpha were measured by multiplex detection. RESULTS: Pretreatment with CERA preserved creatinine clearance and tubular function, as well as the expression of NKCC2 and AQP2. In addition, CERA maintained plasma lactate at normal levels, as well as preserving plasma levels of transaminases and lactate dehydrogenase. Renal expression of TLR4 and NF-κB was lower in CLP+CERA rats than in CLP rats (p<0.05 and p<0.01, respectively, as were CD68-positive cell counts (p<0.01, whereas renal EpoR expression was higher (p<0.05. Plasma levels of all measured cytokines were lower in CLP+CERA rats than in CLP rats. CONCLUSION: CERA protects against sepsis-induced AKI. This protective effect is, in part, attributable to suppression of the inflammatory response.

  8. [Use of human recombinant erythropoietin in children with cancer].

    Science.gov (United States)

    Guyot, D; Margueritte, G

    2005-09-01

    Eighty percent of children with cancer suffer from anemia at the time of diagnosis. The physiopathology of anemia is complex. Although anemia can be life threatening, its consequences on the physical, psychological and social state of the child are often minimized. Blood transfusion is the main treatment of anemia: its efficacy is immediate but shortlasting, and it involves infectious and hemolytic risks. The human recombinant erythropoietin has been used for more than 25-years, and is often prescribed to adults with cancer and anemia. The human recombinant erythropoietin rHuEPO is nowadays used when blood transfusion is contra-indicated because of religious or cultural considerations, although several promising studies have been conducted about rHuEPO and children with cancer since 1996: it might be soon the preferential alternative treatment to anemia in children with cancer.

  9. Erythropoietin reduces the expression of myostatin in mdx dystrophic mice

    OpenAIRE

    D Feder; Rugollini, M.; Santomauro Jr,A.; de Oliveira, L. P.; Lioi,V.P.; R. dos Santos; Ferreira, L.G.; Nunes,M.T.; M.H. Carvalho; P.O. Delgado; A.A.S. Carvalho; Fonseca, F.L.A.

    2014-01-01

    Erythropoietin (EPO) has been well characterized as a renal glycoprotein hormone regulating red blood cell production by inhibiting apoptosis of erythrocyte progenitors in hematopoietic tissues. EPO exerts regulatory effects in cardiac and skeletal muscles. Duchenne muscular dystrophy is a lethal degenerative disorder of skeletal and cardiac muscle. in this study, we tested the possible therapeutic beneficial effect of recombinant EPO (rhEPO) in dystrophic muscles in mdx mice. Total strength ...

  10. Erythropoietin therapy in patients with chronic renal failure.

    OpenAIRE

    Pinevich, A J; Petersen, J.

    1992-01-01

    Symptomatic anemia is a common complication of chronic renal failure. Treatment is now possible with the availability of recombinant human erythropoietin (epoetin alfa). Previous experimental studies have suggested that correcting the anemia of chronic renal failure may be harmful in that renal failure may be accelerated. Although experience with this drug has been primarily restricted to its use in patients with end-stage renal disease, several recent trials have been reported in patients wi...

  11. Erythropoietin Promotes Hepatic Regeneration After Extended Liver Resection in Rats

    OpenAIRE

    Ariyakhagorn, Veeravorn

    2010-01-01

    Erythropoietin (EPO) hat sich in verschiedensten Gewebetypen als potenter Organ- Protektor und Regenerations-Stimulator erwiesen. Bis heute sind jedoch keinerlei Daten bezüglich des Einflusses von EPO auf die Leberregeration verfügbar. Wir haben daher in einem Rattenmodell den Einfluß von EPO auf die Leberregeneration nach 70%-iger Leberteilresektion untersucht. Hierbei wurden drei Studiengruppen gebildet: Gruppe 1 erhielt eine intraportalvenöse EPO-Gabe 30 Minuten vor Resektion (4000 U...

  12. Cisplatin-associated anemia: an erythropoietin deficiency syndrome.

    OpenAIRE

    Wood, P A; Hrushesky, W J

    1995-01-01

    Cisplatin-based therapy results in a cumulative anemia that is disproportionate to the effects on other blood cells. The severity of this treatment-induced anemia and the resultant transfusion requirement in cancer patients correlate with cisplatin-induced renal tubular dysfunction. Observed/expected serum erythropoietin (EPO) ratios decline with progressive cisplatin therapy and are proportionate to the degree of renal dysfunction. Recovery from anemia and of observed/expected serum EPO rati...

  13. Protective

    Directory of Open Access Journals (Sweden)

    Wessam M. Abdel-Wahab

    2013-10-01

    Full Text Available Many active ingredients extracted from herbal and medicinal plants are extensively studied for their beneficial effects. Antioxidant activity and free radical scavenging properties of thymoquinone (TQ have been reported. The present study evaluated the possible protective effects of TQ against the toxicity and oxidative stress of sodium fluoride (NaF in the liver of rats. Rats were divided into four groups, the first group served as the control group and was administered distilled water whereas the NaF group received NaF orally at a dose of 10 mg/kg for 4 weeks, TQ group was administered TQ orally at a dose of 10 mg/kg for 5 weeks, and the NaF-TQ group was first given TQ for 1 week and was secondly administered 10 mg/kg/day NaF in association with 10 mg/kg TQ for 4 weeks. Rats intoxicated with NaF showed a significant increase in lipid peroxidation whereas the level of reduced glutathione (GSH and the activity of superoxide dismutase (SOD, catalase (CAT, glutathione S-transferase (GST and glutathione peroxidase (GPx were reduced in hepatic tissues. The proper functioning of the liver was also disrupted as indicated by alterations in the measured liver function indices and biochemical parameters. TQ supplementation counteracted the NaF-induced hepatotoxicity probably due to its strong antioxidant activity. In conclusion, the results obtained clearly indicated the role of oxidative stress in the induction of NaF toxicity and suggested hepatoprotective effects of TQ against the toxicity of fluoride compounds.

  14. Evidence of Receptor-Mediated Elimination of Erythropoietin by Analysis of Erythropoietin Receptor mRNA Expression in Bone Marrow and Erythropoietin Clearance During Anemia

    OpenAIRE

    Nalbant, Demet; SALEH, Mohammad; Goldman, Frederic D.; Widness, John A.; Veng-Pedersen, Peter

    2010-01-01

    Erythropoietin (Epo) is the primary hormone that stimulates erythroid proliferation and differentiation through its cell surface receptor (EpoR) on erythroid progenitor cells. Previous studies have suggested that the bone marrow plays an important role in Epo's elimination. The changes in the EpoR mRNA levels and Epo's clearance in the bone marrow of 11 newborn lambs were studied to elucidate the role of EpoR in Epo's clearance under anemic conditions. Epo mRNA levels were measured by real-ti...

  15. Erythropoietin in the general population: reference ranges and clinical, biochemical and genetic correlates.

    Directory of Open Access Journals (Sweden)

    Niels Grote Beverborg

    Full Text Available Although erythropoietin has been used for decades in the treatment of anemia, data regarding endogenous levels in the general population are scarce. Therefore, we determined erythropoietin reference ranges and its clinical, biochemical and genetic associations in the general population.We used data from 6,777 subjects enrolled in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND study. Fasting venous blood samples were obtained in the morning from all participants from 2001-2003. Serum erythropoietin concentrations were measured using a fully automated chemiluminescent enzyme-labeled immunometric assay. A genome-wide association study was performed to identify genetic determinants.Mean age (± SD was 53 ± 12 years and 50% were female. Median (IQR erythropoietin concentrations were 7.6 (5.8-9.9 IU/L in men and 7.9 (6.0-10.6 IU/L in women. A strong positive correlation was found between erythropoietin and waist circumference, glucose and systolic blood pressure (all P < 0.05. In subjects with normal renal function there was a strong exponential relation between hemoglobin and erythropoietin, whereas in renal impairment (eGFR < 60 mL/min/1.73m² this relation was linear (men or absent (women (P < 0.001 for interaction. Single-nucleotide polymorphisms at the HBS1L-MYB locus were shown to be related to erythropoietin levels (P < 9x10-21, more significantly than other erythrocyte parameters.We provide age-specific reference ranges for endogenous serum erythropoietin. Erythropoietin levels are positively associated with the components of the metabolic syndrome, except cholesterol. We show that even mild renal failure blunts erythropoietin production and propose the HBS1L-MYB locus as a regulator of erythropoietin.

  16. Erythropoietin decreases carbon tetrachloride-induced hepatic fibrosis by inhibiting transforming growth factor-beta

    Institute of Scientific and Technical Information of China (English)

    Soo Young Park; Joo Young Lee; Won Young Tak; Young Oh Kweon; Mi Suk Lee

    2012-01-01

    Background In addition to hematopoietic effect,the erythropoietin is known as a multifunctional cytokine with anti-fibrosis and organ-protective activities.The purpose of this study was to evaluate the effect of recombinant human erythropoietin (rhEPO) on hepatic fibrosis and hepatic stellate cells (HSCs).Methods Carbon tetrachloride (CCl4) induced hepatic fibrosis mice models were used for in vivo study and HSCs line for in vitro study.CCl4 and rhEPO (0,200 or 1000 U/kg) was injected intraperitoneally in BALB/c mice three times a week for 4 weeks.Immunohistochemistry and immunoblotting were performed to evaluate expressions of transforming growth factor-β31 (TGF-β1),α-smooth muscle actin (α-SMA),and fibronectin in explanted liver.Immunoblotting of α-SMA,phophorylated Smad-2 and Smad-2/3 was performed in HSCs treated with TGF-β1 and/or rhEPO.Results Expressions of TGF-β1,α-SMA,and fibronectin were increased in CCl4 injected mice livers,but significantly attenuated by co-treatment with CCl4 and rhEPO.Co-treatment of rhEPO markedly suppressed fibrosis in Masson's trichrome compared with treatment of only CCl4.TGF-β1 increased phosphorylated α-SMA,Smad-2 expressions in HSCs,which were decreased by rhEPO co-treatment.Conclusions Treatment of rhEPO effectively suppressed fibrosis in CCl4-induced liver fibrosis mice models.Anti-fibrosis effect of rhEPO could be related to inhibition of TGF-β1 induced activation of HSCs.

  17. Transplantation of genetically engineered cardiac fibroblasts producing recombinant human erythropoietin to repair the infarcted myocardium

    Directory of Open Access Journals (Sweden)

    Ruvinov Emil

    2008-11-01

    Full Text Available Abstract Background Erythropoietin possesses cellular protection properties. The aim of the present study was to test the hypothesis that in situ expression of recombinant human erythropoietin (rhEPO would improve tissue repair in rat after myocardial infarction (MI. Methods and results RhEPO-producing cardiac fibroblasts were generated ex vivo by transduction with retroviral vector. The anti-apoptotic effect of rhEPO-producing fibroblasts was evaluated by co-culture with rat neonatal cardiomyocytes exposed to H2O2-induced oxidative stress. Annexin V/PI assay and DAPI staining showed that compared with control, rhEPO forced expression markedly attenuated apoptosis and improved survival of cultured cardiomyocytes. To test the effect of rhEPO on the infarcted myocardium, Sprague-Dawley rats were subjected to permanent coronary artery occlusion, and rhEPO-producing fibroblasts, non-transduced fibroblasts, or saline, were injected into the scar tissue seven days after infarction. One month later, immunostaining identified rhEPO expression in the implanted engineered cells but not in controls. Compared with non-transduced fibroblasts or saline injection, implanted rhEPO-producing fibroblasts promoted vascularization in the scar, and prevented cell apoptosis. By two-dimensional echocardiography and postmortem morphometry, transplanted EPO-engineered fibroblasts did not prevent left ventricular (LV dysfunction and adverse LV remodeling 5 and 9 weeks after MI. Conclusion In situ expression of rhEPO enhances vascularization and reduces cell apoptosis in the infarcted myocardium. However, local EPO therapy is insufficient for functional improvement after MI in rat.

  18. Impact of increased erythropoietin receptor expression and elevated serum erythropoietin levels on clinicopathological features and prognosis in renal cell carcinoma

    OpenAIRE

    ITO, KEIICHI; YOSHII, HIDEHIKO; ASANO, TAKAKO; HORIGUCHI, AKIO; Sumitomo, Makoto; Hayakawa, Masamichi; ASANO, TOMOHIKO

    2012-01-01

    Erythropoietin (EPO) expression and EPO receptor (EpoR) expression have been demonstrated in various malignant tumors. EPO-EpoR signaling can activate several downstream signal transduction pathways that enhance tumor aggressiveness. The present study was undertaken to evaluate the impact of overexpression of EpoR and elevated serum EPO (sEPO) levels on the clinicopathological features and prognosis of patients with renal cell carcinoma (RCC). EpoR expression was evaluated immunohistochemical...

  19. Evaluation of functional erythropoietin receptor status in skeletal muscle in vivo

    DEFF Research Database (Denmark)

    Christensen, Britt; Lundby, Carsten; Jessen, Niels;

    2012-01-01

    as activation of Epo signalling pathways (STAT5, MAPK, Akt, IKK) were analysed by western blotting. Changes in muscle protein profiles after prolonged erythropoietin treatment were evaluated by 2D gel-electrophoresis and mass spectrometry. The presence of the erythropoietin receptor in skeletal muscle...... related to an increased oxidative capacity in this tissue....

  20. Erythropoietin in the General Population : Reference Ranges and Clinical, Biochemical and Genetic Correlates

    NARCIS (Netherlands)

    Grote Beverborg, Niels; Verweij, Niek; Klip, IJsbrand T.; van der Wal, Haye H.; Voors, Adriaan A.; van Veldhuisen, Dirk J.; Gansevoort, Ron T.; Bakker, Stephan J. L.; van der Harst, Pim; van der Meer, Peter

    2015-01-01

    Background Although erythropoietin has been used for decades in the treatment of anemia, data regarding endogenous levels in the general population are scarce. Therefore, we determined erythropoietin reference ranges and its clinical, biochemical and genetic associations in the general population. M

  1. Late-onset blueberry muffin lesions following recombinant erythropoietin administration in a premature infant.

    Science.gov (United States)

    Pandey, Vishal; Dummula, Krishna; Fraga, Garth; Parimi, Prabhu

    2012-10-01

    Recombinant erythropoietin is being used in premature population for anemia of prematurity. It is considered very safe in this population, although risks are still being evaluated. We report the first case of dermal erythropoiesis as a side effect of recombinant erythropoietin in an extremely prematurely born infant presenting with late-onset blueberry muffin lesions.

  2. Human recombinant erythropoietin in the prevention and treatment of anemia of prematurity.

    Science.gov (United States)

    Ohls, Robin K

    2002-01-01

    Human recombinant erythropoietin has been studied extensively as treatment for a variety of anemias. Since in vitro studies showed the primary etiology of the anemia of prematurity to be insufficient serum erythropoietin concentrations, clinical trials have evaluated the administration of human recombinant erythropoietin to preterm infants to treat this indication. These studies were followed by pharmacokinetic determinations in animal models and preterm infants, which revealed that preterm infants required greater doses of human recombinant erythropoietin because of a more rapid clearance and greater volume of distribution. Recent studies have focused on the administration of human recombinant erythropoietin in the first weeks of life to alleviate the anemia caused by excessive phlebotomy losses, and to prevent the anemia of prematurity. In addition, human recombinant erythropoietin has been tried clinically in a variety of neonatal populations in an attempt to decrease or eliminate transfusions. Although much information has been accumulated about the clinical use of human recombinant erythropoietin in preterm infants over the last 15 years, many questions remain unanswered. The evolution of clinical practice in the care of extremely low birthweight infants continues to affect the number of transfusions. It is likely that human recombinant erythropoietin administration in combination with instituting rigorous transfusion guidelines and decreasing phlebotomy losses will have the greatest impact in decreasing transfusion requirements in all preterm and term neonates, regardless of the etiology of their anemia.

  3. Prognostic value of plasma erythropoietin on mortality in patients with chronic heart failure

    NARCIS (Netherlands)

    Van der Meer, P.; Voors, Adriaan; Lipsic, Erik; Smilde, Tom; van Gilst, W.H.; Van Veldhuisen, D.J.

    2004-01-01

    Objectives This study aimed to investigate the prognostic importance of plasma erythropoietin (EPO) levels in chronic heart failure (CHF) patients. Background Anemia is common and is associated with an impaired survival in patients with CHF. Erythropoietin is a hematopoietic growth factor,

  4. The effect of erythropoietin on platelet function and fibrinolysis in chronic renal failure

    DEFF Research Database (Denmark)

    Stenver, Doris Irene; Jeppesen, L; Nielsen, B

    1994-01-01

    The influence of erythropoietin therapy on platelet function and fibrinolysis was evaluated in 12 anemic hemodialysis patients. Six months of therapy with human erythropoietin (50 to 80 IU/kg initially) raised the hemoglobin level to 10.8 g/dl but did not increase platelet activity in vivo as mea...

  5. Recombinant erythropoietin in humans has a prolonged effect on circulating erythropoietin isoform distribution.

    Directory of Open Access Journals (Sweden)

    Niels Jacob Aachmann-Andersen

    Full Text Available The membrane-assisted isoform immunoassay (MAIIA quantitates erythropoietin (EPO isoforms as percentages of migrated isoforms (PMI. We evaluated the effect of recombinant human EPO (rhEPO on the distribution of EPO isoforms in plasma in a randomized, placebo-controlled, double-blinded, cross-over study. 16 healthy subjects received either low-dose Epoetin beta (5000 IU on days 1, 3, 5, 7, 9, 11 and 13; high-dose Epoetin beta (30.000 IU on days 1, 2 and 3 and placebo on days 5, 7, 9, 11 and 13; or placebo on all days. PMI on days 4, 11 and 25 was determined by interaction of N-acetyl glucosamine with the glycosylation dependent desorption of EPO isoforms. At day 25, plasma-EPO in both rhEPO groups had returned to values not different from the placebo group. PMI with placebo, reflecting the endogenous EPO isoforms, averaged 82.5 (10.3 % (mean (SD. High-dose Epoetin beta decreased PMI on days 4 and 11 to 31.0 (4.2% (p<0.00001 and 45.2 (7.3% (p<0.00001. Low-dose Epoetin beta decreased PMI on days 4 and 11 to 46.0 (12.8% (p<0.00001 and 46.1 (10.4% (p<0.00001. In both rhEPO groups, PMI on day 25 was still decreased (high-dose Epoetin beta: 72.9 (19.4% (p=0.029; low-dose Epoetin beta: 73.1 (17.8% (p=0.039. In conclusion, Epoetin beta leaves a footprint in the plasma-EPO isoform pattern. MAIIA can detect changes in EPO isoform distribution up til at least three weeks after administration of Epoetin beta even though the total EPO concentration has returned to normal.

  6. Recombinant erythropoietin in humans has a prolonged effect on circulating erythropoietin isoform distribution.

    Science.gov (United States)

    Aachmann-Andersen, Niels Jacob; Just Christensen, Søren; Lisbjerg, Kristian; Oturai, Peter; Meinild-Lundby, Anne-Kristine; Holstein-Rathlou, Niels-Henrik; Lundby, Carsten; Vidiendal Olsen, Niels

    2014-01-01

    The membrane-assisted isoform immunoassay (MAIIA) quantitates erythropoietin (EPO) isoforms as percentages of migrated isoforms (PMI). We evaluated the effect of recombinant human EPO (rhEPO) on the distribution of EPO isoforms in plasma in a randomized, placebo-controlled, double-blinded, cross-over study. 16 healthy subjects received either low-dose Epoetin beta (5000 IU on days 1, 3, 5, 7, 9, 11 and 13); high-dose Epoetin beta (30.000 IU on days 1, 2 and 3 and placebo on days 5, 7, 9, 11 and 13); or placebo on all days. PMI on days 4, 11 and 25 was determined by interaction of N-acetyl glucosamine with the glycosylation dependent desorption of EPO isoforms. At day 25, plasma-EPO in both rhEPO groups had returned to values not different from the placebo group. PMI with placebo, reflecting the endogenous EPO isoforms, averaged 82.5 (10.3) % (mean (SD)). High-dose Epoetin beta decreased PMI on days 4 and 11 to 31.0 (4.2)% (p<0.00001) and 45.2 (7.3)% (p<0.00001). Low-dose Epoetin beta decreased PMI on days 4 and 11 to 46.0 (12.8)% (p<0.00001) and 46.1 (10.4)% (p<0.00001). In both rhEPO groups, PMI on day 25 was still decreased (high-dose Epoetin beta: 72.9 (19.4)% (p=0.029); low-dose Epoetin beta: 73.1 (17.8)% (p=0.039)). In conclusion, Epoetin beta leaves a footprint in the plasma-EPO isoform pattern. MAIIA can detect changes in EPO isoform distribution up til at least three weeks after administration of Epoetin beta even though the total EPO concentration has returned to normal.

  7. Erythropoietin employs cell longevity pathways of SIRT1 to foster endothelial vascular integrity during oxidant stress.

    Science.gov (United States)

    Hou, Jinling; Wang, Shaohui; Shang, Yan Chen; Chong, Zhao Zhong; Maiese, Kenneth

    2011-08-01

    Given the cytoprotective ability of erythropoietin (EPO) in cerebral microvascular endothelial cells (ECs) and the invaluable role of ECs in the central nervous system, it is imperative to elucidate the cellular pathways for EPO to protect ECs against brain injury. Here we illustrate that EPO relies upon the modulation of SIRT1 (silent mating type information regulator 2 homolog 1) in cerebral microvascular ECs to foster cytoprotection during oxygen-glucose deprivation (OGD). SIRT1 activation which results in the inhibition of apoptotic early membrane phosphatidylserine (PS) externalization and subsequent DNA degradation during OGD becomes a necessary component for EPO protection in ECs, since inhibition of SIRT1 activity or diminishing its expression by gene silencing abrogates cell survival supported by EPO during OGD. Furthermore, EPO promotes the subcellular trafficking of SIRT1 to the nucleus which is necessary for EPO to foster vascular protection. EPO through SIRT1 averts apoptosis through activation of protein kinase B (Akt1) and the phosphorylation and cytoplasmic retention of the forkhead transcription factor FoxO3a. SIRT1 through EPO activation also utilizes mitochondrial pathways to prevent mitochondrial depolarization, cytochrome c release, and Bad, caspase 1, and caspase 3 activation. Our work identifies novel pathways for EPO in the vascular system that can govern the activity of SIRT1 to prevent apoptotic injury through Akt1, FoxO3a phosphorylation and trafficking, mitochondrial membrane permeability, Bad activation, and caspase 1 and 3 activities in ECs during oxidant stress.

  8. Erythropoietin retards DNA breakdown and prevents programmed death in erythroid progenitor cells

    Energy Technology Data Exchange (ETDEWEB)

    Koury, M.J.; Bondurant, M.C. (Vanderbilt Univ. Medical Center, Nashville, TN (USA) Veterans Administration Medical Center, Nashville, TN (USA))

    1990-04-20

    The mechanism by which erythropoietin controls mammalian erythrocyte production is unknown. Labeling experiments in vitro with ({sup 3}H) thymidine demonstrated DNA cleavage in erythroid progenitor cells that was accompanied by DNA repair and synthesis. Erythropoietin reduced DNA cleavage by a factor of 2.6. In the absence of erythropoietin, erythroid progenitor cells accumulated DNA cleavage fragments characteristic of those found in programmed cell death (apoptosis) by 2 to 4 hours and began dying by 16 hours. In the presence of erythropoietin, the progenitor cells survived and differentiated into reticulocytes. Thus, apoptosis is a major component of normal erythropoiesis, and erythropoietin controls erythrocyte production by retarding DNA breakdown and preventing apoptosis in erythroid progenitor cells.

  9. Erythropoietin has a mitogenic and positive chemotactic effect on endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Anagnostou, A.; Kessimian, N.; Steiner, M. (Memorial Hospital of Rhode Island, Pawtucket (USA) Brown Univ. Program in Medicine, Providence, RH (USA)); Lee, Eun Sun (Memorial Hospital of Rhode Island, Pawtucket (USA)); Levinson, R. (Brown Univ. Program in Medicine, Providence, RI (USA))

    1990-08-01

    Erythropoietin is known to be a hematopoietic growth factor with a singularly specific action on the proliferation and differentiation of erythroid progenitor cells. The authors have observed a dose-dependent proliferative action of human recombinant erythropoietin on human umbilical vein endothelial cells and bovine adrenal capillary endothelial cells. Binding studies with radioiodinated recombinant human erythropoietin revealed a large number ({approx}27,000) of an apparent single class of receptors with an affinity in the 10{sup {minus}9} M range. Linkage of the radiolabeled ligand to its receptor via a bifunctional crosslinking agent allowed them to identify an endothelial cell protein of 45 kDa as the principal receptor associated with this mitogenic effect of erythropoietin. Recombinant human erythropoietin also enhanced the migration of endothelial cells.

  10. Diffuse neonatal hemangiomatosis in a very low-birthweight infant treated with erythropoietin.

    Science.gov (United States)

    Okuno, Takashi; Tokuriki, Shuko; Yoshino, Tomomi; Tanaka, Nanae; Ohshima, Yusei

    2015-04-01

    Diffuse neonatal hemangiomatosis (DNH) is a rare condition characterized by the concomitant development of multiple cutaneous infantile hemangiomas (IH) and visceral hemangiomas. Recently, an association between erythropoietin treatment and an increased incidence of infantile hemangioma was noted. A Japanese male infant was born via cesarean section at 27 weeks of gestation. Following the commencement of erythropoietin treatment for anemia of prematurity, he developed multiple cutaneous hemangiomas, high cardiac output heart failure and hepatomegaly. Abdominal imaging indicated comorbidity of diffuse infantile hepatic hemannigomas, resulting in the final diagnosis of DNH. The discontinuation of erythropoietin treatment and long-term therapy with propranolol improved the hepatic lesions and cutaneous hemangiomas. The possibility of multiple organ involvement and the exacerbating effects of erythropoietin treatment should be considered in cases in which multiple cutaneous hemangiomas develop in preterm infants receiving erythropoietin treatment. © 2015 Japan Pediatric Society.

  11. Erythropoietin reduces storage lesions and decreases apoptosis indices in blood bank red blood cells

    Science.gov (United States)

    Penuela, Oscar Andrés; Palomino, Fernando; Gómez, Lina Andrea

    2015-01-01

    Background Recent evidence shows a selective destruction of the youngest circulating red blood cells (neocytolysis) trigged by a drop in erythropoietin levels. Objective The aim of this study was to evaluate the effect of recombinant human erythropoietin beta on the red blood cell storage lesion and apoptosis indices under blood bank conditions. Methods Each one of ten red blood cell units preserved in additive solution 5 was divided in two volumes of 100 mL and assigned to one of two groups: erythropoietin (addition of 665 IU of recombinant human erythropoietin) and control (isotonic buffer solution was added). The pharmacokinetic parameters of erythropoietin were estimated and the following parameters were measured weekly, for six weeks: Immunoreactive erythropoietin, hemolysis, percentage of non-discocytes, adenosine triphosphate, glucose, lactate, lactate dehydrogenase, and annexin-V/esterase activity. The t-test or Wilcoxon's test was used for statistical analysis with significance being set for a p-value 6 weeks under blood bank conditions, with persistent supernatant concentrations of erythropoietin during the entire storage period. Adenosine triphosphate was higher in the Erythropoietin Group in Week 6 (4.19 ± 0.05 μmol/L vs. 3.53 ± 0.02 μmol/L; p-value = 0.009). The number of viable cells in the Erythropoietin Group was higher than in the Control Group (77% ± 3.8% vs. 71% ± 2.3%; p-value <0.05), while the number of apoptotic cells was lower (9.4% ± 0.3% vs. 22% ± 0.8%; p-value <0.05). Conclusions Under standard blood bank conditions, an important proportion of red blood cells satisfy the criteria of apoptosis. Recombinant human erythropoietin beta seems to improve storage lesion parameters and mitigate apoptosis. PMID:26969770

  12. Effect of erythropoietin on Glasgow Coma Scale and Glasgow Outcome Sale in patient with diffuse axonal injury

    Directory of Open Access Journals (Sweden)

    Saeid Abrishamkar

    2012-01-01

    Full Text Available Background: Erythropoietin (EPO as a major stimulator of red blood cell (RBC production play a key role on brain protection and have a caring effect on neurons from hypoxic or traumatic injury. The objective of this trial was to study the safety and efficacy of recombinant human EPO (rhEPO on level of consciousness and other outcomes in patient with post traumatic diffuse axonal injury (PTDAI. Methods: In a controlled double-blind randomized clinical trial, 54 patients aged 20-47 years were randomly allocated to 2 groups. Subjects in intervention group (n = 27 received 2000U open-label rhEPO (Erythropoietin-ί; Roche, Gren-zach-Wyhlen, Germany subcutaneously for six doses in two weeks (on days: 2, 4, 6, 8 and 10. The efficacies of the intervention were evaluated by GCS (Glasgow Coma Scale and GOS (Glasgow Outcome Scale. Results: The patients that were treated by rhEPO improved earlier with the difference between the treatment groups occurring on the day 10 (score differences of 9.6 for GCS and 1.9 for GOS. The better course of the rhEPO-treated patients continued throughout the remaining study period. The hematocrit and red blood cell counts did not increase to levels exceeding the normal range in rhEPO patients. Conclusions: Intravenous EPO was well tolerated in diffuse axonal injury and was associated with an improvement in patients′ outcome in 2 weeks.

  13. Hemopoietic cell precursor responses to erythropoietin in plasma clot cultures

    Energy Technology Data Exchange (ETDEWEB)

    Kennedy, W.L.

    1979-01-01

    The time dependence of the response of mouse bone marrow cells to erythropoietin (Ep) in vitro was studied. Experiments include studies on the Ep response of marrow cells from normal, plethoric, or bled mice. Results with normal marrow reveal: (1) Not all erythroid precursors (CFU-E) are alike in their response to Ep. A significant number of the precursors develop to a mature erythroid colony after very short Ep exposures, but they account for only approx. 13% of the total colonies generated when Ep is active for 48 hrs. If Ep is active more than 6 hrs, a second population of erythroid colonies emerges at a nearly constant rate until the end of the culture. Full erythroid colony production requires prolonged exposure to erythropoietin. (2) The longer erythropoietin is actively present, the larger the number of erythroid colonies that reach 17 cells or more. Two distinct populations of immediate erythroid precursors are also present in marrow from plethoric mice. In these mice, total colony numbers are equal to or below those obtained from normal mice. However, the population of fast-responding CFU-E is consistently decreased to 10 to 20% of that found in normal marrow. The remaining colonies are formed from plethoric marrow at a rate equal to normal marrow. With increasing Ep exposures, the number of large colonies produced increases. From the marrow of bled mice, total erythroid colony production is equal to or above that of normal marrow. Two populations of colony-forming cells are again evident, with the fast-responding CFU-E being below normal levels. The lack of colonies from this group was compensated in bled mice by rapid colony production in the second population. A real increase in numbers of precursors present in this pool increased the rate of colony production in culture to twice that of normal marrow. The number of large colonies obtained from bled mice was again increased as the Ep exposure was lengthened. (ERB)

  14. Investigation of purification process stresses on erythropoietin peptide mapping profile.

    Science.gov (United States)

    Sepahi, Mina; Kaghazian, Hooman; Hadadian, Shahin; Norouzian, Dariush

    2015-01-01

    Full compliance of recombinant protein peptide mapping chromatogram with the standard reference material, is one of the most basic quality control tests of biopharmaceuticals. Changing a single amino acid substitution or side chain diversity for a given peptide changes protein hydrophobicity and causes peak shape or retention time alteration in a peptide mapping assay. In this work, the effect of different stresses during the recombinant erythropoietin (EPO) purification process, including pH 4, pH 5, and room temperature were checked on product peptide mapping results. Cell culture harvest was purified under stress by different chromatographic techniques consisting of gel filtration, anionic ion exchange, concentration by ultrafiltration, and high resolution size exclusion chromatography. To induce more pH stresses, the purified EPO was exposed to pH stress 4 and 5 by exchanging buffer by a 10 KDa dialysis sac overnight. The effects of temperature and partial deglycosylation (acid hydrolysis) on purified EPO were also studied by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and peptide mapping analysis. Removal of sialic acid by mild hydrolysis was performed by exposure to two molar acetic acid at 80°C for 3 h. No significant effect was observed between intact and stressed erythropoietin peptide mapping profiles and SDS-PAGE results. To validate the sensibility of the technique, erythropoietin was partially acid hydrolyzed and significant changes in the chromatographic peptide map of the intact form and a reduction on its molecular weight were detected, which indicates some partial deglycosylation. Purification process does not alter the peptide mapping profile and purification process stresses are not the cause of peptide mapping noncompliance.

  15. Functional significance of erythropoietin receptor on tumor cells

    Institute of Scientific and Technical Information of China (English)

    Kodetthoor B Udupa

    2006-01-01

    Erythropoietin (Epo) is the regulator of red blood cell formation. Its receptor (EpoR) is now found in many cells and tissues of the body. EpoR is also shown to occur in tumor cells and Epo enhances the proliferation of these cells through cell signaling. EpoR antagonist can reduce the growth of the tumor in vivo. In view of our current knowledge of Epo, its recombinant forms and receptor,use of Epo in cancer patients to enhance the recovery of hematocrit after chemotherapy treatment has to be carefully evaluated.

  16. Recombinant Human Erythropoietin for Treating Treatment-Resistant Depression

    DEFF Research Database (Denmark)

    Miskowiak, Kamilla W; Vinberg, Maj; Christensen, Ellen M;

    2014-01-01

    Pharmacological treatments for depression have insufficient efficacy in 30-40% of patients and fail to reverse cognitive deficits. Erythropoietin (EPO) has neurotrophic actions and aids neurocognitive function. The aim of this exploratory study was to determine whether recombinant human EPO...... improves mood and memory in treatment-resistant depression. Forty treatment-resistant depressed unipolar patients with Hamilton Depression Rating Scale-17 (HDRS-17) score ≥ 17 were randomized to eight weekly EPO (Eprex; 40,000 IU) or saline infusions in a double-blind, placebo-controlled, parallel...

  17. Erythropoietin in liver cirrhosis: Two questions without answers

    Institute of Scientific and Technical Information of China (English)

    Cosimo Marcello Bruno; Claudio Sciacca; Danila Cilio; Gaetano Bertino; Rinaldo Pellicano

    2005-01-01

    @@ TO THE EDITOR In a recent paper[1], and in a subsequent letter[2], Tacke et al. reported the investigation of plasma erythropoietin (Epo) levels in patients affected by chronic liver disease of various aetiologies. The authors also compared[2] their data to our previous work[3]. The results show a substantial agreement but also some important differences between the two works. We would like to highlight, from our point of view, this issue. Both the papers demonstrated increased Epo values in anaemic cirrhotic subjects when compared to healthy controls and non-anemic patients with liver disease.

  18. Effects of intraosseous erythropoietin during hemorrhagic shock in swine.

    Directory of Open Access Journals (Sweden)

    Vesna Borovnik-Lesjak

    Full Text Available OBJECTIVE: To determine whether erythropoietin given during hemorrhagic shock (HS ameliorates organ injury while improving resuscitation and survival. METHODS: Three series of 24 pigs each were studied. In an initial series, 50% of the blood volume (BV was removed in 30 minutes and normal saline (threefold the blood removed started at minute 90 infusing each third in 30, 60, and 150 minutes with shed blood reinfused at minute 330 (HS-50BV. In a second series, the same HS-50BV protocol was used but removing an additional 15% of BV from minute 30 to 60 (HS-65BV. In a final series, blood was removed as in HS-65BV and intraosseous vasopressin given from minute 30 (0.04 U/kg min(-1 until start of shed blood reinfusion at minute 150 (HS-65BV+VP. Normal saline was reduced to half the blood removed and given from minute 90 to 120 in half of the animals. In each series, animals were randomized 1:1 to receive erythropoietin (1,200 U/kg or control solution intraosseously after removing 10% of the BV. RESULTS: In HS-50BV, O2 consumption remained near baseline yielding minimal lactate increases, 88% resuscitability, and 60% survival at 72 hours. In HS-65BV, O2 consumption was reduced and lactate increased yielding 25% resuscitability. In HS-65BV+VP, vasopressin promoted hemodynamic stability yielding 92% resuscitability and 83% survival at 72 hours. Erythropoietin did not affect resuscitability or subsequent survival in any of the series but increased interleukin-10, attenuated lactate increases, and ameliorated organ injury based on lesser troponin I, AST, and ALT increases and lesser neurological deficits in the HS-65BV+VP series. CONCLUSIONS: Erythropoietin given during HS in swine failed to alter resuscitability and 72 hour survival regardless of HS severity and concomitant treatment with fluids and vasopressin but attenuated acute organ injury. The studies also showed the efficacy of vasopressin and restrictive fluid resuscitation for hemodynamic

  19. Pharmacokinetics of erythropoietin in intact and anephric dogs

    Energy Technology Data Exchange (ETDEWEB)

    Fu, J.S.; Lertora, J.J.; Brookins, J.; Rice, J.C.; Fisher, J.W.

    1988-06-01

    The present studies were performed to determine the pharmacokinetic parameters of erythropoietin in intact and anephric dogs by use of unlabeled crude native erythropoietin (nEp) and iodine 125-labeled purified recombinant erythropoietin (rEp) given by intravenous infusion for 15 minutes. Sephadex G-75 gel filtration was used to confirm that the 125I-rEp molecule remained iodinated in dog plasma during the 24-hour period of these studies. The plasma disappearance of erythropoietin conformed to a biexponential equation for both nEp and 125I-rEp, with the central compartment being larger than the peripheral compartment. The mean distribution half-life of 75.3 +/- 21.2 minutes for nEp was significantly (p less than 0.05) longer than that of 125I-rEp (23.7 +/- 5.0 minutes) in intact dogs. The intercompartmental clearance (CIic) for nEp (0.018 +/- 0.006 L/kg/hr) was significantly smaller than that of 125I-rEp (0.068 +/- 0.018 L/kg/hr) in intact dogs (p less than 0.05). There were no significant differences in apparent volume of distribution, elimination half-life, and elimination clearance (CIe) for nEp and rEp in intact dogs. The mean elimination half-life for 125I-rEp in intact dogs (9.0 +/- 0.6 hours) and anephric dogs (13.8 +/- 1.4 hours) was significantly different (p less than 0.05). The CIe for 125I-rEp in anephric dogs (0.008 +/- 0.001 L/kg/hr) was significantly (p less than 0.05) smaller than that of 125I-rEp in intact dogs (0.011 +/- 0.001 L/kg/hr). There were no significant differences in apparent volume of distribution, distribution half-life, and CIic for 125I-rEp in intact and anephric dogs.

  20. Skeletal muscle alterations and exercise performance decrease in erythropoietin-deficient mice: a comparative study

    Directory of Open Access Journals (Sweden)

    Mille-Hamard Laurence

    2012-06-01

    Full Text Available Abstract Background Erythropoietin (EPO is known to improve exercise performance by increasing oxygen blood transport and thus inducing a higher maximum oxygen uptake (VO2max. Furthermore, treatment with (or overexpression of EPO induces protective effects in several tissues, including the myocardium. However, it is not known whether EPO exerts this protective effect when present at physiological levels. Given that EPO receptors have been identified in skeletal muscle, we hypothesized that EPO may have a direct, protective effect on this tissue. Thus, the objectives of the present study were to confirm a decrease in exercise performance and highlight muscle transcriptome alterations in a murine EPO functional knock-out model (the EPO-d mouse. Methods We determined VO2max peak velocity and critical speed in exhaustive runs in 17 mice (9 EPO-d animals and 8 inbred controls, using treadmill enclosed in a metabolic chamber. Mice were sacrificed 24h after a last exhaustive treadmill exercise at critical speed. The tibialis anterior and soleus muscles were removed and total RNA was extracted for microarray gene expression analysis. Results The EPO-d mice’s hematocrit was about 50% lower than that of controls (p  1.4 and 115 were strongly down-regulated (normalized ratio  Conclusions Our results showed that the lack of functional EPO induced a decrease in the aerobic exercise capacity. This decrease was correlated with the hematocrit and reflecting poor oxygen supply to the muscles. The observed alterations in the muscle transcriptome suggest that physiological concentrations of EPO exert both direct and indirect muscle-protecting effects during exercise. However, the signaling pathway involved in these protective effects remains to be described in detail.

  1. Erythropoietin (EPO) increases myelin gene expression in CG4 oligodendrocyte cells through the classical EPO receptor.

    Science.gov (United States)

    Cervellini, Ilaria; Annenkov, Alexander; Brenton, Thomas; Chernajovsky, Yuti; Ghezzi, Pietro; Mengozzi, Manuela

    2013-08-28

    Erythropoietin (EPO) has protective effects in neurodegenerative and neuroinflammatory diseases, including in animal models of multiple sclerosis, where EPO decreases disease severity. EPO also promotes neurogenesis and is protective in models of toxic demyelination. In this study, we asked whether EPO could promote neurorepair by also inducing remyelination. In addition, we investigated whether the effect of EPO could be mediated by the classical erythropoietic EPO receptor (EPOR), since it is still questioned if EPOR is functional in nonhematopoietic cells. Using CG4 cells, a line of rat oligodendrocyte precursor cells, we found that EPO increases the expression of myelin genes (myelin oligodendrocyte glycoprotein [MOG] and myelin basic protein [MBP]). EPO had no effect in wild-type CG4 cells, which do not express EPOR, whereas it increased MOG and MBP expression in cells engineered to overexpress EPOR (CG4-EPOR). This was reflected in a marked increase in MOG protein levels, as detected by Western blot. In these cells, EPO induced by 10-fold the early growth response gene 2 (Egr2), which is required for peripheral myelination. However, Egr2 silencing with a siRNA did not reverse the effect of EPO, indicating that EPO acts through other pathways. In conclusion, EPO induces the expression of myelin genes in oligodendrocytes and this effect requires the presence of EPOR. This study demonstrates that EPOR can mediate neuroreparative effects.

  2. Studying of the standardization principles of pharmacological activity of recombinant erythropoietin preparations

    Directory of Open Access Journals (Sweden)

    A. K. Yakovlev

    2016-01-01

    Full Text Available Analysis of the publications devoted to the structure, functions, mechanism of action of erythropoietin is given in the article. Erythropoietin preparations derived from recombinant DNA technology are a mixture of isoforms with different biological activity, which determine the biological properties pharmacological activity, pharmacokinetics, efficacy and safety of medicinal product. Erythropoietin preparations derived by using recombinant DNA technology are a mixture of isoforms with different biological activity, that determine the biological properties, pharmacological activity, pharmacokinetics, safety and therapeutic efficacy of the drug. However, at production of erythropoietin, its pharmacological activity is controlled only by the ability to stimulate erythropoiesis, despite the multiplicity of different directions of action of drugs erythropoietin. The drug is dispensed and applied on this indicator. The international reference standard, a European reference biologic drug or calibrated by him enterprise standard samples are used by manufacturers to assess the quality of erythropoietin in the Russian Federation. The urgency of developing domestic standard samples for the evaluation of biological activity and physico-chemical characteristics of erythropoietin preparations produced by recombinant DNA technology.

  3. The effect of erythropoietin on healing of obstructive vs nonobstructive left colonic anastomosis: an experimental study

    Directory of Open Access Journals (Sweden)

    Renda Nurten

    2007-05-01

    Full Text Available Abstract Background Anastomotic leakage is an important problem following primary resection in the left colon and is even more prominent when obstruction is present. We aimed to evaluate the possible effects of erythropoietin on the healing of anastomosis under both obstructive and non-obstructive states. Methods Forty male Wistar albino rats were divided into four groups. In group I, two cm left colonic resection and primary anastomosis were done. In group II, left colon were completely ligated and 24 hours later animals were re-operated for segmental resection. The same procedures were performed for rats in group III and IV in respect to group I and II and, 500 IU/kg a day erythropoietin were given in the latter two groups for seven days. For the quantative description of anastomotic healing mechanical, biochemical and histopathological parameters were employed on the seventh day and the animals were sacrificied. Results Although erythropoietin had positive effects on bursting pressure in group IV when compared to group II, it has no effect in group III. Despite the increased tissue hydroxyproline levels in group IV, erythropoietin failed to show any effects in group III. Erythropoietin had positive effects on neovascularization, fibroblast proliferiation and storage of collagen in group IV. Conclusion We failed to find any direct and evident effects of erythropoietin on healing of left colonic anastomosis. On the other hand, erythropoietin might prevent negative effects of obstruction on healing.

  4. Serum immunoreactive erythropoietin and red blood cell mass during pregnancy in conscious rats.

    Science.gov (United States)

    Del Valle, G O; Mosher, M D; Conrad, K P

    1993-08-01

    Serum erythropoietin concentration increases during human pregnancy and presumably accounts for expansion of red blood cell mass. The mechanism(s) underlying gestational changes of serum erythropoietin are unknown. Moreover, if erythropoietin synthesis increases, then the organ(s) questions about erythropoietin in pregnancy, we first set out to establish an animal model. Chronically instrumented, conscious unrestrained rats were studied. 51Cr-labeled red blood cells and radioimmunoassay were used to assess red blood cell mass and serum erythropoietin, respectively. Except for a lower hematocrit (P pregnancy rats were comparable to those measured in virgin control animals. Significant increases in total blood volume, plasma volume, and red blood cell mass were observed by gestational day 13 (midpregnancy) when compared with virgin control rats. These changes were even more pronounced on gestational day 20. Serum immunoreactive erythropoietin was also significantly increased at both of these stages of pregnancy. We conclude that the gravid rat is a reliable animal model of human gestation in which to further investigate erythropoietin in pregnancy.

  5. Expression of adrenomedullin in rats after spinal cord injury and intervention effect of recombinant human erythropoietin

    Science.gov (United States)

    Zhao, Liang; Jing, Yu; Qu, Lin; Meng, Xiangwei; Cao, Yang; Tan, Huibing

    2016-01-01

    The expression of adrenomedullin (ADM) in injured tissue of rat spinal cord was observed and the effect of recombinant human erythropoietin was analyzed. A total of 45 Sprague-Dawley rats were selected and divided into 3 equal groups including, a sham-operation group in which rats received an excision of vertebral plate; a spinal cord injury model group and a recombinant human erythropoietin group in which rats with spinal cord injury received a caudal vein injection of 300 units recombinant human erythropoietin after injury. Hematoxylin and eosin staining was performed to observe the spinal cord injury conditions. Immunohistochemical staining was performed to observe the expression of ADM. Pathologic changes in the group of recombinant human erythropoietin at various times were significantly less severe than those in the group of spinal cord injury model. The expression of ADM was increased particularly in the group of recombinant human erythropoietin (P<0.01). The improved Tarlov scores of the group of spinal cord injury model and the group of recombinant human erythropoietin were lower than those of the sham-operation group at 3, 6 and 9 days (P<0.01). Thus, the recombinant human erythropoietin is capable of alleviating the secondary injury of spinal cord. One of the mechanisms may be achieved by promoting the increase of ADM expression. PMID:28101163

  6. Erythropoietin improves operant conditioning and stability of cognitive performance in mice

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    Ehrenreich Hannelore

    2009-07-01

    Full Text Available Abstract Background Executive functions, learning and attention are imperative facets of cognitive performance, affected in many neuropsychiatric disorders. Recently, we have shown that recombinant human erythropoietin improves cognitive functions in patients with chronic schizophrenia, and that it leads in healthy mice to enhanced hippocampal long-term potentiation, an electrophysiological correlate of learning and memory. To create an experimental basis for further mechanistic insight into erythropoietin-modulated cognitive processes, we employed the Five Choice Serial Reaction Time Task. This procedure allows the study of the effects of erythropoietin on discrete processes of learning and attention in a sequential fashion. Results Male mice were treated for 3 weeks with erythropoietin (5,000 IU/kg versus placebo intraperitoneally every other day, beginning at postnatal day 28. After termination of treatment, mice were started on the Five Choice Serial Reaction Time Task, with daily training and testing extending to about 3 months. Overall, a significantly higher proportion of erythropoietin-treated mice finished the task, that is, reached the criteria of adequately reacting to a 1.0 sec flash light out of five arbitrarily appearing choices. During acquisition of this capability, that is, over almost all sequential training phases, learning readouts (magazine training, operant and discriminant learning, stability of performance were superior in erythropoietin-treated versus control mice. Conclusion Early erythropoietin treatment leads to lasting improvement of cognitive performance in healthy mice. This finding should be exploited in novel treatment strategies for brain diseases.

  7. Anti-carbamylated protein antibodies in unaffected first-degree relatives of rheumatoid arthritis patients: lack of correlation with anti-cyclic citrullinated protein antibodies and rheumatoid factor.

    Science.gov (United States)

    Alessandri, C; Bartosiewicz, I; Pendolino, M; Mancini, R; Colasanti, T; Pecani, A; Morello, F; Mastrangelo, A; Sabatinelli, D; Riccieri, V; Di Franco, M; Ceccarelli, F; Perricone, C; Conti, F; Valesini, G

    2015-01-01

    To investigate the prevalence of anti-carbamylated protein antibodies (anti-CarP) in the healthy first-degree relatives (HFDRs) of patients with rheumatoid arthritis (RA). We enrolled 141 HFDRs of 63 patients with RA diagnosed accordingly to the 2010 ACR/EULAR criteria. Fifty-six normal healthy subjects (NHS), sex- and age-matched, served as controls. Anti-CarP IgG, anti-cyclic citrullinated peptide antibody (anti-CCP) IgG and rheumatoid factors (RF) isotypes (IgG, IgA, IgM) were assessed by solid-phase ELISA. Anti-CarP were detectable in 13 HFDRs (9.2%), anti-CCP in 9 (6.3%), IgG-RF in 10 (7%), IgA-RF in 17 (12%), and IgM-RF in 13 (9.2%) HFDRs. Twenty-nine (46%) RA patients were positive for anti-CarP, 31 (49.2%) for anti-CCP, and 34 (53.9%) for RF. One NHS (1.7%) resulted positive for anti-CarP, none for anti-CCP and RF. Anti-CarP showed significantly higher serum levels in RA and HFDRs than in NHS (pautoantibodies tested in the HFDRs. Anti-CarP can be found in the sera of HFDRs of RA patients and their prevalence is significantly higher than in NHS. No correlation of anti-CarP with anti-CCP and RF antibodies in RA HFDRs was found.

  8. The effect of erythropoietin on platelet function and fibrinolysis in chronic renal failure

    DEFF Research Database (Denmark)

    Stenver, Doris Irene; Jeppesen, L; Nielsen, B

    1994-01-01

    The influence of erythropoietin therapy on platelet function and fibrinolysis was evaluated in 12 anemic hemodialysis patients. Six months of therapy with human erythropoietin (50 to 80 IU/kg initially) raised the hemoglobin level to 10.8 g/dl but did not increase platelet activity in vivo...... as measured by beta-thromboglobulin or platelet factor 4. There was no change in the platelet aggregation thresholds in vitro for ADP, adrenaline, thrombin or collagen during treatment. Platelet number and volume were also unaffected. Fibrinolytic activity intensified as erythropoietin treatment proceeded...

  9. Involvement of BDNF and NGF in the mechanism of neuroprotective effect of human recombinant erythropoietin nanoforms.

    Science.gov (United States)

    Solev, I N; Balabanyan, V Yu; Volchek, I A; Elizarova, O S; Litvinova, S A; Garibova, T L; Voronina, T A

    2013-06-01

    Human recombinant erythropoietin adsorbed on poly(butyl)cyanoacrylate nanoparticles and administered intraperitoneally in a dose of 0.05 mg/kg exhibited a neuroprotective effect in experimental intracerebral posttraumatic hematomas (hemorrhagic stroke) and reduced animal mortality. Human recombinant erythropoietin, native and adsorbed on lactic and glycolic acid copolymer-based nanoparticles, exhibited no antistroke effect on this model. Analysis of reverse transcription PCR products showed that human recombinant erythropoietin adsorbed on poly(butyl)cyanoacrylate nanoparticles more than 2-fold increased the expression of BDNF and NGF neurotrophins in the rat brain frontal cortex and hippocampus.

  10. Erythropoietin Biosimilar Products and Immunogenicity: A Pharmacovigilance Study

    Directory of Open Access Journals (Sweden)

    Yasser Bustanji

    2016-06-01

    Full Text Available The aim of the present study was to evaluate the immunogenicity of a generic product of erythropoietin registered in Jordan, by detecting the presence of anti-recombinant human erythropoietin antibodies in the serum via an ELISA technique. Materials and Methods: Briefly, polystyrene micro-titer plates (96-well were coated with rhEPO (the generic product at 10 µg/1mL. Goat anti-human IgG:HRP or rabbit polyclonal to human IgM:HRP was added to the wells and incubated. A prepared substrate solution was then added to each well. The absorbance was measured with a microplate reader after green color development (n=3. The sera of 95 patients were tested for the presence of IgM or IgG antibodies. Results: Antibodies were detected in 26.3% of the population; where 16.8% were found to have only IgG antibodies, 7.4% had only IgM antibodies, and 2.1% had both antibodies. Cigarette smoking correlated significantly with the development of IgG antibodies. Moreover folate administration correlated inversely with decreasing the risk of developing IgM antibodies. Conclusions: this study proves the immunogenic effect for this product

  11. Production and Characterization of Monoclonal Antibody Against Recombinant Human Erythropoietin

    Institute of Scientific and Technical Information of China (English)

    JIE-BO MI; JIN YAN; XIAO-JIE DING; ZHEN-QUAN GUO; MEI-PING ZHAO; WEN-BAO CHANG

    2007-01-01

    Objective To produce specific monoclonal antibody(mAb)against recombinant human erythropoietin(rHuEPO)for development of higmy efficient methods for erythropoietin detection in biological fluids.Methods rHuEPO was covalently coupled with bovine serum albumin(BSA)and the conjugate was used to immunize mice to produce specific mAb against rHuEPO based on hybridoma technology.The obtained F3-mAb was characterized by enzyme-linked immunosorbent assay (ELISA),SDS-PAGE and Western blot.Results The isotype of F3-mAb Was found to be IgM with an affinity constant of 2.1x108 L/mol.The competitive ELISA using the obtained IgM showed a broader linear range and lower detection limit compared with previous work.Conclusions The modification of rHuEPO was proved to be successful in generating required specific mAb with high avidity to rHuEPO.

  12. A single subcutaneous bolus of erythropoietin normalizes cerebral blood flow autoregulation after subarachnoid haemorrhage in rats

    DEFF Research Database (Denmark)

    Springborg, Jacob Bertram; Ma, XiaoDong; Rochat, Per;

    2002-01-01

    Systemic administration of recombinant erythropoietin (EPO) has been demonstrated to mediate neuroprotection. This effect of EPO may in part rely on a beneficial effect on cerebrovascular dysfunction leading to ischaemic neuronal damage. We investigated the in vivo effects of subcutaneously...

  13. Erythropoietin improves place learning in an 8-arm radial maze in fimbria-fornix transected rats

    DEFF Research Database (Denmark)

    Malá, Hana; Alsina, Carina Gili; Madsen, Kathrine Skak;

    2005-01-01

    erythropoietin, EOP, fimbria-fornix, hippocampus, place learning, hjerneskade, funktionel genopretning, posttraumatisk rehabilitering, plasticitet, neuroprotektion, neurotrofiske effekter, 8-arms labyrint, rotte, indlæring, problemløsning...

  14. Neural correlates of improved executive function following erythropoietin treatment in mood disorders

    DEFF Research Database (Denmark)

    Miskowiak, K W; Vinberg, M; Glerup, L

    2016-01-01

    BACKGROUND: Cognitive dysfunction in depression and bipolar disorder (BD) is insufficiently targeted by available treatments. Erythropoietin (EPO) increases neuroplasticity and may improve cognition in mood disorders, but the neuronal mechanisms of these effects are unknown. This functional magne...

  15. Possible complications of erythropoietin therapy in patients with chronic renal failure

    Directory of Open Access Journals (Sweden)

    Plješa Steva J.

    2004-01-01

    Full Text Available Introduction There have been many publications in the past 20 years about positive effects of human recombinant erythropoietin, which is used in treatment of anemia, especially in patients on dialysis. Complications The most important complications in patients treated with erythropoietin include: hypertensive reactions; thrombosis of AV fistula in patients on hemodialysis and appearance of severe anemia as a part of Pure Red Cell Aplasia (PRCA. The first two complications were managed quite easily with adequate erythropoietin dosage, and slower establishment of normal hemoglobin kevel, hematocrit level and red blood cell count, (our "target" Hb varied between 100 and 110 g/dl. Pure Red Cell Aplasia (PRCA Pure Red Cell Aplasia is a progressive, marked anemia with sudden appearance of signifacnt loss or complete absence of erythrocyte precursor cells in normal bone marrow. In patients with end stage renal disease treated with erythropoietin PRCA appears in acute form as a consequence of production of neutralizing antibodies to erythropoietin. Time period between the beginning of erythropoietin therapy and appearance of PRCA is from 3 weeks to approximately 9 months. Symptoms and signs PRCA is characterized by sudden appearance of anemia in patients who had a satisfactory response to erythropoietin therapy till that moment. In PRCA, anemia is normocytic, normochromic with normal survival of red blood cells, without deficit in components such as iron, folic acid or vitamin B12, low reticulocyte count, decrease in Hg and normal platelet count. Diagnosis Diagnosis is based on clinical data (marked anemia, bone marrow biopsy, which shows a lower number of precursor red blood cells and presence of antibodies against erythropoietin. Before PRCA is diagnosed, all other causes for erythropoietin resistance must be excluded. Therapy Therapy of PRCA is based on cessation of erythropoietin therapy (all kinds, and correction of anemia with blood transfusions

  16. Mechanism of Protective Effect of High Dosage Erythropoietin (EPO) on Renal Anemia Treated with Combination of Chinese and Western Medicine%中西医结合治疗肾性贫血的红细胞保护机理研究

    Institute of Scientific and Technical Information of China (English)

    张熙; 王怡

    2013-01-01

    Objective: To study the effect of combination of yangxueyin Recipe and high dosage erythropoietin ( EPO ) in the treatment of renal anemia and the influence on change of CD55, CD59 and ROS, so as to explore the possible mechanism of inte-grative Chinese and Western medicine (ICWM) in treating renal anemia. Methods :60 patients with renal anemia were randomly divided into two groups:the ICWM group and the control group with 30 in each group. The symptomatic and supporting treatment, such as dialysis supplementing of ferrous .foliac acid and vitamin B12,was given to both groups. 3 months later,blood levels of hemoglobin (Hb) , hematocrit ( Hct) ,CD55,CD59 and ROS were measured and the therapeutic effect was observed. Results: After treatment, levels of HB and HCT in two groups were obviously increased (P <0. 01) ,but there was on difference between the two groups. CD55 and CD59 in two groups had no difference before and after treatment and there was also no difference between the two groups. ROS level in two groups was obviously higher than that in normal group and after treatment it was decreased more significantly (P <0. 01) ,but there was no difference between the two groups. Conclusion: The control and ICWM groups both could significantly inhibit the production of ROS, and this may be an important factor for ICWM and control group in effectively improving renal anemia.%目的:评价养血饮联合促红细胞生成素(EPO)对肾性贫血患者临床症状及其对红细胞膜的保护作用.方法:60例肾性贫血患者随机分为养血饮合益比奥治疗组30例(中西组),西药益比奥组30例(对照组),治疗3个月后用流式细胞仪检测CD55、CD59、ROS,并检测和评估血常规的变化.结果:实验前后.结果:对照组和中西组治疗后HB,HCT均较前明显上升(P<0.01),两组之间无明显差异.红细胞膜上CD55、CD59治疗前后无明显差异,两组间比较也无明显差异.红细胞膜上ROS均明显高于正常组;治

  17. La eritropoyetina un neuroprotector potencial Erythropoietin: A potential neuroreceptor

    Directory of Open Access Journals (Sweden)

    Alain Valdivia Acosta

    2007-08-01

    Full Text Available La importante función fisiológica de la hormona eritropoyetina en el proceso eritropoyético se descubrió hace alrededor de un siglo. Mas recientemente se ha trabajado en su obtención por vía recombinante para su aplicación en pacientes con anemias agudas o crónicas, causadas por diferentes afecciones. Esta terapia mejora, sin lugar a duda, la calidad de vida de estos pacientes. A partir del año 1998, se reportaron por primera vez las propiedades neuroprotectoras de la eritropoyetina y se realizaron estudios que así lo corroboraron con el empleo de modelos de daño cerebral, tanto in vitro como in vivo. Los estudios actuales consisten en dilucidar a profundidad los mecanismos de acción por los cuales la eritropoyetina muestra sus propiedades neuroprotectoras y en obtener una adecuada biodisponibildad de la molécula para su aplicación segura en la terapéutica de afecciones del cerebro. El presente trabajo recopila información actualizada sobre la eritropoyetina como agente neuroprotector y refiere la continuidad de estudios para su aplicación en la clínica.A century ago, significant physiolgical function of Erithropoietin was discovered. More recently, it has been working on its obtention by a recombinant via for application in patients presenting with acute and chronic anemia, from different afections. This type of therapy improves undoubtedly, life quality of these patients. From 1998, neuroprotective properties of Erythropoietin were retorted for the first time, and we performed studies corroborating it b y means of use of bran damage model, both, in vitro and in vivo. Present studies are designed to elucidate deeply action mechanisms by which Erythropoietin shows its neuroprotective properties and to obtain a appropriate bioavailability of molecule for a accurate application in therapeutics of bran afections. Present paper collets updated information on Erythropoietin as a neuroprotective agent, and refers to continuity of

  18. Effects of erythropoietin and its receptor on nervous system

    Institute of Scientific and Technical Information of China (English)

    Ping Wang; Wei Zhou

    2006-01-01

    OBJECTIVE: To investigate the effects of erythropoietin (EPO) and its receptor (EPOR) on nervous system, and its possible mechanism.DATA SOURCES: By inputting the key words "erythropoietin ,nervous system", we performed a search of Medline for English articles, which were published during September 1996 to August 2006, about EPO and EPOR in nervous system.STUDY SELECTION: The materials were selected firstly, literatures were chosen for treatment group and control group and those obviously non-randomized studies were excluded. The full texts of the left literatures were searched. Inclusive criteria: ① Randomized controlled study. ②Experimental or clinical studies (parallel control group included). ③Treatment group was recombinant human erythropoietin(rHuEPO)-treated group. Exclusive criteria: repetitive study.DATA EXTRACTION: A number of 380 randomized or non-randomized articles about the effect of EPO on nervous system were collected, and 49 experiments or clinical trials met the inclusive criteria. Among 331 exclusive articles, 237 were non-randomized or repetitive studies and 94 were review articles. DATA SYNTHESIS: Forty-nine experiments or clinical trials confirmed that EPO and EPOR were expressed in the central nervous system (CNS) and peripheral nervous system(PNS) of gnawer, primate and human being; rHuEPO had obvious neuroprotective effects on brain hypoxia, brain ischemia, experimental intracranial hemorrhage, brain trauma, experimental autoimmune encephalomyelitis, human immunodeficiency virus (HIV)-related sensory neuropathy, distal axonopathy, experimental diabetic neuropathy and acute spinal injury models. Its mechanism maybe involve anti-excitatory toxicity, preventing the production of nitric oxide (NO), lessening inflammatory reaction, resisting apoptosis, maintaining vascular integrity, promoting angiogenesis, promoting the proliferation and differentiation of neural stem cells and progenitor cells and so on. Exogenous EPO could be

  19. Erythropoietin in traumatic brain injury: study protocol for a randomised controlled trial.

    LENUS (Irish Health Repository)

    Nichol, Alistair

    2015-02-08

    Traumatic brain injury is a leading cause of death and disability worldwide. Laboratory and clinical studies demonstrate a possible beneficial effect of erythropoietin in improving outcomes in the traumatic brain injury cohort. However, there are concerns regarding the association of erythropoietin and thrombosis in the critically ill. A large-scale, multi-centre, blinded, parallel-group, placebo-controlled, randomised trial is currently underway to address this hypothesis.

  20. Anti-Inflammatory Effect of Erythropoietin in the TNBS-induced Colitis.

    Science.gov (United States)

    Mateus, Vanessa; Rocha, João; Alves, Paula; Mota-Filipe, Helder; Sepodes, Bruno; Pinto, Rui Manuel Amaro

    2017-02-01

    Erythropoietin is a potent stimulator of erythroid progenitor cells, which is able to inhibit NF-kB activation, due to its pleiotropic properties, thus promoting an anti-inflammatory effect. As inflammatory bowel disease is a chronic disease with reduced quality of life, and the current pharmacotherapy only induces or maintains the patient in remission, there is a crucial need of new pharmacological approaches. The main objective of this study was to evaluate the effect of erythropoietin in the TNBS-induced colitis model in mice with a normal intestinal flora. Mice with TNBS-induced colitis were treated with a daily dose of erythropoietin at 500 IU/kg bw/day and 1000 IU/Kg bw/day IP during 4 days. As to clinical symptoms/signs, erythropoietin attenuated the decreased body-weight and reduced diarrhoea and oedema of the anus registered in the non-treated mice group in a dose-dependent manner. The anti-inflammatory properties of erythropoietin in the TNBS-induced colitis were confirmed by suppression of pro-inflammatory mediators, such as TNF-α, IL-1β and MPO, as well as a significant increase in the anti-inflammatory cytokine, IL-10, was promoted. These treated mice also presented a reduction in haemoglobin faecal and ALP, suggesting a beneficial effect of erythropoietin in the haemorrhagic focus and destruction of the enterocyte associated with the colon injury induced by TNBS, respectively. The histopathological score was reduced after treatment with erythropoietin, decreasing the severity and extension of the colitis. Furthermore, renal and hepatic biomarkers, as well as haematocrit concentration, remained stabilized after treatment. In conclusion, erythropoietin reduces the inflammatory response associated with TNBS-induced colitis in mice.

  1. High-dose phenobarbital or erythropoietin for the treatment of perinatal asphyxia in term newborns.

    Science.gov (United States)

    Avasiloaiei, Andreea; Dimitriu, Cristina; Moscalu, Mihaela; Paduraru, Luminita; Stamatin, Maria

    2013-10-01

    The aim of this study was to compare two neuroprotective strategies to supportive care in the treatment of perinatal asphyxia. A total of 67 term newborns with perinatal asphyxia were included and randomized into three groups: one group received supportive treatment; another group received a single dose of 40 mg/kg phenobarbital; and the third received three daily doses of 1000 IU/kg erythropoietin. The following parameters were analyzed: gestational age, birthweight, Apgar scores, cord blood pH, total serum antioxidant status (TAS), superoxide dismutase (SOD), glutathione peroxidase (GPx) and malondialdehyde (MDA). The newborns were included in the follow-up program and examined up to 18 months of age. TAS was higher in the erythropoietin group than in the other groups. SOD and GPx were lower for infants treated with phenobarbital or erythropoietin compared to control infants. MDA was lower in the erythropoietin group compared to the other groups, although the difference was not statistically significant (P > 0.05). The mortality rate was lower in the phenobarbital and erythropoietin groups (both 4.6%) than in the control group (17.4%). Long-term neurologic follow up showed a high incidence of sequelae in the control group compared to the phenobarbital and erythropoietin groups. Follow-up results were better in the phenobarbital group than in the erythropoietin group for motor and cognitive function at 3 and 6 months and worse for expressive language. At 18 months, however, the differences between these two groups were not significant. High-dose phenobarbital or erythropoietin along with supportive treatment has a positive influence on the outcome of newborns with perinatal asphyxia. Phenobarbital has the advantage of low cost and simplicity. © 2013 The Authors. Pediatrics International © 2013 Japan Pediatric Society.

  2. [Application of recombinant erythropoietin during preparation for hepatic transplantation operation from the living kindred donor].

    Science.gov (United States)

    Kotenko, O G; Mazur, A P; Dykhovichnaia, N Iu; Popov, A O; Gusev, A V

    2007-07-01

    First experience of application of the blood autodonorship programme, using recombinant erythropoietin (Eprex) plus preparations containing iron during their preparation for partial hepatic resection, was analyzed. Realization of this programme had permitted to escape the performance of allogenic hemotransfusion in 71.4% of donors, in whom the right or left hepatic lobe was taken out and in 100%--the left lateral section. The erythropoietin dosage regimes in different types of hepatic resections in living kindred donors were proposed.

  3. Nonerythropoietic Erythropoietin-Derived Peptide Suppresses Adipogenesis, Inflammation, Obesity and Insulin Resistance

    Science.gov (United States)

    Liu, Yuqi; Luo, Bangwei; Shi, Rongchen; Wang, Jinsong; Liu, Zongwei; Liu, Wei; Wang, Shufeng; Zhang, Zhiren

    2015-01-01

    Erythropoietin (EPO) has been identified as being crucial for obesity modulation; however, its erythropoietic activity may limit its clinical application. EPO-derived Helix B-surface peptide (pHBSP) is nonerythrogenic but has been reported to retain other functions of EPO. The current study aimed to evaluate the effects and potential mechanisms of pHBSP in obesity modulation. We found that pHBSP suppressed adipogenesis, adipokine expression and peroxisome proliferator-activated receptor γ (PPARγ) levels during 3T3-L1 preadipocyte maturation through the EPO receptor (EPOR). In addition, also through EPOR, pHBSP attenuated macrophage inflammatory activation and promoted PPARγ expression. Furthermore, PPARγ deficiency partly ablated the anti-inflammatory activity of pHBSP in macrophages. Correspondingly, pHBSP administration to high-fat diet (HFD)-fed mice significantly improved obesity, insulin resistance (IR) and adipose tissue inflammation without stimulating hematopoiesis. Therefore, pHBSP can significantly protect against obesity and IR partly by inhibiting adipogenesis and inflammation. These findings have therapeutic implications for metabolic disorders, such as obesity and diabetes. PMID:26459940

  4. Schwann cells express erythropoietin receptor and represent a major target for Epo in peripheral nerve injury.

    Science.gov (United States)

    Li, Xiaoqing; Gonias, Steven L; Campana, W Marie

    2005-09-01

    Erythropoietin (Epo) expresses potent neuroprotective activity in the peripheral nervous system; however, the underlying mechanism remains incompletely understood. In this study, we demonstrate that Epo is upregulated in sciatic nerve after chronic constriction injury (CCI) and crush injury in rats, largely due to local Schwann cell production. In uninjured and injured nerves, Schwann cells also express Epo receptor (EpoR), and its expression is increased during Wallerian degeneration. CCI increased the number of Schwann cells at the injury site and the number was further increased by exogenously administered recombinant human Epo (rhEpo). To explore the activity of Epo in Schwann cells, primary cultures were established. These cells expressed cell-surface Epo receptors, with masses of 71 and 62 kDa, as determined by surface protein biotinylation and affinity precipitation. The 71-kDa species was rapidly but transiently tyrosine-phosphorylated in response to rhEpo. ERK/MAP kinase was also activated in rhEpo-treated Schwann cells; this response was blocked by pharmacologic antagonism of JAK-2. RhEpo promoted Schwann cell proliferation, as determined by BrdU incorporation. Cell proliferation was ERK/MAP kinase-dependent. These results support a model in which Schwann cells are a major target for Epo in injured peripheral nerves, perhaps within the context of an autocrine signaling pathway. EpoR-induced cell signaling and Schwann cell proliferation may protect injured peripheral nerves and promote regeneration.

  5. The nonhematopoietic effects of erythropoietin in skin regeneration and repair: from basic research to clinical use.

    Science.gov (United States)

    Sorg, Heiko; Harder, Yves; Krueger, Christian; Reimers, Kerstin; Vogt, Peter M

    2013-05-01

    Erythropoietin (EPO) is the main regulator of red blood cell production but there exists also a variety of nonhematopoietic properties. More recent data show that EPO is also associated with the protection of tissues suffering from ischemia and reperfusion injury as well as with improved regeneration in various organ systems, in particular the skin. This review highlights the mechanisms of EPO in the different stages of wound healing and the reparative processes in the skin emphasizing pathophysiological mechanisms and potential clinical applications. There is clear evidence that EPO effectively influences all wound-healing phases in a dose-dependent manner. This includes inflammation, tissue, and blood vessel formation as well as the remodeling of the wound. The molecular mechanism is predominantly based on an increased expression of the endothelial and inducible nitric oxide (NO) synthase with a consecutive rapid supply of NO as well as an increased content of vascular endothelial growth factor (VEGF) in the wound. The improved understanding of the functions and regulatory mechanisms of EPO in the context of wound-healing problems and ischemia/reperfusion injury, especially during flap surgery, may lead to new considerations of this growth hormone for its regular clinical application in patients.

  6. Statins inhibited erythropoietin-induced proliferation of rat vascular smooth muscle cells.

    Science.gov (United States)

    Kaneda, Tae; Tsuruoka, Shuichi; Fujimura, Akio

    2010-12-15

    Erythropoietin (EPO) directly stimulates the proliferation of vascular smooth muscle cells, and this is believed to be one of the mechanisms of vascular access failure of hemodialysis patients. However, precise mechanisms of the EPO-induced proliferation of vascular smooth muscle cells are not certain. HMG-CoA reductase inhibitors (statins) are primarily used to reduce cholesterol levels, but also exert other effects, including reno-protective effects. We evaluated the effect of several statins with various hydrophilicities on the EPO-induced proliferation of primary cultured rat vascular smooth muscle cells (VSMCs) in vitro. EPO significantly and concentration-dependently increased DNA synthesis as assessed by [³H]thymidine incorporation, cell proliferation as assessed by WST-1 assay, and activation of the p44/42MAPK pathway. Therapeutic doses of statins (pravastatin, simvastatin, atorvastatin and fluvastatin) in patients with hypercholesterolemia almost completely suppressed all of the EPO-induced effects in a concentration-dependent manner. Co-addition of mevalonic acid almost completely reversed the effects of statins. Statin alone did not affect the basal proliferation capacity of the cells. The effects were almost similar among the statins. We concluded that statins inhibited EPO-induced proliferation in rat VSMCs at least partly through their inhibition of HMG-CoA reductase activity. In the future, statins might prove useful for the treatment of EPO-induced hyperplasia of vascular access. Because the statins all showed comparable effects irrespective of their hydrophilicities, these effects might be a class effect.

  7. Erythropoietin and a nonerythropoietic peptide analog promote aortic endothelial cell repair under hypoxic conditions: role of nitric oxide

    Directory of Open Access Journals (Sweden)

    Heikal L

    2016-08-01

    Full Text Available Lamia Heikal,1 Pietro Ghezzi,1 Manuela Mengozzi,1 Blanka Stelmaszczuk,2 Martin Feelisch,2 Gordon AA Ferns1 1Brighton and Sussex Medical School, Falmer, Brighton, 2Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital and Institute for Life Sciences, Southampton, UK Abstract: The cytoprotective effects of erythropoietin (EPO and an EPO-related nonerythropoietic analog, pyroglutamate helix B surface peptide (pHBSP, were investigated in an in vitro model of bovine aortic endothelial cell injury under normoxic (21% O2 and hypoxic (1% O2 conditions. The potential molecular mechanisms of these effects were also explored. Using a model of endothelial injury (the scratch assay, we found that, under hypoxic conditions, EPO and pHBSP enhanced scratch closure by promoting cell migration and proliferation, but did not show any effect under normoxic conditions. Furthermore, EPO protected bovine aortic endothelial cells from staurosporine-induced apoptosis under hypoxic conditions. The priming effect of hypoxia was associated with stabilization of hypoxia inducible factor-1α, EPO receptor upregulation, and decreased Ser-1177 phosphorylation of endothelial nitric oxide synthase (NOS; the effect of hypoxia on the latter was rescued by EPO. Hypoxia was associated with a reduction in nitric oxide (NO production as assessed by its oxidation products, nitrite and nitrate, consistent with the oxygen requirement for endogenous production of NO by endothelial NOS. However, while EPO did not affect NO formation in normoxia, it markedly increased NO production, in a manner sensitive to NOS inhibition, under hypoxic conditions. These data are consistent with the notion that the tissue-protective actions of EPO-related cytokines in pathophysiological settings associated with poor oxygenation are mediated by NO. These findings may be particularly relevant to atherogenesis and postangioplasty restenosis. Keywords

  8. Erythropoietin inhibits gamma-irradiation-induced apoptosis by upregulation of Bcl-2 and decreasing the activation of caspase 3 in human UT-7/erythropoietin cell line.

    Science.gov (United States)

    Liu, Yuan-Yuan; She, Zhen-Jue; Yao, Ming-Hui

    2010-05-01

    1. Erythropoietin (EPO) can reverse radiotherapy-induced anaemia by stimulating bone marrow cells to produce erythrocytes. However, there are limited studies that address the mechanisms by which EPO exerts its beneficial effects in radiotherapy-induced anaemia. In the present study, we used a human bone marrow-derived EPO-dependent leukaemia cell line UT-7/EPO that progressed further in erythroid development to evaluate the anti-apoptotic effects of EPO on irradiated human erythroid progenitor. 2. The UT-7/EPO cells exposed to gamma-irradiation were cultured in the presence or absence of EPO at a concentration of 7 U/mL. The cell viability, cell apoptosis and the expression of apoptosis-related proteins Bcl-2, Bax and caspase 3 were examined. 3. The results showed that EPO protected the viability of human UT-7/EPO cells exposed to gamma-irradiation. EPO significantly inhibited gamma-irradiation-induced apoptosis in human UT-7/EPO cells: a significant decrease in the percentage of apoptotic cells was observed (62, 69 and 62% at 24, 48 and 72 h, respectively). Furthermore, EPO significantly increased the expression of Bcl-2 protein and the relative Bcl-2/Bax ratio, and decreased the activation of caspase 3 and formation of the p17 and p12 cleavage in similar conditions. 4. In conclusion, EPO exerts anti-apoptotic effects on irradiated human UT-7/EPO cells through upregulation of Bcl-2 protein and the relative Bcl-2/Bax ratio, and by decreasing the activation of caspase 3. These findings may contribute to our understanding of the beneficial function of EPO in radiotherapy-induced anaemia.

  9. Erythropoietin Action in Stress Response, Tissue Maintenance and Metabolism

    Directory of Open Access Journals (Sweden)

    Yuanyuan Zhang

    2014-06-01

    Full Text Available Erythropoietin (EPO regulation of red blood cell production and its induction at reduced oxygen tension provides for the important erythropoietic response to ischemic stress. The cloning and production of recombinant human EPO has led to its clinical use in patients with anemia for two and half decades and has facilitated studies of EPO action. Reports of animal and cell models of ischemic stress in vitro and injury suggest potential EPO benefit beyond red blood cell production including vascular endothelial response to increase nitric oxide production, which facilitates oxygen delivery to brain, heart and other non-hematopoietic tissues. This review discusses these and other reports of EPO action beyond red blood cell production, including EPO response affecting metabolism and obesity in animal models. Observations of EPO activity in cell and animal model systems, including mice with tissue specific deletion of EPO receptor (EpoR, suggest the potential for EPO response in metabolism and disease.

  10. Effects of recombinant humant erythropoietin in normal humans

    DEFF Research Database (Denmark)

    Lundby, Carsten; Olsen, Niels Vidiendal

    2011-01-01

    , and although it has been speculated that non-erythropoietic effects of EPO (angiogenesis, shift in muscle fibre types, cognitive effects) may be responsible for the increase in exercise performance, this has not been confirmed. EPO induced haemodynamic effects call for careful monitoring during......This review describes some of the physiological effects of recombinant human erythropoietin (EPO) in healthy humans. At the blood level EPO increases the arterial O2 content not only by increasing red blood cell volume, but also by an equally important decrease in plasma volume. Well before that...... result in suppression of endogenous EPO production through a decrease in intrarenal oxygen consumption. EPO elevates the arterial blood pressure even in healthy subjects. The receptor for EPO is present in many tissues. However, the functional effects of EPO in the skeletal muscle seem limited...

  11. Diurnal variations of serum erythropoietin in trained and untrained subjects

    DEFF Research Database (Denmark)

    Klausen, T; Dela, F; Hippe, E

    1993-01-01

    The diurnal variations of serum-erythropoietin concentration ([s-EPO]) were investigated in six physically trained (T) and eight untrained (UT) men. The T subjects had a higher mean maximal oxygen uptake than UT subjects [75.7 (SEM 1.6) ml.min-1.kg-1 versus 48.3 (SEM 1.4) ml.min-1.kg-1, P ... and UT had a nadir of [s-EPO] 120 min after awakening [10.0 (SEM 0.3) U.l-1 versus 11.5 (SEM 2.1) U.l-1, P > 0.05]. The UT and T increased their [s-EPO] to peak values at 960 min and 960-1200 min, respectively (ANOVA P = 0.03) after awakening [UT: 18.4 (SEM 2.8) U.l-1; T: 16.2 (SEM 2.5) U.l-1, P > 0...

  12. The Antioxidant Effect of Erythropoietin on Thalassemic Blood Cells

    Directory of Open Access Journals (Sweden)

    Johnny Amer

    2010-01-01

    Full Text Available Because of its stimulating effect on RBC production, erythropoietin (Epo is used to treat anemia, for example, in patients on dialysis or on chemotherapy. In β-thalassemia, where Epo levels are low relative to the degree of anemia, Epo treatment improves the anemia state. Since RBC and platelets of these patients are under oxidative stress, which may be involved in anemia and thromboembolic complications, we investigated Epo as an antioxidant. Using flow-cytometry technology, we found that in vitro treatment with Epo of blood cells from these patients increased their glutathione content and reduced their reactive oxygen species, membrane lipid peroxides, and external phosphatidylserine. This resulted in reduced susceptibility of RBC to undergo hemolysis and phagocytosis. Injection of Epo into heterozygous (Hbbth3/+ β-thalassemic mice reduced the oxidative markers within 3 hours. Our results suggest that, in addition to stimulating RBC and fetal hemoglobin production, Epo might alleviate symptoms of hemolytic anemias as an antioxidant.

  13. Renal erythropoietin-producing cells in health and disease

    Directory of Open Access Journals (Sweden)

    Tomokazu eSouma

    2015-06-01

    Full Text Available Erythropoietin (Epo is an indispensable erythropoietic hormone primarily produced from renal Epo-producing cells (REPs. Epo production in REPs is tightly regulated in a hypoxia-inducible manner to maintain tissue oxygen homeostasis. Insufficient Epo production by REPs causes renal anemia and anemia associated with chronic disorders. Recent studies have broadened our understanding of REPs from prototypic hypoxia-responsive cells to dynamic fibrogenic cells. In chronic kidney disease, REPs are the major source of scar-forming myofibroblasts and actively produce fibrogenic molecules, including inflammatory cytokines. Notably, myofibroblast-transformed REPs recover their original physiological properties after resolution of the disease insults, suggesting that renal anemia and fibrosis could be reversible to some extent. Therefore, understanding the plasticity of REPs will lead to the development of novel targeted therapeutics for both renal fibrosis and anemia. This review summarizes the regulatory mechanisms how hypoxia-inducible Epo gene expression is attained in health and disease conditions.

  14. The role of recombinant erythropoietin in childhood cancer.

    Science.gov (United States)

    Shankar, Ananth Gouri

    2008-02-01

    Anemia in children with cancer is not an uncommon complication and is usually multifactorial in etiology. In numerous trials in adult cancer patients, treatment with recombinant erythropoietin has been shown to increase hemoglobin levels, reduce red blood cell transfusion requirements, and improve quality of life. Much less has been published of its use in the prevention or treatment of cancer-associated anemia (CAA) in children, in whom chemotherapy is usually more intensive and likely to result in greater myelosuppression. This review critically evaluates the published evidence of its use in childhood cancer especially; its safety and efficacy in the prevention and treatment of CAA and some indications for its use in childhood cancer are suggested.

  15. Procedures for monitoring recombinant erythropoietin and analogues in doping control.

    Science.gov (United States)

    Segura, Jordi; Pascual, José A; Gutiérrez-Gallego, Ricardo

    2007-08-01

    The present report summarizes the main analytical strategies developed to identify the presence of recombinant erythropoietin (EPO) administered as a doping agent. Indirect evidence is based on the analysis of blood parameters (haemoglobin, haematocrit, reticulocytes, macrocytes, etc.) and serum markers (concentration of EPO and serum transferrin receptors, etc.). The problem of intertechnique comparison for reliable results evaluation is emphasized, especially for serum markers. Charge differences between isoforms of recombinant EPO and native urinary EPO are the grounds for the isoelectric focusing-double blotting-chemiluminescence detection method presently approved for doping control. Works addressing its advantages and limitations are presented and commented on. The chemical bases of the differential detection are highlighted and some future approaches for detection are also presented. The appearance and detectability of EPO analogues and mimetics susceptible for abuse are also addressed.

  16. Erythropoietin treatment enhances muscle mitochondrial capacity in humans

    DEFF Research Database (Denmark)

    Plenge, Ulla; Belhage, Bo; Guadalupe-Grau, Amelia;

    2012-01-01

    Erythropoietin (Epo) treatment has been shown to induce mitochondrial biogenesis in cardiac muscle along with enhanced mitochondrial capacity in mice. We hypothesized that recombinant human Epo (rhEpo) treatment enhances skeletal muscle mitochondrial oxidative phosphorylation (OXPHOS) capacity...... in humans. In six healthy volunteers rhEpo was administered by sub-cutaneous injection over 8 weeks with oral iron (100 mg) supplementation taken daily. Mitochondrial OXPHOS was quantified by high-resolution respirometry in saponin-permeabilized muscle fibers obtained from biopsies of the vastus lateralis...... before and after rhEpo treatment. OXPHOS was determined with the mitochondrial complex I substrates malate, glutamate, pyruvate, and complex II substrate succinate in the presence of saturating ADP concentrations, while maximal electron transport capacity (ETS) was assessed by addition of an uncoupler...

  17. [Anemia in chronic lymphatic leukemia: is erythropoietin the solution?].

    Science.gov (United States)

    de Gaona, E Ruiz; Rifón, J; Pérez-Calvo, J; Bendandi, M; Iglesias, R; Panizo, C

    2007-01-01

    Anemia is a common complication in the clinical course of chronic lymphocytic leukemia. Low hemoglobin levels both correlate with an adverse prognosis and adversely affect the quality of life of chronic lymphocytic leukemia patients. Different physiopathological phenomena may lead to anemia: marrow infiltration, hypersplenism, immune hemolysis or toxicity of chemotherapy. Treatment with human recombinant erythropoietic agents has been shown to be effective for anemia associated with different lymphoproliferative syndromes. This paper analyses the available evidence on erythropoietic agent treatment for chronic lymphocytic leukemia associated anemia. The comparative effect of different dosage schemes, the role of possible response-prediction factors such as the endogenous erythropoietin level and the results achieved using darbopoietin alpha are reviewed.

  18. CLINICAL APPLICATION OF RECOMBINANT ERYTHROPOIETIN IN BETA-THALASSAEMIA INTERMEDIA.

    Science.gov (United States)

    Asadov, Ch; Alimirzoyeva, Z; Hasanova, M; Mammadova, T; Shirinova, A

    2016-06-01

    Research objective is to study the efficacy of recombinant erythropoietin (epoetin alfa) as alternative method of treatment beta-thalassemia intermedia. Study involved 58 patients with beta-thalassemia intermedia (23 women and 35 men). In all observed patients was defined levels of hemoglobin (Hb), red blood cells (RBC), erythrocyte indexes (MCV, MCH, MCHC), hemoglobin fractions (HbA, HbA2, HbF), serum ferritin, serum erythropoietin before and after administrated rEPO. All patients received rEPO during 6 month at the dose - 10000 IU subcutaneously. The majority of patients - 39 (67%) had a good response to rEPO (increase in hemoglobin level more than 20 g/l); 16 patients (28%) had a mean response (increase in Hb 10 - 20 g/l); in 3 (5%) patients occurred poor response to rEPO therapy (increase in Hb treatment of beta-thalassemia intermedia patients there was a statistically significant change in the number of RBC, levels of HbF and sEPO. The evaluation of interdependence between the indices of the baseline sEPO and increased Hb values in patients after rEPO treatment revealed the presence of the reverse direct relationship (r=-0.67). Based on the results, it can be concluded that the use of rEPO in complex therapy of beta-thalassemia intermedia leads to increased levels of Hb and consequently reducing the need for blood transfusions, and accordingly expected to prevent severe complications of blood transfusion (alloimmunization, hypersplenism, iron overload, contamination transmissible infections) facilitating normal growth and development, and a better quality of life.

  19. Cardiovascular effects of recombinant human erythropoietin in predialysis patients.

    Science.gov (United States)

    Portolés, J; Torralbo, A; Martin, P; Rodrigo, J; Herrero, J A; Barrientos, A

    1997-04-01

    Treatment with recombinant human erythropoietin (rHuEPO) has solved the problem of anemia in patients on dialysis. However, its application to predialysis patients has raised some doubts about its effects on the progression of renal disease and on blood pressure (BP) and hemodynamic regulation. We have prospectively studied over at least 6 months a group of 11 predialysis patients receiving rHuEPO treatment (initial dose, 1,000 U subcutaneously three times a week). Clinical assessment and biochemical and hematologic measurements were made once every 2 weeks. Twenty-four-hour ambulatory BP monitoring, echocardiography, and determination of neurohumoral mediators of hemodynamics were performed once every 3 months. An adequate hematologic response was found (hemoglobin, 11.7 +/- 0.4 g/dL v 9 +/- 0.3 g/dL) without changes in the progression of renal disease. A decrease in cardiac output and an increase in total peripheral resistance was seen as anemia improved. A trend toward decreased left ventricular (LV) thickness and a significant decrease in LV mass index (from 178.2 +/- 20.6 g/m2 to 147.3 +/- 20.6 g/m2) were observed. Blood pressure control did not improve; moreover, in some patients an increase in systolic values was detected by ambulatory BP. Casual BP remained seemingly stable. Sequential determinations of neurohumoral mediators of hemodynamic substances (endothelin, renin, norepinephrine, epinephrine, dopamine) failed to explain these results. Ambulatory BP reveals a worse control in some patients who were previously hypertensive and confirms the utility of this technique in the assessment of patients under erythropoietin treatment. The trend toward LV hypertrophy regression without improved BP control confirms the role of anemia among the multiple factors leading to LV hypertrophy in end-stage renal disease (ESRD), and opens therapeutic possibilities. Better control of BP may avoid a potential offsetting of beneficial effects that correcting anemia would

  20. Tratamiento con eritropoyetina humana recombinante Human recombinant erythropoietin therapy

    Directory of Open Access Journals (Sweden)

    Hugo Donato

    2006-02-01

    Full Text Available La eritropoyetina recombinante (rHuEPO se ha transformado en la citoquina más utilizada terapéuticamente en el mundo. Luego del éxito obtenido en pacientes con insuficiencia renal terminal, se pudo establecer la utilidad de la terapia con rHuEPO para mejorar otras anemias, incluso en pacientes pediátricos y neonatos. El tratamiento o la prevención de la anemia del prematuro mediante el uso de rHuEPO llevó a una significativa reducción en cantidad de transfusiones y en exposición a dadores. Aún debe establecerse una clara definición sobre cuáles niños prematuros deben recibir tratamiento rutinariamente. Otras indicaciones en período neonatal incluyen anemias hiporregenerativas y hemolíticas. La eficacia de la rHuEPO en niños mayores, con excepción de la insuficiencia renal crónica, no ha sido tan exhaustivamente evaluada como en adultos. Mientras que durante los últimos años se han realizado gran cantidad de estudios en adultos con anemia asociada al cáncer o a infección por HIV, permitiendo establecer conclusiones claras sobre su eficacia, sólo escasa cantidad de estudios con pequeño número de pacientes han sido realizados en niños. Hasta la fecha, los resultados sugieren que la terapia con rHuEPO en niños es tan útil como en adultos, pero la realización de estudios aleatorizados prospectivos incluyendo gran número de pacientes es esencial para alcanzar conclusiones definitivas. Los resultados de estudios dirigidos a evaluar la eficacia de la rHuEpo para mantener una dosis adecuada de ribavirina en pacientes en tratamiento por hepatitis C son alentadores. La utilización potencial de los efectos no hemopoyéticos de la rHuEPO en neonatos es un terreno novedoso y apasionante. El rol de la Epo como citoprotector para sistema nervioso central y mucosa intestinal está bajo investigación exhaustiva.Recombinant human erythropoietin (rHuEpo has become the most widely used cytokine in the world. Following the success of

  1. Development of an erythropoietin prescription simulator to improve abilities for the prescription of erythropoietin stimulating agents: Is it feasible?

    Directory of Open Access Journals (Sweden)

    Weibel Nadir

    2011-02-01

    Full Text Available Abstract Background The increasing use of erythropoietins with long half-lives and the tendency to lengthen the administration interval to monthly injections call for raising awareness on the pharmacokinetics and risks of new erythropoietin stimulating agents (ESA. Their pharmacodynamic complexity and individual variability limit the possibility of attaining comprehensive clinical experience. In order to help physicians acquiring prescription abilities, we have built a prescription computer model to be used both as a simulator and education tool. Methods The pharmacokinetic computer model was developed using Visual Basic on Excel and tested with 3 different ESA half-lives (24, 48 and 138 hours and 2 administration intervals (weekly vs. monthly. Two groups of 25 nephrologists were exposed to the six randomised combinations of half-life and administration interval. They were asked to achieve and maintain, as precisely as possible, the haemoglobin target of 11-12 g/dL in a simulated naïve patient. Each simulation was repeated twice, with or without randomly generated bleeding episodes. Results The simulation using an ESA with a half-life of 138 hours, administered monthly, compared to the other combinations of half-lives and administration intervals, showed an overshooting tendency (percentages of Hb values > 13 g/dL 15.8 ± 18.3 vs. 6.9 ± 12.2; P Conclusions Computer-based simulations can be a useful tool for improving ESA prescription abilities among nephrologists by raising awareness about the pharmacokinetic characteristics of the various ESAs and recognizing the factors that influence haemoglobin variability.

  2. Recognition and characterization of Erythropoietin binding-proteins in the brain of mice

    Science.gov (United States)

    Kowsari, Reza; Yazdian-Robati, Rezvan; Razavi, Bibi Marjan; Pourtaji, Atena; Ghorbani, Maryam; Moghadam-Omranipour, Hediye; Hosseinzadeh, Hossein; Lari, Parisa; Abnous, Khalil

    2016-01-01

    Objective(s): Erythropoietin (EPO), is a 34KDa glycoprotein hormone, which belongs to type 1 cytokine superfamily. EPO involves in erythrocyte maturation through inhibition of apoptosis in erythroid cells. Besides its main function, protective effects of EPO in heart and brain tissues have been reported. EPO has a critical role in development, growth, and homeostasis of brain. Furthermore EPO has great potential in the recovery of different brain diseases which are still under studying. In this research, EPO binding pattern to brain proteins in animal model was studied. Materials and Methods: EPO antibody was covalently crosslinked to protein A/G agarose. in order to interact between EPO and its target in brain, about 5µg EPO added to brain homogenates(500ul of 1 mg/ml) and incubate at 4ο C for 30 min. brain tissue lysate were added to agarose beads, After isolation of target proteins(EPO - protein) both one and two-dimensional gel electrophoresis were performed. Proteins were identified utilizing MALDI-TOF/TOF and MASCOT software. Results: This research showed that EPO could physically interact with eightproteins including Tubulin beta, Actin cytoplasmic 2, T-complex protein 1, TPR and ankyrin repeat-containing protein 1, Centromere-associated protein E, Kinesin-like protein KIF7, Growth arrest-specific protein 2 and Pleckstrin homology-like domain family B member 2. Conclusion: Since EPO is a promising therapeutic drug for the treatment of neurological diseases, identified proteins may help us to have a better understanding about the mechanism of protective effects of EPO in the brain. Our data needs to be validated by complementary bioassays. PMID:27803781

  3. Neuroprotective effect of erythropoietin against pressure ulcer in a mouse model of small fiber neuropathy.

    Directory of Open Access Journals (Sweden)

    Aurore Danigo

    Full Text Available An increased risk of skin pressure ulcers (PUs is common in patients with sensory neuropathies, including those caused by diabetes mellitus. Recombinant human erythropoietin (rhEPO has been shown to protect the skin against PUs developed in animal models of long-term diabetes. The aim of this work was to determine whether rhEPO could prevent PU formation in a mouse model of drug-induced SFN. Functional SFN was induced by systemic injection of resiniferatoxin (RTX, 50 µg/kg, i.p.. RhEPO (3000 UI/kg, i.p. was given the day before RTX injection and then every other day. Seven days after RTX administration, PUs were induced by applying two magnetic plates on the dorsal skin. RTX-treated mice expressed thermal and mechanical hypoalgesia and showed calcitonin gene-related peptide (CGRP and substance P (SP depletion without nerve degeneration or vascular dysfunction. RTX mice developed significantly larger stage 2 PUs than Vehicle mice. RhEPO prevented thermal and mechanical hypoalgesia and neuropeptide depletion in small nerve fibers. RhEPO increased hematocrit and altered endothelium-dependent vasodilatation without any effect on PU formation in Vehicle mice. The characteristics of PUs in RTX mice treated with rhEPO and Vehicle mice were found similar. In conclusion, RTX appeared to increased PU development through depletion of CGRP and SP in small nerve fibers, whereas systemic rhEPO treatment had beneficial effect on peptidergic nerve fibers and restored skin protective capacities against ischemic pressure. Our findings support the evaluation of rhEPO and/or its non-hematopoietic analogs in preventing to prevent PUs in patients with SFN.

  4. Recognition and characterization of Erythropoietin binding-proteins in the brain of mice

    Directory of Open Access Journals (Sweden)

    Reza Kowsari

    2016-09-01

    Full Text Available Objective(s: Erythropoietin (EPO, is a 34KDa glycoprotein hormone, which belongs to type 1 cytokine superfamily. EPO involves in erythrocyte maturation through inhibition of apoptosis in erythroid cells. Besides its main function, protective effects of EPO in heart and brain tissues have been reported. EPO has a critical role in development, growth, and homeostasis of brain. Furthermore EPO has great potential in the recovery of different brain diseases which are still under studying. In this research, EPO binding pattern to brain proteins in animal model was studied. Materials and Methods:EPO antibody was covalently crosslinked to protein A/G agarose. in order to interact between EPO  and its target in brain,  about 5µg EPO added to brain homogenates(500ul of 1 mg/ml and incubate at 4ο C for 30 min. brain tissue lysate were added to agarose beads, After isolation of target proteins(EPO - protein both one and two-dimensional gel electrophoresis were performed. Proteins were identified utilizing MALDI-TOF/TOF and MASCOT software. Results: This research showed that EPO could physically interact with eightproteins including  Tubulin beta, Actin cytoplasmic 2, T-complex protein 1, TPR and ankyrin repeat-containing protein 1, Centromere-associated protein E, Kinesin-like protein KIF7, Growth arrest-specific protein 2 and  Pleckstrin homology-like domain family B member 2. Conclusion: Since EPO is a promising therapeutic drug for the treatment of neurological diseases, identified proteins may help us to have a better understanding about the mechanism of protective effects of EPO in the brain. Our data needs to be validated by complementary bioassays.

  5. Neuroprotective Effect of Erythropoietin against Pressure Ulcer in a Mouse Model of Small Fiber Neuropathy

    Science.gov (United States)

    Danigo, Aurore; Magy, Laurent; Richard, Laurence; Desmoulière, Alexis; Bourthoumieu, Sylvie; Funalot, Benoît; Demiot, Claire

    2014-01-01

    An increased risk of skin pressure ulcers (PUs) is common in patients with sensory neuropathies, including those caused by diabetes mellitus. Recombinant human erythropoietin (rhEPO) has been shown to protect the skin against PUs developed in animal models of long-term diabetes. The aim of this work was to determine whether rhEPO could prevent PU formation in a mouse model of drug-inducedSFN. Functional SFN was induced by systemic injection of resiniferatoxin (RTX, 50 µg/kg, i.p.). RhEPO (3000 UI/kg, i.p.) was given the day before RTX injection and then every other day. Seven days after RTX administration, PUs were induced by applying two magnetic plates on the dorsal skin. RTX-treated mice expressed thermal and mechanical hypoalgesia and showed calcitonin gene-related peptide (CGRP) and substance P (SP) depletion without nerve degeneration or vascular dysfunction. RTX mice developed significantly larger stage 2 PUs than Vehicle mice. RhEPO prevented thermal and mechanical hypoalgesia and neuropeptide depletion in small nerve fibers. RhEPO increased hematocrit and altered endothelium-dependent vasodilatation without any effect on PU formation in Vehicle mice. The characteristics of PUs in RTX mice treated with rhEPO and Vehicle mice were found similar. In conclusion, RTX appeared to increased PU development through depletion of CGRP and SP in small nerve fibers, whereas systemic rhEPO treatment had beneficial effect on peptidergic nerve fibers and restored skin protective capacities against ischemic pressure. Our findings support the evaluation of rhEPO and/or its non-hematopoietic analogs in preventing to prevent PUs in patients with SFN. PMID:25422898

  6. Anemia in diffuse large B-cell non-Hodgkin lymphoma: the role of interleukin-6, hepcidin and erythropoietin

    NARCIS (Netherlands)

    Tisi, M.C.; Bozzoli, V.; Giachelia, M.; Massini, G.; Ricerca, B.M.; Maiolo, E.; D'Alo, F.; Larocca, L.M.; Piciocchi, A.; Tjalsma, H.; Swinkels, D.W.; Voso, M.T.; Leone, G.; Hohaus, S.

    2014-01-01

    Anemia is a frequent sign in patients with diffuse large B-cell lymphoma (DLBCL) at diagnosis. We determined erythropoietin, hepcidin and interleukin-6 (IL-6) in plasma samples of 53 patients with DLBCL. The majority of patients (40/53, 75%) showed defective endogenous erythropoietin production, in

  7. Erythropoietin-Like Effects of Dihydroartemisinin in Wistar Albino Rats

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    Utoh-Nedosa U. Anastasia

    2011-01-01

    Full Text Available Artemisinin drugs were active during the intra-erythrocytic stage of malaria parasite infection. The activity of artemisinin and synthetic endoperoxides was related to their interaction with heme. The electrophillic intermediate formed from artemisinin in the presence of heme alkylates the protein portion of hemoglobin preferentially to the heme portion. Problem statement: Since there might be an interaction between artemisinin and the heme of the blood, we studied the effects of 5-day and 7-day oral Dihydroartemisinin (DHA treatments with 5 dosage regimens of dihydroartemisinin on the blood and six vital organs of Wistar albino rats. Approach: The dosages of DHA tested on 5 test adult Wistar albino rats (weight = 106-140 grams were 1, 2, 60 or 80 mg Kg-1 rat weight of DHA by oral intubation for 5 or 7 days. Four rats of similar weight which served as controls in each experiment were given distilled water equivalents of the administered doses of DHA. Another group of 5 test rats and four control rats (weight 75-90 gms were given 1 mg kg-1 rat weight of DHA or distilled water for 5 or 7 days and were allowed to rest for one week after which the treatment was repeated. Results: The findings of the study showed that Dihydroartemisinin (DHA had erythropoietin-like properties. In the study DHA produced dose, repetition and time dependent statistically significant increases in the Packed Cell Volume (PCV (PConclusion: This result suggested that the administered DHA inhibited its own stimulated statistically significant increases in the PCV and the WBC of the treated rats through an inhibitory (negative feed-back effect. The structure and composition of the blood cell types like the presence of large numbers of reticlocytes and left-shifted neutrophils in the blood samples of 5-day DHA -treated rats but not in those of 7-day DHA treated rats indicated that new haemopoiesis was actively going on in the first 5 days of DHA treatment but had slowed down

  8. The hematopoietic growth factor "erythropoietin" enhances the therapeutic effect of mesenchymal stem cells in Alzheimer's disease.

    Science.gov (United States)

    Khairallah, M I; Kassem, L A; Yassin, N A; El Din, M A Gamal; Zekri, M; Attia, M

    2014-01-01

    Alzheimer's disease is a neurodegenerative disorder clinically characterized by cognitive dysfunction and by deposition of amyloid plaques, neurofibrillary tangles in the brain. The study investigated the therapeutic effect of combined mesenchymal stem cells and erythropoietin on Alzheimer's disease. Five groups of mice were used: control group, Alzheimer's disease was induced in four groups by a single intraperitoneal injection of 0.8 mg kg(-1) lipopolysaccharide and divided as follows: Alzheimer's disease group, mesenchymal stem cells treated group by injecting mesenchymal stem cells into the tail vein (2 x 10(6) cells), erythropoietin treated group (40 microg kg(-1) b.wt.) injected intraperitoneally 3 times/week for 5 weeks and mesenchymal stem cells and erythropoietin treated group. Locomotor activity and memory were tested using open field and Y-maze. Histological, histochemical, immunohistochemical studies, morphometric measurements were examined in brain sections of all groups. Choline transferase activity, brain derived neurotrophic factor expression and mitochondrial swellings were assessed in cerebral specimens. Lipopolysaccharide decreased locomotor activity, memory, choline transferase activity and brain derived neurotrophic factor. It increased mitochondrial swelling, apoptotic index and amyloid deposition. Combined mesenchymal stem cells and erythropoietin markedly improved all these parameters. This study proved the effective role of mesenchymal stem cells in relieving Alzheimer's disease symptoms and manifestations; it highlighted the important role of erythropoietin in the treatment of Alzheimer's disease.

  9. Evaluation of the role of erythropoietin and methotrexate in multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Sandipan Dasgupta

    2011-01-01

    Full Text Available Background : Erythropoietin, originally recognized for its role in erythropoiesis, has been shown to improve neurological outcome after stroke. Low-dose methotrexate is effective against certain inflammatory diseases, such as severe psoriasis and rheumatoid arthritis as well as Crohn′s disease. Immunosuppressive effect of methotrexate also reduces the proportion of patients with chronic progressive multiple sclerosis with modest clinical benefits. Combination of erythropoietin and methotrexate can target neuroinflammation along with immunosupression. Objective : To evaluate the role of erythropoietin and methotrexate in experimental autoimmune encephalomyelitis, a commonly used animal model of several degenerative human diseases like multiple sclerosis. Materials and Methods : In the present study, C57BL/J6 mice were immunized with 200 mg of myelin basic protein (MBP emulsified in complete Freund′s adjuvant (CFA supplemented with 1 mg/ml of killed mycobacterium tuberculosis (MBP: CFA in 1:1 ratio. These animals were given a combination of methotrexate and erythropoietin. Neurological function tests were scored daily by grading of clinical signs. Cerebral histopathology was performed to detect inflammatory infiltrates and demyelination. Results : Treatment with erythropoietin and methotrexate significantly improved the neurological function recovery, reduced inflammatory infiltrates, and demyelination as compared to controls possibly by stimulating oligodendrogenesis and down-regulating proinflammatory infiltrates. Conclusion : The findings suggest an adjunctive use of methotrexate in demyelinating disease.

  10. Diurnal variations of serum erythropoietin at sea level and altitude

    DEFF Research Database (Denmark)

    Klausen, T; Poulsen, T D; Fogh-Andersen, N

    1996-01-01

    This study tested the hypothesis that the diurnal variations of serum-erythropoietin concentration (serum-EPO) observed in normoxia also exist in hypoxia. The study also attempted to investigate the regulation of EPO production during sustained hypoxia. Nine subjects were investigated at sea level...... and during 4 days at an altitude of 4350 m. Median sea level serum-EPO concentration was 6 (range 6-13) U.l-1. Serum-EPO concentration increased after 18 and 42 h at altitude, [58 (range 39-240) and 54 (range 36-340) U.l-1, respectively], and then decreased after 64 and 88 h at altitude [34 (range 18...... in 2, 3 diphosphoglycerate. After 64 h at altitude, six of the nine subjects had down-regulated their serum-EPO concentrations so that median values were three times above those at sea level. These six subjects had significant diurnal variations of serum-EPO concentration at sea level; the nadir...

  11. Erythropoietin treatment enhances mitochondrial function in human skeletal muscle

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    Ulla ePlenge

    2012-03-01

    Full Text Available Abstract Erythropoietin (Epo treatment has been shown to induce mitochondrial biogenesis in cardiac muscle along with enhanced mitochondrial capacity in mice. We hypothesized that recombinant human Epo (rhEpo treatment enhances skeletal muscle mitochondrial oxidative phosphorylation (OXPHOS capacity in humans. In six healthy volunteers rhEpo was administered by sub-cutaneous injection over eight weeks with oral iron (100 mg supplementation taken daily. Mitochondrial OXPHOS was quantified by high-resolution respirometry in saponin-permeabilized muscle fibers obtained from biopsies of the vastus lateralis before and after rhEpo treatment. OXPHOS was determined with the mitochondrial complex I substrates malate, glutamate, pyruvate and complex II substrate succinate in the presence of saturating ADP concentrations, while maximal electron transport capacity (ETS was assessed by addition of an uncoupler. rhEpo treatment increased OXPHOS (from 92±5 to 113±7 pmol.sec-1.mg-1 and ETS (107±4 to 143±14 pmol.sec-1.mg-1, P<0.05, demonstrating that Epo treatment induces an upregulation of OXPHOS and ETS in human skeletal muscle.

  12. Erythropoietin elevation in the chronically hyperglycemic fetal lamb

    Energy Technology Data Exchange (ETDEWEB)

    Philipps, A.F. (Univ. of Connecticut Health Center, Farmington) Widness, J.A.; Garcia, J.F.; Raye, J.R.; Swartz, R.

    1982-05-01

    The effects of chronic fetal glucose infusion upon fetal oxygenation and endogenous erythropoietin (Ep) production were studied using the chronically catheterized fetal lamb. Fetal glucose infusion at rates between 5 and 20 mg/kg/min resulted in sustained fetal hyperglycemia. During glucose infusion (maximal glucose concentration achieved = 55.4 +/- 3.7 mg/dl) fetal arterial oxygen contents fell from 5.8 +/- 0.9 to 4.2 +/- 1.0 ml/dl while no changes were observed in simultaneously sampled, noninfused twins. Although plasma insulin concentration rose in the infused fetuses, the elevations were inconstant and no relationship between fetal plasma insulin concentration and decrement in fetal oxygen content was evident. The changes in plasma Ep concentration were noted prior to any significant fetal metabolic acidosis (as evidence of tissue hypoxia) and no changes in plasma Ep concentration were observed in simultaneously sampled noninfused twins. No relationship was apparent between fetal arterial plasma insulin and Ep concentrations. Since neither fetal anemia nor hemodilution occurred in these preparations, glucose-induced fetal hyposemia is the likely mechanism behind elevated fetal Ep concentrations in these experiments. Similarities between this animal model and human fetuses and infants of diabetic mothers suggest that chronic in utero hypoxemia may be a common feature responsible for such diverse abnomalities as polycythemia, hyperbilirubinemia, and late fetal demise. The mechanism behind the glucose-induced fetal hypoxemia is not known.

  13. Erythropoietin regulates Treg cells in asthma through TGFβ receptor signaling.

    Science.gov (United States)

    Wan, Guoshi; Wei, Bing

    2015-01-01

    Asthma is a chronic inflammatory disorder of the airways, the development of which is suppressed by regulatory T cells (Treg). Erythropoietin (EPO) is originally defined as a hematopoietic growth factor. Recently, the anti-inflammatory effects of EPO in asthma have been acknowledged. However, the underlying mechanisms remain ill-defined. Here, we showed that EPO treatment significantly reduced the severity of an ovalbumin (OVA)-induced asthma in mice, seemingly through promoting Foxp3-mediated activation of Treg cells in OVA-treated mouse lung. The activation of Treg cells resulted from increases in transforming growth factor β1 (TGFβ1), which were mainly produced by M2 macrophages (M2M). In vitro, Co-culture with M2M increased Foxp3 levels in Treg cells and the Treg cell number, in a TGFβ receptor signaling dependent manner. Moreover, elimination of macrophages abolished the therapeutic effects of EPO in vivo. Together, our data suggest that EPO may increase M2M, which activate Treg cells through TGFβ receptor signaling to mitigate the severity of asthma.

  14. Erythropoietin, Stem Cell Factor, and Cancer Cell Migration.

    Science.gov (United States)

    Vazquez-Mellado, Maria J; Monjaras-Embriz, Victor; Rocha-Zavaleta, Leticia

    2017-01-01

    Cell migration of normal cells is tightly regulated. However, tumor cells are exposed to a modified microenvironment that promotes cell migration. Invasive migration of tumor cells is stimulated by receptor tyrosine kinases (RTKs) and is regulated by growth factors. Erythropoietin (Epo) is a glycoprotein hormone that regulates erythropoiesis and is also known to be a potent chemotactic agent that induces cell migration by binding to its receptor (EpoR). Expression of EpoR has been documented in tumor cells, and the potential of Epo to induce cell migration has been explored. Stem cell factor (SCF) is a cytokine that synergizes the effects of Epo during erythropoiesis. SCF is the ligand of c-Kit, a member of the RTKs family. Molecular activity of RTKs is a primary stimulus of cell motility. Thus, expression of the SCF/c-Kit axis is associated with cell migration. In this chapter, we summarize data describing the potential effect of Epo/EpoR and SCF/c-Kit as promoters of cancer cell migration. We also integrate recent findings on molecular mechanisms of Epo/EpoR- and SCF/c-Kit-mediated migration described in various cancer models. © 2017 Elsevier Inc. All rights reserved.

  15. Radioimmunoassay of erythropoietin in chronic uraemia or anephric patients

    Energy Technology Data Exchange (ETDEWEB)

    Naets, J.P.; Waks, D.; Garcia, J.F.; Tousaaint, C.; Buset, M.

    1986-01-01

    The erythropoietin (Ep) plasma titre of 41 anaemic patients with normal renal function or with renal insufficiency (with or without kidney) was measured by RIA and compared to values observed with the polycythaemic mouse assay. A good correlation was found with both methods (r = 0.88). However, about 20% of samples gave higher values with the bioassay. 21 Ep titres measurable by the bioassay ranged from 40 to 4400 mU (mean 717.1 mU) compared to 14.8 to 3788 mU (mean 484.7 mU) measured by the RIA. Low levels of Ep plasma titre have been observed in patients with renal insufficiency and no difference was found between nephric uraemic patients and the anephric group. These results suggest that the increased blood requirements in anephrics are not due to a smaller production of Ep, but ultimately to the presence of an inhibitor of erythropoiesis. The well-known inverse relationship between haematocrit and Ep level was not found in renal insufficiency. However, some humoral regulation of erythropoiesis seems to persist in these patients since the elevation of red blood cells by transfusions was followed by a decrease of the Ep level.

  16. Regulated expression of erythropoietin by two human hepatoma cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Goldberg, M.A.; Glass, G.A.; Cunningham, J.M.; Bunn, H.F.

    1987-11-01

    The development of a cell culture system that produces erythropoietin (Epo) in a regulated manner has been the focus of much effort. The authors have screened multiple renal and hepatic cell lines for either constitutive or regulated expression of Epo. Only the human hepatoma cell lines, Hep3B and HepG2, made significant amounts of Epo as measured both by radioimmunoassay and in vitro bioassay (as much as 330 milliunits per 10/sup 6/ cells in 24 hr). The constitutive production of Epo increased dramatically as a function of cell density in both cell lines. At cell densities < 3.3 x 10/sup 5/ cells per cm/sup 2/, there was little constitutive release of Epo in the medium. With Hep3B cells grown at low cell densities, a mean 18-fold increase in Epo expression was seen in response to hypoxia and a 6-fold increase was observed in response to incubation in medium containing 50 ..mu..M cobalt(II) chloride. At similar low cell densities, Epo production in HepG2 cells could be enhanced an average of about 3-fold by stimulation with either hypoxia or cobalt(II) chloride. Upon such stimulation, both cell lines demonstrated markedly elevated levels of Epo mRNA. Hence, both Hep3B and HepG2 cell lines provide an excellent in vitro system in which to study the physiological regulation of Epo expression.

  17. Erythropoietin reduces the expression of myostatin in mdx dystrophic mice

    Directory of Open Access Journals (Sweden)

    D. Feder

    2014-11-01

    Full Text Available Erythropoietin (EPO has been well characterized as a renal glycoprotein hormone regulating red blood cell production by inhibiting apoptosis of erythrocyte progenitors in hematopoietic tissues. EPO exerts regulatory effects in cardiac and skeletal muscles. Duchenne muscular dystrophy is a lethal degenerative disorder of skeletal and cardiac muscle. In this study, we tested the possible therapeutic beneficial effect of recombinant EPO (rhEPO in dystrophic muscles in mdx mice. Total strength was measured using a force transducer coupled to a computer. Gene expression for myostatin, transforming growth factor-β1 (TGF-β1, and tumor necrosis factor-α (TNF-α was determined by quantitative real time polymerase chain reaction. Myostatin expression was significantly decreased in quadriceps from mdx mice treated with rhEPO (rhEPO=0.60±0.11, control=1.07±0.11. On the other hand, rhEPO had no significant effect on the expression of TGF-β1 (rhEPO=0.95±0.14, control=1.05±0.16 and TNF-α (rhEPO=0.73±0.20, control=1.01±0.09. These results may help to clarify some of the direct actions of EPO on skeletal muscle.

  18. Local erythropoietin signaling enhances regeneration in peripheral axons.

    Science.gov (United States)

    Toth, C; Martinez, J A; Liu, W Q; Diggle, J; Guo, G F; Ramji, N; Mi, R; Hoke, A; Zochodne, D W

    2008-06-23

    Erythropoietin (EPO) and its receptor (EPO-R), mediate neuroprotection from axonopathy and apoptosis in the peripheral nervous system (PNS). We examined the impact and potential mechanisms of local EPO signaling on regenerating PNS axons in vivo and in vitro. As a consequence of injury, peripheral nerve axons and DRG neurons have a marked increase in the expression of EPO and EPO-R. Local delivery of EPO via conduit over 2 weeks to rat sciatic nerve following crush injury increased the density and maturity of regenerating myelinated axons growing distally from the crush site. In addition, EPO also rescued retrograde degeneration and atrophy of axons. EPO substantially increased the density and intensity of calcitonin gene-related peptide (CGRP) expression within outgrowing axons. Behavioral improvements in sensorimotor function also occurred in rats exposed to near nerve EPO delivery. EPO delivery led to decreased nuclear factor kappaB (NFkB) activation but increased phosphorylation of Akt and STAT3 within nerve and dorsal root ganglia neurons indicating rescue from an injury phenotype. Spinal cord explant studies also demonstrated a similar dose-dependent effect of EPO upon motor axonal outgrowth. Local EPO signaling enhances regenerating peripheral nervous system axons in addition to its known neuroprotection. Exogenous EPO may have a therapeutic role in a large number of peripheral nerve diseases through its impact on regeneration.

  19. Erythropoietin, Forkhead Proteins, and Oxidative Injury: Biomarkers and Biology

    Directory of Open Access Journals (Sweden)

    Kenneth Maiese

    2009-01-01

    Full Text Available Oxidative stress significantly impacts multiple cellular pathways that can lead to the initiation and progression of varied disorders throughout the body. It therefore becomes imperative to elucidate the components and function of novel therapeutic strategies against oxidative stress to further clinical diagnosis and care. In particular, both the growth factor and cytokine erythropoietin (EPO, and members of the mammalian forkhead transcription factors of the O class (FoxOs, may offer the greatest promise for new treatment regimens, since these agents and the cellular pathways they oversee cover a range of critical functions that directly influence progenitor cell development, cell survival and degeneration, metabolism, immune function, and cancer cell invasion. Furthermore, both EPO and FoxOs function not only as therapeutic targets, but also as biomarkers of disease onset and progression, since their cellular pathways are closely linked and overlap with several unique signal transduction pathways. Yet, EPO and FoxOs may sometimes have unexpected and undesirable effects that can raise caution for these agents and warrant further investigations. Here we present the exciting as well as the complex role that EPO and FoxOs possess to uncover the benefits as well as the risks of these agents for cell biology and clinical care in processes that range from stem cell development to uncontrolled cellular proliferation.

  20. Erythropoietin, forkhead proteins, and oxidative injury: biomarkers and biology.

    Science.gov (United States)

    Maiese, Kenneth; Hou, Jinling; Chong, Zhao Zhong; Shang, Yan Chen

    2009-10-02

    Oxidative stress significantly impacts multiple cellular pathways that can lead to the initiation and progression of varied disorders throughout the body. It therefore becomes imperative to elucidate the components and function of novel therapeutic strategies against oxidative stress to further clinical diagnosis and care. In particular, both the growth factor and cytokine erythropoietin (EPO), and members of the mammalian forkhead transcription factors of the O class (FoxOs), may offer the greatest promise for new treatment regimens, since these agents and the cellular pathways they oversee cover a range of critical functions that directly influence progenitor cell development, cell survival and degeneration, metabolism, immune function, and cancer cell invasion. Furthermore, both EPO and FoxOs function not only as therapeutic targets, but also as biomarkers of disease onset and progression, since their cellular pathways are closely linked and overlap with several unique signal transduction pathways. Yet, EPO and FoxOs may sometimes have unexpected and undesirable effects that can raise caution for these agents and warrant further investigations. Here we present the exciting as well as the complex role that EPO and FoxOs possess to uncover the benefits as well as the risks of these agents for cell biology and clinical care in processes that range from stem cell development to uncontrolled cellular proliferation.

  1. High doses of recombinant erythropoietin stimulate platelet production in mice

    Energy Technology Data Exchange (ETDEWEB)

    McDonald, T.P.; Cottrell, M.B.; Clift, R.E.; Cullen, W.C.; Lin, F.K.

    1987-07-01

    Previously, recombinant erythropoietin (rEpo) was shown to increase the number and size of megakaryocytic colonies in vitro, and in vivo it elevates the number of megakaryocytes in mouse spleens. To test the hypothesis that rEpo would stimulate platelet production in mice, both normal mice and mice in rebound-thrombocytosis were injected with rEpo and the %35S incorporation into platelets was measured. A thrombocytopoiesis-stimulating factor (TSF or thrombopoietin) was used as a positive control. rEpo increased isotopic incorporation into platelets of both normal mice and mice in rebound-thrombocytosis, as did TSF, but required large doses (15 U rEpo/mouse). In other mice, hematocrits, platelet counts, platelet sizes, and 24-hr %35S incorporation into platelets were measured 2 days after injection of two equally divided doses of either rEpo or TSF. Significant increases in both platelet sizes and %35S incorporation into platelets were found after injections of 15 U rEpo/mouse or 2.3 U TSF/mouse. These data indicate that rEpo, at high doses, will stimulate platelet production in mice, and may suggest molecular similarities between rEpo and TSF and their ability to compete for common receptor sites on megakaryocytes and their progenitor cells.

  2. Efficiency of recombinant erythropoietin administration in hemoglobinopathy H.

    Science.gov (United States)

    Hasanova, M; Asadov, Ch; Alimirzoyeva, Z; Mammadova, T; Shirinova, A

    2014-01-01

    Alpha-thalassemia is widely spread in human population and one of the most common types of α-thalassemia is hemoglobinopathy H which develops with mild microcytic hypochromic anemia, hepatosplenomegaly and jaundice. The basic method of anemia correction is blood transfusion. However this method has crucial deficiencies. As it is known recombinant erythropoetin (rEPO) contributes to erythroid proliferation and could be used for anemia treatment. The aim of the study was to qualify efficiency of administration rEPO in complex therapy of hemaglobinopathy H. Study involved irregularly transfused 14 patients with hemoglobinopathy H (2 males and 12 females). Control group included 30 healthy persons. Recombinant erythropoietin (Eprex) administrated hypodermically 10,000 units 3 times a week during 6 months. Average hemoglobin level before treatment was 62 g/l. Responses to the rEPO treatment varied from 9 to 70 g/l, 9 (64%) of patients had a good response, showed an increase in hemoglobin level more than 20 g/l. In 4 patients (29%) had a moderate response (10-20 g/l), but only in 1 (7%) patient occurred poor response. Changing the parameters of erithrocyte indices, hemoglobin fractions, serum iron and serum ferritin level are not statistically significant. It can be concluded that the use of rEPO in complex therapy of hemaglobinopathy H, leads to increased levels of hemoglobin and consequently reducing the need for blood transfusions.

  3. Erythropoietin reduces the expression of myostatin in mdx dystrophic mice

    Energy Technology Data Exchange (ETDEWEB)

    Feder, D.; Rugollini, M.; Santomauro, A. Jr; Oliveira, L.P.; Lioi, V.P. [Faculdade de Medicina do ABC, Santo André, SP (Brazil); Santos, R. dos; Ferreira, L.G.; Nunes, M.T.; Carvalho, M.H. [Universidade de São Paulo, Instituto de Ciências Biomédicas, São Paulo, SP (Brazil); Delgado, P.O.; Carvalho, A.A.S. [Faculdade de Medicina do ABC, Santo André, SP (Brazil); Fonseca, F.L.A. [Faculdade de Medicina do ABC, Santo André, SP (Brazil); Universidade Federal de São Paulo, Ambientais e Farmacêuticas, Instituto de Ciências Químicas, Diadema, SP (Brazil)

    2014-09-05

    Erythropoietin (EPO) has been well characterized as a renal glycoprotein hormone regulating red blood cell production by inhibiting apoptosis of erythrocyte progenitors in hematopoietic tissues. EPO exerts regulatory effects in cardiac and skeletal muscles. Duchenne muscular dystrophy is a lethal degenerative disorder of skeletal and cardiac muscle. In this study, we tested the possible therapeutic beneficial effect of recombinant EPO (rhEPO) in dystrophic muscles in mdx mice. Total strength was measured using a force transducer coupled to a computer. Gene expression for myostatin, transforming growth factor-β1 (TGF-β1), and tumor necrosis factor-α (TNF-α) was determined by quantitative real time polymerase chain reaction. Myostatin expression was significantly decreased in quadriceps from mdx mice treated with rhEPO (rhEPO=0.60±0.11, control=1.07±0.11). On the other hand, rhEPO had no significant effect on the expression of TGF-β1 (rhEPO=0.95±0.14, control=1.05±0.16) and TNF-α (rhEPO=0.73±0.20, control=1.01±0.09). These results may help to clarify some of the direct actions of EPO on skeletal muscle.

  4. Diurnal variations of serum erythropoietin at sea level and altitude

    DEFF Research Database (Denmark)

    Klausen, T; Poulsen, T D; Fogh-Andersen, N;

    1996-01-01

    This study tested the hypothesis that the diurnal variations of serum-erythropoietin concentration (serum-EPO) observed in normoxia also exist in hypoxia. The study also attempted to investigate the regulation of EPO production during sustained hypoxia. Nine subjects were investigated at sea level...... and during 4 days at an altitude of 4350 m. Median sea level serum-EPO concentration was 6 (range 6-13) U.l-1. Serum-EPO concentration increased after 18 and 42 h at altitude, [58 (range 39-240) and 54 (range 36-340) U.l-1, respectively], and then decreased after 64 and 88 h at altitude [34 (range 18......-290) and 31 (range 17-104) U.l-1, respectively]. These changes of serum-EPO concentration were correlated to the changes in arterial blood oxygen saturation (r = -0.60, P = 0.0009), pH (r = 0.67, P = 0.003), and in-vivo venous blood oxygen half saturation tension (r = -0.68, P = 0.004) but not to the changes...

  5. Erythropoietin regulations in humans under different environmental and experimental conditions.

    Science.gov (United States)

    Gunga, H-C; Kirsch, K A; Roecker, L; Kohlberg, E; Tiedemann, J; Steinach, M; Schobersberger, W

    2007-09-30

    In the adult human, the kidney is the main organ for the production and release of erythropoietin (EPO). EPO is stimulating erythropoiesis by increasing the proliferation, differentiation and maturation of the erythroid precursors. In the last decades, enormous efforts were made in the purification, molecular encoding and description of the EPO gene. This led to an incredible increase in the understanding of the EPO-feedback-regulation loop at a molecular level, especially the oxygen-dependent EPO gene expression, a key function in the regulation loop. However, studies in humans at a systemic level are still very scanty. Therefore, it is the purpose of the present review to report on the main recent investigations on EPO production and release in humans under different environmental and experimental conditions, including: (i) studies on EPO circadian, monthly and even annual variations, (ii) studies in connection with short-, medium- and long-term exercise at sea-level which will be followed (iii) by studies performed at moderate and high altitude.

  6. Erythropoietin research, 80 years after the initial studies by Carnot and Deflandre.

    Science.gov (United States)

    Jelkmann, W

    1986-03-01

    The discovery and present state of knowledge of the specific hormonal mechanism controlling erythropoiesis are briefly reviewed. 80 years ago, Carnot and Deflandre postulated the existence of a humoral erythropoietic factor ('hémopoïétine') produced in response to anemia. The general approval of this concept required almost 50 years, when the factor was recognized to be a glycoprotein hormone and termed 'erythropoietin'. Very recently, human erythropoietin has been purified and its amino acid sequence been identified. The hormone is mainly of renal origin. Its production is stimulated by tissue hypoxia of different causes. The mechanism of O2 sensing and the exact site of erythropoietin synthesis in the kidney still remain to be clarified.

  7. The anemia of microgravity and recumbency. Role of sympathetic neural control of erythropoietin production

    Science.gov (United States)

    Robertson, David; Krantz, Sanford B.; Biaggioni, Italo

    We hypothesize that reduced sympathetic stimulation of erythropoietin production may maintain the anemia which develops in virtually all space travellers. We tested this hypothesis in a human model of reduced sympathetic activity. Thirty-three patients with the Bradbury-Eggleston syndrome were divided into three groups according to their hemoglobin (Hgb) level. Patients with low Hgb had lower upright norepinephrine and lower upright renin. Patients with anemia also had inappropriately low plasma erythropoietin levels. We administered recombinant erythropoietin (Epogen) 25-50 units/kg s.c. 3 times per week and found that the anemia seen in autonomic failure could be reversed by this treatment. These results support the hypothesis that erythropoiesis is modulated by the sympathetic nervous system and that such mechanisms may also operate in the microgravity environment where sympathetic activity is reduced.

  8. Expression and analysis of the glycosylation properties of recombinant human erythropoietin expressed in Pichia pastoris

    Directory of Open Access Journals (Sweden)

    Ser Huy Teh

    2011-01-01

    Full Text Available The Pichia pastoris expression system was used to produce recombinant human erythropoietin, a protein synthesized by the adult kidney and responsible for the regulation of red blood cell production. The entire recombinant human erythropoietin (rhEPO gene was constructed using the Splicing by Overlap Extension by PCR (SOE-PCR technique, cloned and expressed through the secretory pathway of the Pichia expression system. Recombinant erythropoietin was successfully expressed in P. pastoris. The estimated molecular mass of the expressed protein ranged from 32 kDa to 75 kDa, with the variation in size being attributed to the presence of rhEPO glycosylation analogs. A crude functional analysis of the soluble proteins showed that all of the forms were active in vivo.

  9. Erythropoietin ameliorates renal interstitial fibrosis via the inhibition of fibrocyte accumulation.

    Science.gov (United States)

    Geng, Xu Chang; Hu, Zhou Pang; Lian, Guo Yong

    2015-05-01

    Erythropoietin (EPO) is a hematopoietic hormone that protects against renal interstitial fibrosis in animal models; however, the mechanism underlying the anti‑fibrotic activity of EPO has remained elusive. The present study aimed to elucidate this mechanism. Twenty‑four male C57BL6 mice were randomly divided into four groups, each comprising six mice: (i) control group (Sh); (ii) unilateral ureteral obstruction (UUO) plus vehicle group (U+V); (ⅲ) UUO plus 300 U/kg body weight recombinant human (rh)EPO (U+E1) and (ⅳ) UUO plus 1,000 U/kg body weight rhEPO (U+E2). Seven days post‑surgery, the mice were sacrificed for examination. UUO induced significant deposition of extracellular matrix, detected by picro‑sirius red staining, which was decreased following rhEPO treatment. UUO also induced deposition of collagen I and fibronectin, rhEPO treatment was able to attenuate this effect at protein and mRNA levels. Compared with the control groups, UUO resulted in the accumulation of α‑smooth muscle actin‑positive cells in the interstitium, an effect which was ameliorated by rhEPO. Furthermore, rhEPO abrogated the UUO‑induced increase in the number of bone marrow‑derived myofibroblasts. Mechanistically, it was discovered that rhEPO decreased CXC chemokine ligand 16 (CXCL16) expression at protein level. However, treatment with rhEPO did not alter the protein expression of CC chemokine ligand 21 or CXCL12. These results suggested that rhEPO decreased fibrocyte accumulation via the suppression of renal CXCL16, which resulted in the attenuation of renal fibrosis.

  10. Erythropoietin: a potent inducer of peripheral immuno/inflammatory modulation in autoimmune EAE.

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    RuiRong Yuan

    Full Text Available BACKGROUND: Beneficial effects of short-term erythropoietin (EPO therapy have been demonstrated in several animal models of acute neurologic injury, including experimental autoimmune encephalomyelitis (EAE--the animal model of multiple sclerosis. We have found that EPO treatment substantially reduces the acute clinical paralysis seen in EAE mice and this improvement is accompanied by a large reduction in the mononuclear cell infiltration and downregulation of glial MHC class II expression within the inflamed CNS. Other reports have recently indicated that peripherally generated anti-inflammatory CD4(+Foxp3(+ regulatory T cells (Tregs and the IL17-producing CD4+ T helper cell (Th17 subpopulations play key antagonistic roles in EAE pathogenesis. However, no information regarding the effects of EPO therapy on the behavior of the general mononuclear-lymphocyte population, Tregs or Th17 cells in EAE has emerged. METHODS AND FINDINGS: We first determined in vivo that EPO therapy markedly suppressed MOG specific T cell proliferation and sharply reduced the number of reactive dendritic cells (CD11c positive in EAE lymph nodes during both inductive and later symptomatic phases of MOG(35-55 induced EAE. We then determined the effect in vivo of EPO on numbers of peripheral Treg cells and Th17 cells. We found that EPO treatment modulated immune balance in both the periphery and the inflamed spinal cord by promoting a large expansion in Treg cells, inhibiting Th17 polarization and abrogating proliferation of the antigen presenting dendritic cell population. Finally we utilized tissue culture assays to show that exposure to EPO in vitro similarly downregulated MOG-specific T cell proliferation and also greatly suppressed T cell production of pro-inflammatory cytokines. CONCLUSIONS: Taken together, our findings reveal an important new locus whereby EPO induces substantial long-term tissue protection in the host through signaling to several critical subsets of

  11. Erythropoietin promotes survival and regeneration of insect neurons in vivo and in vitro.

    Science.gov (United States)

    Ostrowski, D; Ehrenreich, H; Heinrich, R

    2011-08-11

    In addition to its function as a regulator of hematopoiesis, the cytokine erythropoietin (Epo) initiates adaptive cellular responses to both moderate environmental challenges and tissue damaging insults in various non-hematopoietic mammalian tissues. Epo's neuroprotective and neuroregenerative functions mediated through janus kinases (JAK)/signal transducers and activators of transcription (STAT) transduction pathways and regulation of Epo and Epo receptor expression in the nervous system by hypoxia inducible factor (HIF) have been documented in a variety of in vitro and in vivo studies and homologs of the human Epo gene are present in fish, amphibians and mammals. The present study reproduces the hallmarks of Epo-mediated mammalian neuroprotection in the grasshopper nervous system. Recombinant human Epo (rhEpo) increases the survival of dissociated grasshopper brain neurons under normoxic and hypoxic conditions and promotes the regeneration of neurites in vitro. In addition, reestablishment of sound source localization after unilateral tympanic nerve crush injury was accelerated and more complete after application of rhEpo, demonstrating in vivo support of auditory receptor cell axon regeneration. Immunoblots of central nervous tissue extracts from mouse, grasshopper, crayfish and leech labeled protein bands of ∼38 kDa, fitting to the molecular weight of Epo reported in earlier studies. These results indicate that a ligand/receptor system that shares structural and functional similarities with mammalian Epo and Epo receptor exerts neuroprotective and neuroregenerative effects in insects. With both upstream (HIF system) and downstream (JAK/STAT pathway) elements of the mammalian Epo system being present in insects and other invertebrates, Epo-like signaling involved in tissue protection appears to be an ancient beneficial function shared by vertebrates and invertebrates.

  12. Pyruvate-fortified cardioplegia evokes myocardial erythropoietin signaling in swine undergoing cardiopulmonary bypass.

    Science.gov (United States)

    Ryou, Myoung-Gwi; Flaherty, Devin C; Hoxha, Besim; Sun, Jie; Gurji, Hunaid; Rodriguez, Steven; Bell, Glenn; Olivencia-Yurvati, Albert H; Mallet, Robert T

    2009-11-01

    Pyruvate-fortified cardioplegia protects myocardium and hastens postsurgical recovery of patients undergoing cardiopulmonary bypass (CPB). Pyruvate reportedly suppresses degradation of the alpha-subunit of hypoxia-inducible factor-1 (HIF-1), an activator of the gene encoding the cardioprotective cytokine erythropoietin (EPO). This study tested the hypothesis that pyruvate-enriched cardioplegia evoked EPO expression and mobilized EPO signaling mechanisms in myocardium. Hearts of pigs maintained on CPB were arrested for 60 min with 4:1 blood-crystalloid cardioplegia. The crystalloid component contained 188 mM glucose + or - 24 mM pyruvate. After 30-min cardiac reperfusion with cardioplegia-free blood, the pigs were weaned from CPB. Left ventricular myocardium was sampled 4 h after CPB for immunoblot assessment of HIF-1alpha, EPO and its receptor, the signaling kinases Akt and ERK, and endothelial nitric oxide synthase (eNOS), an effector of EPO signaling. Pyruvate-fortified cardioplegia stabilized arterial pressure post-CPB, induced myocardial EPO mRNA expression, and increased HIF-1alpha, EPO, and EPO-R protein contents by 60, 58, and 123%, respectively, vs. control cardioplegia (P Pyruvate cardioplegia also increased ERK phosphorylation by 61 and 118%, respectively, vs. control cardioplegia-treated and non-CPB sham myocardium (P pyruvate cardioplegia prevented these declines, yielding 49 and 80% greater NOS activity and eNOS content vs. respective control values (P Pyruvate-fortified cardioplegia induced myocardial EPO expression and mobilized the EPO-ERK-eNOS mechanism. By stabilizing HIF-1alpha, pyruvate-fortified cardioplegia may evoke sustained activation of EPO's cardioprotective signaling cascade in myocardium.

  13. Caveat oncologist: clinical findings and consequences of distributing counterfeit erythropoietin in the United States.

    Science.gov (United States)

    Qureshi, Zaina P; Norris, Leann; Sartor, Oliver; McKoy, June M; Armstrong, John; Raisch, Dennis W; Garg, Vishvas; Stafkey-Mailey, Dana; Bennett, Charles Lee

    2012-03-01

    Counterfeit pharmaceuticals pose risks domestically. Because of their cost, cancer pharmaceuticals are vulnerable. We review findings from a domestic counterfeiting episode involving erythropoietin and outline anticounterfeiting recommendations for policy makers, patients, and health care professionals. Information was obtained on patients who received counterfeit erythropoietin, its distribution, and criminal investigations into counterfeiting networks. Interview sources included a physician, an attorney, employees of the Florida Department of Health and Human Services and the US Food and Drug Administration's (FDA) Office of Criminal Investigation, manufacturers, and wholesalers. Other sources included the book "Dangerous Doses," LexisNexis (search terms "counterfeit" and "erythropoietin") and the FDA database. Counterfeit product consisted of 2,000 U vials with counterfeit labels denoting 40,000 U. The counterfeiters, in collaboration with a Miami pharmacy, purchased 110,000 erythropoietin 2,000 U vials and affixed counterfeit labels to each vial. Products were then sold via the pharmaceutical "gray market" to wholesalers, then pharmacy chains. Investigations by Florida government officials implicated 17 persons, all of whom were found guilty of trafficking in counterfeit pharmaceuticals. Despite the large size of the operation, the FDA received reports of only 12 patients who had received counterfeit erythropoietin and detailed information for only two individuals. A 17-year-old liver transplant recipient and a 61-year-old patient with breast cancer experienced loss of efficacy after receiving counterfeit erythropoietin. Wider use of FDA anticounterfeit initiatives, limiting pharmaceutical suppliers to reputable distributors, and educating providers and patients about signs of counterfeit drugs can improve the safety of cancer pharmaceuticals.

  14. Erythropoietin, ferritin, haptoglobin, hemoglobin and transferrin receptor in metabolic syndrome: a case control study

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    Hämäläinen Päivi

    2012-09-01

    Full Text Available Abstract Background Increased ferritin concentrations are associated with metabolic syndrome (MetS. The association between ferritin as well as hemoglobin level and individual MetS components is unclear. Erythropoietin levels in subjects with MetS have not been determined previously. The aim of this study was to compare serum erythropoietin, ferritin, haptoglobin, hemoglobin, and transferrin receptor (sTFR levels between subjects with and without MetS and subjects with individual MetS components. Methods A population based cross-sectional study of 766 Caucasian, middle-aged subjects (341 men and 425 women from five age groups born in Pieksämäki, Finland who were invited to a health check-up in 2004 with no exclusion criteria. Laboratory analyzes of blood samples collected in 2004 were done during year 2010. MetS was defined by National Cholesterol Education Program criteria. Results 159 (53% men and 170 (40% women of study population met MetS criteria. Hemoglobin and ferritin levels as well as erythropoietin and haptoglobin levels were higher in subjects with MetS (p  Conclusion Subjects with MetS have elevated hemoglobin, ferritin, erythropoietin and haptoglobin concentrations. Higher hemoglobin levels are related to all components of MetS. Higher ferritin levels associate with TG, abdominal obesity, elevated glucose or low high density cholesterol. Haptoglobin levels associate with blood pressure or elevated glucose. However, erythropoietin levels are related only with abdominal obesity. Higher serum erythropoietin concentrations may suggest underlying adipose tissue hypoxemia in MetS.

  15. The role of renal adenosine 3',5'-monophosphate in the control of erythropoietin production.

    Science.gov (United States)

    Rodgers, G M; Fisher, J W; George, W J

    1975-01-01

    A regulatory role for adenosine 3',5'-monophosphate (cyclic AMP) in the production of the renal hormone rythropoietin following erythropoietic stimulation with cobaltous chloride hexahydrate is proposed. Studies in rates reveal a temporal relationship between renal cyclic AMP levels and plasma titers of erythropoietin. In addition, cobalt increases the activity of an erythropoietin-generating enzyme (renal erythropoietic factor) with maximal enzyme activity occurring after the rise in cyclic AMP levels but before the increase in erythropoietin titers. This increase in renal cyclic AMP is localized to the renal cortex. Cobalt stimulates renal cortical adenylate cyclase but has no effect on renal cyclic nucleotide phosphodiesterase. The addition of cyclic AMP (3 time 10-6 M) and a partially purified cyclic AMP-dependent protein kinase from rat kidney to an inactive preparation of renal erythropoietic factor increases the ability of renal erythropoietic factor to generate erythropoietin. Data from the polycythemic mouse assay, a bioassay used to quantitate erythropoietic activity of test substances, indicate that dibutyryl cyclic AMP is erythropoietically active with respect to its ability to increase radioactive-labelled iron (59Fe) incorporation into heme of newly formed red blood cells. Theophylline, which by itself is erythropoietically inactive, potentiated the erythropoietic effect of cobalt in polycythemic mice. These results suggest that cyclic AMP plays a significant role in the renal production of erythropoietin following cobalt administration. It is postulated that cobalt stimulates renal cortical adenyoate cyclase, thus increasing renal cyclic AMP levels. Cyclic AMP then activates a protein kinase which subsequently stimulates renal erythropoietic factor to generate erythropoietin. A similar cyclic AMP mechanism may be operative after erythropoietic stimulation by exposure to hypoxia or prostaglandin treatment.

  16. The anemia of primary autonomic failure and its reversal with recombinant erythropoietin

    Science.gov (United States)

    Biaggioni, I.; Robertson, D.; Krantz, S.; Jones, M.; Haile, V.

    1994-01-01

    OBJECTIVE: To determine if chronic sympathetic deprivation is associated with anemia and a low erythropoietin response. DESIGN: Survey of the prevalence and characteristics of anemia in patients with severe primary autonomic failure. SETTING: A referral service for autonomic failure in a tertiary teaching hospital. PATIENTS: 84 patients with primary autonomic failure who had symptomatic orthostatic hypotension. INTERVENTION: Open-label trial with human recombinant erythropoietin. RESULTS: Anemia was present in 32 of 84 patients (38%; 95% Cl, 27% to 50%). Plasma norepinephrine levels, measured in patients standing upright, were lower in the patient group with lower hemoglobin levels. Mean values in 22 patients with a hemoglobin level of less than 120 g/L were as follows: hemoglobin, 108 g/L (range, 87 to 118 g/L); hematocrit, 0.33; corrected reticulocyte counts, 0.008; mean corpuscular volume, 89 fL (89 microns 3); serum iron, 16.5 mumol/L (92 micrograms/dL); total iron binding capacity, 43.3 mumol/L (242 micrograms/dL); ferritin, 184 micrograms/L; serum vitamin B12, 410 pmol/L (556 pg/mL); and serum folate, 22.7 nmol/L (10 ng/mL). No relation was found between serum erythropoietin and blood hemoglobin levels. In seven of nine patients with autonomic failure who had hemoglobin levels less than 120 g/L, serum erythropoietin levels decreased below the 95% confidence interval corresponding to patients with iron deficiency anemia. Therapy with recombinant erythropoietin improved mean hemoglobin levels (from 108 to 133 g/L) in all patients treated (n = 5) at relatively low doses (25 to 50 units/kg body weight, subcutaneously, three times a week). CONCLUSIONS: Our data support the hypothesis that the sympathetic nervous system stimulates erythropoiesis in humans because anemia is a frequent occurrence in patients with severe autonomic failure and is associated with a blunted erythropoietin response.

  17. The Effect of Human Recombinant Erythropoietin on Prevention of Anemia of Prematurity

    Directory of Open Access Journals (Sweden)

    K Hajian

    2007-06-01

    Full Text Available Objective: Premature infants often develop significant anemia that requires blood transfusion, this carries significant risks. This study was carried out to determine the effect of recombinant human erythropoietin (r-HuEPO on prevention of anemia of prematurity. Material & Methods: From April 2001 to March 2002, 24 neonates in  newborn services at Amirkola childrens hospital randomly were assigned to erythropoietin group and control (no treatment group. Inclusion criteria were birth weight of ≤1750 grams and gestational age ≤34 weeks. Exclusion criteria were problems of hemolytic anemia, congenital infections, congenital malformations, severe asphyxia, intraventricular hemorrhage (grade III and IV, need for exchange transfusion and death during the first week of life. Erythropoietin group received r-HuEPO400 unit/kg/dose subcutaneously three times a week plus 4 mg/kg/day iron orally. White blood cell, hemoglobin (Hgb, hematocrit (Hct, platelet and reticulocyte count were obtained every 2 weeks until the 42nd day of life. Anemia was defined as Hgb≤8gr/dl and Hct≤24%. Student t test and Fisher exact were used to evaluate differences between the two groups.Findings: Hemoglobin and hematocrit values were significantly higher in erythropoietin group than the control group after the 14th day of the study (P<0.04 and this difference was getting higher until the end of the trial (P<0.001. Five neonates developed anemia; all of them were from control group. One of these neonates required transfusion. None of the erythropoietin group newborns developed anemia.Conclusion: The results of this study confirm the efficacy of recombinant human erythropoietin in the prevention of anemia of prematurity.

  18. The anemia of primary autonomic failure and its reversal with recombinant erythropoietin

    Science.gov (United States)

    Biaggioni, I.; Robertson, D.; Krantz, S.; Jones, M.; Haile, V.

    1994-01-01

    OBJECTIVE: To determine if chronic sympathetic deprivation is associated with anemia and a low erythropoietin response. DESIGN: Survey of the prevalence and characteristics of anemia in patients with severe primary autonomic failure. SETTING: A referral service for autonomic failure in a tertiary teaching hospital. PATIENTS: 84 patients with primary autonomic failure who had symptomatic orthostatic hypotension. INTERVENTION: Open-label trial with human recombinant erythropoietin. RESULTS: Anemia was present in 32 of 84 patients (38%; 95% Cl, 27% to 50%). Plasma norepinephrine levels, measured in patients standing upright, were lower in the patient group with lower hemoglobin levels. Mean values in 22 patients with a hemoglobin level of less than 120 g/L were as follows: hemoglobin, 108 g/L (range, 87 to 118 g/L); hematocrit, 0.33; corrected reticulocyte counts, 0.008; mean corpuscular volume, 89 fL (89 microns 3); serum iron, 16.5 mumol/L (92 micrograms/dL); total iron binding capacity, 43.3 mumol/L (242 micrograms/dL); ferritin, 184 micrograms/L; serum vitamin B12, 410 pmol/L (556 pg/mL); and serum folate, 22.7 nmol/L (10 ng/mL). No relation was found between serum erythropoietin and blood hemoglobin levels. In seven of nine patients with autonomic failure who had hemoglobin levels less than 120 g/L, serum erythropoietin levels decreased below the 95% confidence interval corresponding to patients with iron deficiency anemia. Therapy with recombinant erythropoietin improved mean hemoglobin levels (from 108 to 133 g/L) in all patients treated (n = 5) at relatively low doses (25 to 50 units/kg body weight, subcutaneously, three times a week). CONCLUSIONS: Our data support the hypothesis that the sympathetic nervous system stimulates erythropoiesis in humans because anemia is a frequent occurrence in patients with severe autonomic failure and is associated with a blunted erythropoietin response.

  19. The possibility of harmonizing the recombinant erythropoietin specific activity determination method with European Pharmacopoeia

    Directory of Open Access Journals (Sweden)

    A. K. Yakovlev

    2016-01-01

    Full Text Available Rationale. The task of import substitution in health care and the development of normative legal acts in the framework of the Eurasian Economic Community raises the questions of harmonization of national requirements with international ones, including the standardization of drugs. Thereby, the assessment of the quality of domestic recombinant human erythropoietin in accordance with European Pharmacopoeia requirements is very actual. The main indicator of drug quality is specific activity of drug (rhepo. In Russian Federation it is determined by the influence of the drug on erythropoiesis stimulation. This effect of erythropoietin is measured by counting the number of reticulocytes using the flow cytometry and light microscopy. The latter method of calculation is not included in European Pharmacopoeia. Adequate assessment of this indicator is required for the development of national requirements for quality control of drugs rhepo harmonized with European Pharmacopoeia. Purpose of the work. The study aimed the comparative evaluation of the accuracy of the specific erythropoietin activity determination method using the flow cytometry and light microscopy data to provide the harmonization of the draft General monograph with European Pharmacopoeia. Research methods. The erythropoietin specific activity was determined in vivo in normocythaemic mice using the flow cytometry in accordance with the European Pharmacopoeia and light microscopy. We have compared the effects of two independent dilution series of erythropoietin European Pharmacopoeia standard sample. Results. The results of specific erythropoietin activity determination obtained by two different methods of measurement differed in the offset from the reference value (certified value. In flow cytometry data, the offset varied between 1-8%, the results of light microscopy showed higher variability ranging from 4 to 31%. The estimation of intermediate precision showed twice lower dispersion of

  20. Erythropoietin treatment does not compromise cardiovascular function in chronic renal failure

    DEFF Research Database (Denmark)

    Haedersdal, C; Mehlsen, J; Stenver, Doris Irene

    1994-01-01

    The anemia in patients with chronic renal failure can be corrected through treatment with recombinant human erythropoietin treatment. This correction is associated with changes in the rheologic variables, which could explain the changes in hemodynamics found by many investigators. The authors have...... followed up 11 patients with chronic renal failure on hemodialysis before and during six months of therapy with erythropoietin. The measurements were made before treatment, after four months of therapy, and after six months of therapy. The measurements included hematocrit, osmotic resistance of the red...

  1. Erythropoietin treatment does not compromise cardiovascular function in chronic renal failure

    DEFF Research Database (Denmark)

    Haedersdal, C; Mehlsen, J; Stenver, Doris Irene

    1994-01-01

    The anemia in patients with chronic renal failure can be corrected through treatment with recombinant human erythropoietin treatment. This correction is associated with changes in the rheologic variables, which could explain the changes in hemodynamics found by many investigators. The authors have...... followed up 11 patients with chronic renal failure on hemodialysis before and during six months of therapy with erythropoietin. The measurements were made before treatment, after four months of therapy, and after six months of therapy. The measurements included hematocrit, osmotic resistance of the red...

  2. Erythropoietin messenger RNA levels in developing mice and transfer of /sup 125/I-erythropoietin by the placenta

    Energy Technology Data Exchange (ETDEWEB)

    Koury, M.J.; Bondurant, M.C.; Graber, S.E.; Sawyer, S.T.

    1988-07-01

    Erythropoietin (EP) mRNA was measured in normal and anemic mice during fetal and postnatal development. Normal fetal livers at 14 d of gestation contained a low level of EP mRNA. By day 19 of gestation, no EP mRNA was detected in normal or anemic fetal livers or normal fetal kidneys, but anemic fetal kidneys had low levels of EP mRNA. Newborn through adult stage mice responded to anemia by accumulating renal and hepatic EP mRNA. However, total liver EP mRNA was considerably less than that of the kidneys. Juvenile animals, 1-4 wk old, were hyperresponsive to anemia in that they produced more EP mRNA than adults. Moreover, nonanemic juveniles had readily measured renal EP mRNA, whereas the adult level was at the lower limit of detection. Because of the very low level of fetal EP mRNA, placental transfer of EP was evaluated. When administered to the pregnant mouse, /sup 125/I-EP was transferred in significant amounts to the fetuses. These results indicate that in mice the kidney is the main organ of EP production at all stages of postnatal development and that adult kidney may also play some role in providing EP for fetal erythropoiesis via placental transfer of maternal hormone.

  3. Novel Tissue Protective Agents for the Treatment of Acute Radiation-induced BMF

    Science.gov (United States)

    2013-03-01

    2012). Induction of DNA fragmentation , chromosome aberrations and micronuclei by cisplatin in rat bone-marrow cells: protective effect of recombinant...recombinant human erythropoietin in mitomycin C-induced genotoxicity: Analysis of DNA fragmentation , chromosome aberrations and micronuclei in rat

  4. Darbepoietin-alfa has comparable erythropoietic stimulatory effects to recombinant erythropoietin whilst preserving the bone marrow microenvironment.

    Science.gov (United States)

    Dewamitta, Sita R; Russell, Megan R; Nandurkar, Harshal; Walkley, Carl R

    2013-05-01

    Erythropoiesis stimulating agents are widely used for the treatment of anemia. Recently, we reported erythroid expansion with impaired B lymphopoiesis and loss of trabecular bone in C57BL/6 mice following ten days of treatment with low-dose short acting recombinant human erythropoietin. We have assessed erythropoietin against longer-acting darbepoietin-alfa at a comparable erythroid stimulatory dosage regime. Darbepoietin-alfa and erythropoietin induced similar in vivo erythropoietic expansion. Both agents induced an expansion of the colony-forming unit-erythroid populations. However, unlike erythropoietin, darbepoietin-alfa did not impair bone marrow B lymphopoiesis. Strikingly the bone loss observed with erythropoietin was not apparent following darbepoietin-alfa treatment. This analysis demonstrates that whilst darbepoietin-alfa has similar in vivo erythropoietic potency to erythropoietin, it preserves the bone marrow microenvironment. Thus erythropoietin and darbepoietin-alfa manifest different action showing that erythropoiesis stimulating agents have differential non-erythroid effects dependent on their duration of action.

  5. Recombinant human erythropoietin improves neurological outcomes in very preterm infants

    Science.gov (United States)

    Song, Juan; Sun, Huiqing; Xu, Falin; Kang, Wenqing; Gao, Liang; Guo, Jiajia; Zhang, Yanhua; Xia, Lei; Wang, Xiaoyang

    2016-01-01

    Objective To evaluate the efficacy and safety of repeated low‐dose human recombinant erythropoietin (rhEPO) in the improvement of neurological outcomes in very preterm infants. Methods A total of 800 infants of ≤32‐week gestational age who had been in an intensive care unit within 72 hours after birth were included in the trial between January 2009 and June 2013. Preterm infants were randomly assigned to receive rhEPO (500IU/kg; n = 366) or placebo (n = 377) intravenously within 72 hours after birth and then once every other day for 2 weeks. The primary outcome was death or moderate to severe neurological disability assessed at 18 months of corrected age. Results Death and moderate/severe neurological disability occurred in 91 of 338 very preterm infants (26.9%) in the placebo group and in 43 of 330 very preterm infants (13.0%) in the rhEPO treatment group (relative risk [RR] = 0.40, 95% confidence interval [CI] = 0.27–0.59, p < 0.001) at 18 months of corrected age. The rate of moderate/severe neurological disability in the rhEPO group (22 of 309, 7.1%) was significantly lower compared to the placebo group (57 of 304, 18.8%; RR = 0.32, 95% CI = 0.19–0.55, p < 0.001), and no excess adverse events were observed. Interpretation Repeated low‐dose rhEPO treatment reduced the risk of long‐term neurological disability in very preterm infants with no obvious adverse effects. Ann Neurol 2016;80:24–34 PMID:27130143

  6. Predialysis versus postdialysis hematocrit evaluation during erythropoietin therapy.

    Science.gov (United States)

    Movilli, Ezio; Pertica, Nicoletta; Camerini, Corrado; Cancarini, Giovanni C; Brunori, Giuliano; Scolari, Francesco; Maiorca, Rosario

    2002-04-01

    American guidelines for the management of renal anemia by recombinant human erythropoietin (rHuEPO) recommend collecting a predialysis blood sample to evaluate hemoglobin (Hb) and hematocrit (Hct) levels in hemodialysis patients. Although a predialysis blood sample is appropriate for evaluating when to start rHuEPO treatment, the same sample would not be appropriate for evaluating the target Hb/Hct to be maintained, particularly when normal or near-normal values are pursued. We measured the degree of intradialytic and extradialytic variation of Hb, Hct, and body weight in 68 stable hemodialysis patients on maintenance subcutaneous rHuEPO treatment. Hb and Hct concentrations were determined before and after dialysis. In 16 patients, Hb and Hct concentrations also were assessed 24 hours after the end of dialysis. Predialysis versus postdialysis Hb and Hct concentrations for all patients were 10.5 +/- 1.3 g/dL versus 11.5 +/- 1.3 g/dL (P < 0.0001) and 32 +/- 4% versus 35 +/- 4% (P < 0.0001). The intradialytic percent variation (%Delta) of Hct and body weight were 10 +/- 6% and -6.3 +/- 3.5%. There was a close inverse correlation between %Delta of Hct and Hb and %Delta of body weight (P < 0.0001). In patients with body weight losses 2.5 kg or more per session, the mean %Delta of Hct was 12 +/- 7%. In the 16 patients studied 24 hours after the end of the dialysis session, Hct and Hb values remained significantly higher compared with the predialysis levels (P < 0.001), suggesting a slow reequilibration of the intravascular volume in the first 24 hours after hemodialysis. For these reasons, predialysis samples for monitoring the target Hb and Hct levels in patients treated by rHuEPO should be considered with caution.

  7. Erythropoietin improves cardiac function through endothelial progenitor cell and vascular endothelial growth factor mediated neovascularization

    NARCIS (Netherlands)

    Westenbrink, B. Daan; Lipsic, Erik; van der Meer, Peter; van der Harst, Pirn; Oeseburg, Hisko; Sarvaas, Gideon J. Du Marchie; Koster, Johan; Voors, Adriaan A.; van Veldhuisen, Dirk J.; van Gilst, Wiek H.; Schoemaker, Regien G.

    2007-01-01

    Aims Erythropoietin (EPO) improves cardiac function and induces neovascutarization in chronic heart failure (CHF), although the exact mechanism has not been elucidated. We studied the effects of EPO on homing and incorporation of endothelial progenitor cells (EPC) into the myocardial microvasculatur

  8. Therapeutic levels of erythropoietin (EPO) achieved after gene electrotransfer to skin in mice

    DEFF Research Database (Denmark)

    Gothelf, A; Hojman, P; Gehl, Julie

    2010-01-01

    Gene electrotransfer refers to gene transfection by electroporation and is an effective non-viral method for delivering naked DNA into cells and tissues. This study presents data from gene electrotransfer with erythropoietin (EPO) to mouse skin. Nine-week-old female NMRI mice received one, two...

  9. How bio-questionable are the different recombinant human erythropoietin copy products in Thailand?

    NARCIS (Netherlands)

    Halim, Liem Andhyk; Brinks, Vera; Jiskoot, Wim; Romeijn, Stefan; Praditpornsilpa, Kearkiat; Assawamakin, Anunchai; Schellekens, Huub

    2014-01-01

    PURPOSE: The high prevalence of pure red cell aplasia in Thailand has been associated with the sharp increase in number of recombinant human erythropoietin (rhEPO) copy products, based on a classical generic regulatory pathway, which have entered the market. This study aims to assess the quality of

  10. A lentiviral gene therapy strategy for the in vitro production of feline erythropoietin.

    Directory of Open Access Journals (Sweden)

    Natalia Vapniarsky

    Full Text Available Nonregenerative anemia due to chronic renal failure is a common problem in domestic cats. Unfortunately, administration of recombinant human erythropoietin often only improves anemia temporarily due to antibody development. In this in vitro study, feline erythropoietin cDNA was cloned from feline renal tissue and utilized in the construction of a replication-defective lentiviral vector. The native recombinant feline erythropoietin (rfEPO sequence was confirmed by sequencing. Upon viral vector infection of human 293H cells, Crandall Renal Feline Kidney cell line and primary feline peripheral blood mononuclear cells, bioactive rfEPO protein was produced. The presence of cellular rfEPO cDNA was confirmed by standard PCR, production of abundant rfEPO mRNA was confirmed by real-time PCR, and secretion of rfEPO protein was demonstrated by Western blot analyses, while rfEPO protein bioactivity was confirmed via an MTT proliferation bioassay. This in vitro study demonstrates the feasibility of a replication-defective lentiviral vector delivery system for the in vitro production of biologically active feline erythropoietin. Anemic cats with chronic renal failure represent a potential in vivo application of a lentiviral gene therapy system.

  11. How bio-questionable are the different recombinant human erythropoietin copy products in Thailand?

    NARCIS (Netherlands)

    Halim, Liem Andhyk; Brinks, Vera; Jiskoot, Wim; Romeijn, Stefan; Praditpornsilpa, Kearkiat; Assawamakin, Anunchai; Schellekens, Huub

    2014-01-01

    PURPOSE: The high prevalence of pure red cell aplasia in Thailand has been associated with the sharp increase in number of recombinant human erythropoietin (rhEPO) copy products, based on a classical generic regulatory pathway, which have entered the market. This study aims to assess the quality of

  12. Combined therapy with amifostine plus erythropoietin for the treatment of myelodysplastic syndromes

    DEFF Research Database (Denmark)

    Musto, Pellegrino; Santini, Valeria; Balestri, Francesca;

    2002-01-01

    Twelve patients with myelodysplasia were treated with amifostine plus recombinant human erythropoietin (rHuEpo) for 6 weeks. A complete erythroid response was obtained in 2/12(16.6%) and a partial response in 4/12 (33.3%). Two of 8 patients with a platelet count

  13. Characterization of recombinant human erythropoietin produced in Chinese hamster ovary cells

    Energy Technology Data Exchange (ETDEWEB)

    Davis, J.M.; Arakawa, T.; Strickland, T.W.; Yphantis, D.A.

    1987-05-05

    Physicochemical properties of recombinant human erythropoietin were examined. This protein, produced in Chinese hamster ovary cells, showed a conformation apparently identical with the natural product isolated from human urine when examined by circular dichroism, UV absorbance, and fluorescence spectroscopy. Sedimentation equilibrium experiments showed the recombinant erythropoietin preparation to be essentially a single macromolecular component with a molecular weight of 30,400 and a carbohydrate content of 39%. The Stokes radius of recombinant erythropoietin was estimated to be 32 A from gel filtration, much larger than the 20-A radius calculated for a sphere of the observed molecular weight. This difference may be ascribed to the extensive glycosylation. The fluorescence and phosphorescence spectra showed that the luminescent tryptophan(s) is (are) solvent-exposed and can be quenched by I/sup -/ and acrylamide but not by Cs/sup +/. On acid titration, the recombinant erythropoietin showed a conformational transition with a midpoint of pH 4.1. This suggests that the net charges on the protein moiety rather than on the whole molecule play a role in protein structure stability.

  14. Adequacy of endogenous erythropoietin levels and mortality in anaemic heart failure patients

    NARCIS (Netherlands)

    van der Meer, Peter; Lok, Dirk J.; Januzzi, James L.; de la Porte, Pieta W. Bruggink-Andre; Lipsic, Erik; van Wijngaarden, Jan; Voors, Adriaan A.; van Gilst, Wiek H.; van Veldhuisen, Dirk J.

    2008-01-01

    Aims We examined the adequacy of endogenous erythropoietin (EPO) levels for the degree of anaemia in patients with chronic heart failure (CHF) and its relation to prognosis. Methods and results We studied 74 anaemic CHF patients from a cohort of 240 patients. The adequacy of endogenous EPO levels wa

  15. OPTIMAL ERYTHROID CELL PRODUCTION DURING ERYTHROPOIETIN TREATMENT OF MICE OCCURS BY EXPLOITING THE SPLENIC MICROENVIRONMENT

    NARCIS (Netherlands)

    NIJHOF, W; GORIS, H; DONTJE, B; DRESZ, J; LOEFFLER, M

    1993-01-01

    In this study, quantitative effects on erythroid cell production by a prolonged recombinant human erythropoietin (rhEpo) treatment of mice are presented. Epo treatments, given subcutaneously (s.c.) twice per day in doses of 0.5 to 500 U per day, were performed under steady-state production condition

  16. Erythropoietin Receptor in Human Tumor Cells: Expression and Aspects Regarding Functionality

    NARCIS (Netherlands)

    T.A. Knoch (Tobias); G. Westphal; E. Niederberger; C. Blum; Y. Wollman; W. Rebel; J. Debus; E. Friedrich

    2001-01-01

    textabstractRecombinant human erythropoietin (Epo)and granu l o cy t e - c o l o ny - s t i mulating factor (G-CSF) are used to stimulate hematopoiesis in patients with malignant dise a s e s . These cytokines transduce their biological signal via the Epo receptor (EpoR) and G-CSF receptor (G-CSF-R)

  17. Prolonged administration of recombinant human erythropoietin increases submaximal performance more than maximal aerobic capacity

    DEFF Research Database (Denmark)

    Thomsen, J J; Rentsch, R L; Robach, P

    2007-01-01

    The effects of recombinant human erythropoietin (rHuEpo) treatment on aerobic power (VO2max) are well documented, but little is known about the effects of rHuEpo on submaximal exercise performance. The present study investigated the effect on performance (ergometer cycling, 20-30 min at 80...

  18. Detection of erythropoietin misuse by the Athlete Biological Passport combined with reticulocyte percentage

    DEFF Research Database (Denmark)

    Bejder, Jacob; Aachmann-Andersen, Niels Jacob; Bonne, Thomas Christian

    2016-01-01

    The sensitivity of the adaptive model of the Athlete Biological Passport (ABP) and reticulocyte percentage (ret%) in detection of recombinant human erythropoietin (rHuEPO) misuse was evaluated using both a long-term normal dose and a brief high dose treatment regime. Sixteen subjects received...

  19. Carbon monoxide in chronic uraemia related to erythropoietin treatment and smoking habits

    DEFF Research Database (Denmark)

    Thunedborg, P; Nielsen, A L; Brinkenfeldt, H

    1995-01-01

    In 69 patients on chronic haemodialysis, blood sampled randomly during dialysis was analyzed for carboxyhaemoglobin (COHb). The median value was 1.40% (range 0.9-2.3) in non-smoking patients and (1.4-7.5) in smokers. In non-smokers treated with erythropoietin (EPO) correlation was found between C...

  20. Effect of recombinant erythropoietin on ischemia-reperfusion-induced apoptosis in rat liver.

    Science.gov (United States)

    Shawky, Heba M; Younan, Sandra M; Rashed, Leila A; Shoukry, Heba

    2012-03-01

    Ischemia-reperfusion (I/R) cannot be avoided in liver transplantation procedures, and apoptosis is a central mechanism of cell death after liver reperfusion. Protective effect of recombinant erythropoietin (rhEPO) on liver apoptosis has not been clearly investigated. This work investigated intraportal (IP) rhEPO-protective effect in a rat model of hepatic I/R-induced apoptosis and its appropriated time and dose of administration. Eight groups were included (n = 10/group): sham-operated, I/R (45 min ischemia and 2 h reperfusion), preconditioned rhEPO I/R (24 h or 30 min before ischemia), and postconditioned rhEPO I/R (before reperfusion) using two different rhEPO doses (1,000 and 5,000 IU/kg). When compared with the sham-operated group, the I/R group showed significant increase of serum levels of aspartate and alanine aminotransferases (AST, ALT), hepatic caspase-9 activity(894.99 ± 176.90 relative fluorescence units (RFU)/mg/min versus 458.48 ± 82.96 RFU/mg/min), and Fas ligand (FasL) expression, histopathological damages, and significant decrease in the antiapoptotic Bcl-xL/apoptotic Bax ratio(0.38 ± 0.21 versus 3.35 ± 0.77) rhEPO-improved ALT and AST but failed to reduce FasL expression in all groups compared with the I/R group. Thirty minutes and 24 h preconditioning with rhEPO (1,000 IU/kg) increased Bcl-xL/Bax ratio and reduced caspase-9 activity, and the same effect was observed when higher dose was given 24 h before ischemia. Preconditioning was more effective than postconditioning in improving caspase-9 activity, and no dose-dependent effect was observed. In conclusion, single IP rhEPO injection 30 min before ischemia has an advantage over rhEPO postconditioning in improving post-hepatic I/R-induced apoptosis with no additional time- and dose-dependent effects which may provide potentially useful guide in liver transplantation procedures.

  1. Study of the erythropoiesis activity of nano-encapsulated forms of erythropoietin

    Directory of Open Access Journals (Sweden)

    Zhanagul Khasenbekova

    2014-01-01

    Full Text Available Introduction: The recombinant human erythropoietin (rhEPO is used in the treatment of anemia. In order to improve its pharmacokinetic properties, nanoparticles of biodegradable polymers of natural or synthetic origin were used. The aim of this study was to investigate the effect of new nano-encapsulated forms of recombinant human erythropoietin for oral use on the erythropoiesis in the cyclophosphamide immunosuppression model. Material and methods: The CHOpE immortalized cells culture (a primary producer of rhEPO "Vector" in Russia was used. The following biodegradable polymers were chosen: 0.05% and 0.005% carbopol, 0.05% and 0.005% kollidon, and 0.05% and 0.005% pectin. Immunosuppression was obtained by a single dose of i.p. injection of cyclophosphamide (250 mg/kg in white mice (18-20 g. During the next 5 days, the nano-encapsulated erythropoietin (100 ED/mouse was administered orally to each mouse. After 5 and 10 days, the cell count of the number of blood reticulocytes and the myelogram of bone marrow were performed. The control group of mice received injections of Eprex. Results: On the 5th day of the experiment, the highest level of reticulocyte was observed in the samples of erythropoietin with kollidon (0.05% and pectin (0.005% nanoparticles. On the 10th day, the highest activity was observed in the samples of erythropoietin substance with pectin at 0.05% and 0.005% concentrations. The levels of reticulocytes in these groups reached 13.53% and 14.55%, respectively. The results of the myelogram during immunosuppression showed some activity of erythropoietin in conjunction with both concentrations of pectin when a two-fold increase in the number of erythroblasts was observed on the 5th day. High degrees of erythrokaryocytes in the state of mitosis were observed in the 0.05% pectin samples. Similar results were observed in equivalent groups of control animals on the 10th day of the experiment, which is compatible with the data on Eprex

  2. Aberrant phenotypes of transgenic mice expressing dimeric human erythropoietin

    Directory of Open Access Journals (Sweden)

    Yun Seong-Jo

    2012-01-01

    Full Text Available Abstract Background Dimeric human erythropoietin (dHuEPO peptides are reported to exhibit significantly higher biological activity than the monomeric form of recombinant EPO. The objective of this study was to produce transgenic (tg mice expressing dHuEPO and to investigate the characteristics of these mice. Methods A dHuEPO-expressing vector under the control of the goat beta-casein promoter, which produced a dimer of human EPO molecules linked by a 2-amino acid peptide linker (Asp-Ile, was constructed and injected into 1-cell fertilized embryos by microinjection. Mice were screened using genomic DNA samples obtained from tail biopsies. Blood samples were obtained by heart puncture using heparinized tubes, and hematologic parameters were assessed. Using the microarray analysis tool, we analyzed differences in gene expression in the spleens of tg and control mice. Results A high rate of spontaneous abortion or death of the offspring was observed in the recipients of dHuEPO embryos. We obtained 3 founder lines (#4, #11, and #47 of tg mice expressing the dHuEPO gene. However, only one founder line showed stable germline integration and transmission, subsequently establishing the only transgenic line (#11. We obtained 2 F1 mice and 3 F2 mice from line #11. The dHuEPO protein could not be obtained because of repeated spontaneous abortions in the tg mice. Tg mice exhibited symptoms such as short lifespan and abnormal blood composition. The red blood cell count, white blood cell count, and hematocrit levels in the tg mice were remarkably higher than those in the control mice. The spleens of the tg mice (F1 and F2 females were 11- and -21-fold larger than those of the control mice. Microarray analysis revealed 2,672 spleen-derived candidate genes; more genes were downregulated than upregulated (849/764. Reverse transcriptase-polymerase chain reaction (RT-PCR and quantitative real-time PCR (qRT-PCR were used for validating the results of the microarray

  3. Comparison of erythropoietic response to erythropoietin-secreting stimuli in mice following polycythemia induced by transfusion or hypoxia

    Energy Technology Data Exchange (ETDEWEB)

    Alippi, R.M.; Barcelo, A.C.; Bozzini, C.E.

    1985-03-01

    The erythropoietic response, measured as RBC-/sup 59/Fe uptake, in response to either 24-h exposure to hypoxia or administration of dexamethasone, isoproterenol, testosterone, or erythropoietin, was determined in both posthypoxic (PH) and hypertransfused (HT) polycythemic mice. Highly significant differences between PH and HT mice exposed to hypoxia or injected with dexamethasone, isoproterenol, or testosterone were observed, isotope incorporation being always higher in PH than in HT mice. On the other hand, the response to erythropoietin did not show a significant difference between PH and HT mice. These results suggest that PH mice have been preconditioned by exposure to hypoxia in a way that makes them more sensitive to at least some kinds of erythropoietic stimuli. Since these stimuli have been shown by others to increase erythropoietin production, the results support the hypothesis that hypoxia induces sensitization of the erythropoietin- producing organ(s).

  4. Continuous production of erythropoietin by an established human renal carcinoma cell line: development of the cell line

    Energy Technology Data Exchange (ETDEWEB)

    Sherwood, J.B.; Shouval, D.

    1986-01-01

    Establishment of a stable, transformed human renal carcinoma cell line that produces erythropoietin in vitro and has maintained this function continuously since 1981 and for > 150 passages in monolayer culture was accomplished by transplantation of human renal clear cell carcinoma tissue from a patient with erythrocytosis into an immunosuppressed athymic mouse. In addition to its immunocrossreactivity with native human urinary erythropoietin, the tumor erythropoietin demonstrates biological activity in the in vitro mouse erythroid colony-forming unit assay and in tumor-bearing nude mice. The cloned renal carcinoma cell line has an abnormal human karyotype and has ultrastructural features characteristic of human renal clear cell carcinoma. This cell line provides a reproducible model system for the production of an erythropoietin-like material and for the study of its synthesis and secretion.

  5. Erythropoietin Attenuates Pulmonary Vascular Remodeling in Experimental Pulmonary Arterial Hypertension through Interplay between Endothelial Progenitor Cells and Heme Oxygenase

    NARCIS (Netherlands)

    van Loon, Rosa Laura E; Bartelds, Beatrijs; Wagener, Frank A D T G; Affara, Nada; Mohaupt, Saffloer; Wijnberg, Hans; Pennings, Sebastiaan W C; Takens, Janny; Berger, Rolf M F

    2015-01-01

    BACKGROUND: Pulmonary arterial hypertension (PAH) is a pulmonary vascular disease with a high mortality, characterized by typical angio-proliferative lesions. Erythropoietin (EPO) attenuates pulmonary vascular remodeling in PAH. We postulated that EPO acts through mobilization of endothelial progeni

  6. Effects of erythropoietin on posttraumatic place learning in fimbria-fornix transected rats after a 30-day postoperative pause

    DEFF Research Database (Denmark)

    Malá, Hana; Rodriguez Castro, Maria; Dall Jørgensen, Katrine;

    2007-01-01

    Human recombinant erythropoietin (EPO) has been shown to exert neuroprotective effects following both vascular and mechanical brain injury. Previously, we showed that behavioral symptoms associated with mechanical lesions of the hippocampus are nearly abolished due to EPO treatment...

  7. Combination of cyclosporine and erythropoietin improves brain infarct size and neurological function in rats after ischemic stroke

    Directory of Open Access Journals (Sweden)

    Shao Pei-Lin

    2011-08-01

    Full Text Available Abstract Background This study tested the superiority of combined cyclosporine A (CsA-erythropoietin (EPO therapy compared with either one in limiting brain infarction area (BIA and preserving neurological function in rat after ischemic stroke (IS. Methods Fifty adult-male SD rats were equally divided into sham control (group 1, IS plus intra-peritoneal physiological saline (at 0.5/24/48 h after IS (group 2, IS plus CsA (20.0 mg/kg at 0.5/24h, intra-peritoneal (group 3, IS plus EPO (5,000IU/kg at 0.5/24/48h, subcutaneous (group 4, combined CsA and EPO (same route and dosage as groups 3 and 4 treatment (group 5 after occlusion of distal left internal carotid artery. Results BIA on day 21 after acute IS was higher in group 2 than in other groups and lowest in group 5 (all p Conclusion combined treatment with CsA and EPO was superior to either one alone in protecting rat brain from ischemic damage after IS.

  8. Amelioration of cerebral ischemia-reperfusion injury based on liposomal drug delivery system with asialo-erythropoietin.

    Science.gov (United States)

    Ishii, Takayuki; Asai, Tomohiro; Oyama, Dai; Fukuta, Tatsuya; Yasuda, Nodoka; Shimizu, Kosuke; Minamino, Tetsuo; Oku, Naoto

    2012-05-30

    Cerebral ischemia-reperfusion (I/R) injury induces secondary cerebral damage. As drugs for treating this type of injury have shown poor efficacy and adverse side effects in clinical trials, a novel therapeutic strategy has been long awaited. In this study, we focused on the disruption of the blood-brain barrier after stroke, and applied a liposomal drug delivery system (DDS) designed to enhance the pharmacological effect of the neuroprotectant and to avoid side effects. PEGylated liposomes were injected at varying time after the start of reperfusion in transient middle cerebral artery occlusion (t-MCAO) model rats. The results showed PEGylated liposomes accumulated in the ischemic hemisphere at an early stage after reperfusion and were retained in the lesion for at least 24h after injection. We also investigated the effectiveness of asialo-erythropoietin (AEPO)-modified PEGylated liposomes (AEPO-liposomes) in treating the cerebral I/R injury. AEPO-liposome treatment significantly reduced TTC-defined cerebral legion following cerebral I/R injury, and ameliorated motor function compared with vehicle and AEPO treatment. In conclusion, these results indicate that AEPO-liposomes are a promising liposomal formulation for protecting the brain from I/R injury, and that this liposomal DDS has potential as a novel strategy for the treatment of cerebral I/R injury.

  9. Effect of recombinant human erythropoietin on mitomycin C-induced oxidative stress and genotoxicity in rat kidney and heart tissues.

    Science.gov (United States)

    Rjiba-Touati, K; Ayed-Boussema, I; Guedri, Y; Achour, A; Bacha, H; Abid-Essefi, S

    2016-01-01

    Mitomycin C (MMC) is an antineoplastic agent used for the treatment of several human malignancies. Nevertheless, the prolonged use of the drug may result in a serious heart and kidney injuries. Recombinant human erythropoietin (rhEPO) has recently been shown to exert an important cytoprotective effect in experimental brain injury and ischemic acute renal failure. The aim of the present work is to investigate the cardioprotective and renoprotective effects of rhEPO against MMC-induced oxidative damage and genotoxicity. Our results showed that MMC induced oxidative stress and DNA damage. rhEPO administration in any treatment conditions decreased oxidative damage induced by MMC. It reduced malondialdehyde and protein carbonyl levels. rhEPO ameliorated reduced glutathione plus oxidized glutathione modulation and the increased catalase activity after MMC treatment. Furthermore, rhEPO restored DNA damage caused by MMC. We concluded that rhEPO administration especially in pretreatment condition protected rats against MMC-induced heart and renal oxidative stress and genotoxicity.

  10. Erythropoietin prevents PC12 cells from beta-amyloid-induced apoptosis via PI3K⁄Akt pathway

    Directory of Open Access Journals (Sweden)

    Zhi-Kun Sun

    2012-02-01

    Full Text Available Abstract Background Several studies indicated that Erythropoietin (Epo may provide remarkable neuroprotection in some neurological diseases. It also showed the significant decrease of Epo immunoreactivity in the cerebral cortex and hippocampus in aged rats, suggesting the role of Epo in the pathogenesis of age-related neurodegenerative diseases such as AD. Methods The protective effect of Epo was studied in differentiated PC12 cells treated with Abeta. The viability of the cells, the apoptosis of the cells and the level of Bax, Bcl-2, cleaved caspase-3 and cleaved PARP expression were detected by MTT, Hoechst 33258 staining and Western blotting respectively. Results 20 μM Abeta (25-35 could induce a decreased viability and a increased apoptosis in PC12 cell in a time-dependent manner. However, 20 μM Abeta (35-25 had no effect on cell viability and apoptosis. Western blot analysis also showed that Abeta(25-35 treatment could decrease the expression of Bcl-2 (P P P P (25-35 (P P Conclusions Epo prevented cell injuries in PC12 cells exposed to the Abeta(25-35 and this effect may depend on the PI3K⁄Akt pathway. Our study provided an important evidence for the potential application of Epo in the therapy of Alzheimer's disease.

  11. Endogenous erythropoietin level and effects of exogenous erythropoietin in a rat model of blunt chest trauma-induced pulmonary contusion.

    Science.gov (United States)

    Bakan, Vedat; Kurutaş, Ergül Belge; Çıralık, Harun; Gül, Mustafa; Çelik, Ahmet

    2016-07-01

    The present objective was to investigate endogen erythropoietin (EPO) level and relationship to oxidative stress within the first 24 hours of blunt chest trauma-induced pulmo-nary contusion (PCn) in a rat model. Thirty-five rats were divided into 3 groups. In the baseline control group (BC, n=7), rats were uninjured and untreated. In the positive control group (PC, n=21) rats were injured but untreated. In the EPO-24 group (n=7), rats were injured and a single dose of intra-peritoneal EPO (5000 IU/kg) was administered immediately after lung injury. The PC group was divided into 3 subgroups: PC-6 (n=7), PC-12 (n=7), and PC-24 (n=7). The BC group was subjected to thoracotomy, and the right lung was harvested. The PC subgroups were eu-thanized at 6, 12, and 24 hours after injury, respectively. The EPO-24 group was euthanized at the 24th hour after injury. Lung samples were obtained, levels of malondialdehyde (MDA) and EPO were analyzed, and activities of superoxide dismutase (SOD) and catalase (CAT) were then measured in homogenized lung tissue samples. Histologic damage to lung tissue in the BC group, the EPO-24 group, and PC subgroup euthanized at the 24th hour after injury were scored by a single pathologist blinded to group assignation. Mean MDA levels, as well as SOD and CAT activities, of the BC and EPO-24 groups were significantly lower than those of the PC group (p<0.005). Mean EPO concentra-tion of the PC group was significantly higher than that of the BC group (p<0.005). Lung tis-sue damage scores measured at 24 hours after injury were significantly lower in the EPO-24 group than in the PC group (p<0.005). In the present PCn rat model, EPO concentrations, as well as SOD and CAT levels, were high in lung tissue, when measured at 24 hours after PCn. When administered early after chest trauma, EPO significantly attenuated oxidative damage and tissue damage in the early phase, as assessed by biochemical markers and histologic scoring.

  12. Incorporation of Ortho- and Meta-Tyrosine Into Cellular Proteins Leads to Erythropoietin-Resistance in an Erythroid Cell Line

    Directory of Open Access Journals (Sweden)

    Esztella Mikolás

    2014-04-01

    Full Text Available Background/Aims: Erythropoietin-resistance is an unsolved concern in the treatment of renal anaemia. We aimed to investigate the possible role of ortho- and meta-tyrosine - the hydroxyl free radical products of L-phenylalanine - in the development of erythropoietin-resistance. Methods: TF-1 erythroblast cell line was used. Cell concentration was determined on day 1; 2 and 3 by two independent observers simultaneously in Bürker cell counting chambers. Protein concentration was determined with colorimetric method. Para-, ortho- and meta-tyrosine levels were measured using reverse phase-HPLC with fluorescence detection. Using Western blot method activating phosphorylation of STAT5 and ERK1/2 were investigated. Results: We found a time- and concentration-dependent decrease of erythropoietin-induced proliferative activity in case of ortho- and meta-tyrosine treated TF-1 erythroblasts, compared to the para-tyrosine cultured cells. Decreased erythropoietin-response could be regained with a competitive dose of para-tyrosine. Proteins of erythroblasts treated by ortho- or meta-tyrosine had lower para-tyrosine and higher ortho- or meta-tyrosine content. Activating phosphorylation of ERK and STAT5 due to erythropoietin was practically prevented by ortho- or meta-tyrosine treatment. Conclusion: According to this study elevated ortho- and meta-tyrosine content of erythroblasts may lead to the dysfunction of intracellular signaling, resulting in erythropoietin-hyporesponsiveness.

  13. Intraosseous Erythropoietin for Acute Tissue Protection in Battlefield Casualties Suffering Hypovolemic Shock

    Science.gov (United States)

    2013-11-01

    1980 Doctor of Medicine and Surgery, Chile PROFESSIONAL SOCIETY MEMBERSHIP 2005-present Honorary Member “ Sociedad Decano Lorenzo Sazié...Santelices (ed). Cuidados Postoperatorios y Paciente Quirúrgico Crítico. Sociedad de Cirujanos de Chile. Santiago, Chile, 1994, pp.282-283. 11. Gazmuri RJ...Crítico. Sociedad de Cirujanos de Chile. Santiago, Chile, 1994, pp.275-276. 12. Gazmuri RJ. [Mechanisms of blood flow during precordial compression]. In

  14. [Erythropoietin as a protective factor in rat CNS cells receiving radiotherapy -an in vitro study].

    Science.gov (United States)

    Gomez-De la Riva, Álvaro; Isla-Guerrero, Alberto; García-Grande, Antonio

    2014-03-01

    Objetivo. Investigar el efecto de la eritropoyetina en cultivos celulares de corteza cerebral de ratas cuando se administra radioterapia. Materiales y metodos. El estudio se desarrolla con la obtencion de corteza cerebral de embriones de 17 dias de preñez de ratas Wistar. Las celulas cultivadas despues de 72 horas de la extraccion de la corteza se dividieron en dos grupos, a uno de ellos se le administro eritropoyetina alfa a una concentracion de 30 pM y el otro era el grupo control. A los dos grupos de celulas se les radio con 6 Gy mediante un aparato Phoenix. Tras la radioterapia permanecieron 24 horas en la incubadora antes de fijarlas. Las celulas fueron fijadas con formaldehido al 4%. A continuacion, con la tecnica de TUNEL, se valoro el numero de celulas apoptoticas en los cultivos radiados. Resultados. Se observo un porcentaje de apoptosis del 25,22% del grupo de cultivo sin eritropoyetina, mientras que en el grupo de celulas radiadas con eritropoyetina fue del 15,5%. Las variables cuantitativas se analizaron mediante el test t de Student y el resultado de la comparacion entre los dos grupos fue estadisticamente significativo (p sistema nervioso central de ratas por radiacion. Esto abre nuevos campos para la investigacion del efecto protector del sistema nervioso.

  15. Erythropoietin (EPO-receptor signaling induces cell death of primary myeloma cells in vitro

    Directory of Open Access Journals (Sweden)

    Thea Kristin Våtsveen

    2016-08-01

    Full Text Available Abstract Background Multiple myeloma is an incurable complex disease characterized by clonal proliferation of malignant plasma cells in a hypoxic bone marrow environment. Hypoxia-dependent erythropoietin (EPO-receptor (EPOR signaling is central in various cancers, but the relevance of EPOR signaling in multiple myeloma cells has not yet been thoroughly investigated. Methods Myeloma cell lines and malignant plasma cells isolated from bone marrow of myeloma patients were used in this study. Transcript levels were analysed by quantitative PCR and cell surface levels of EPOR in primary cells by flow cytometry. Knockdown of EPOR by short interfering RNA was used to show specific EPOR signaling in the myeloma cell line INA-6. Flow cytometry was used to assess viability in primary cells treated with EPO in the presence and absence of neutralizing anti-EPOR antibodies. Gene expression data for total therapy 2 (TT2, total therapy 3A (TT3A trials and APEX 039 and 040 were retrieved from NIH GEO omnibus and EBI ArrayExpress. Results We show that the EPOR is expressed in myeloma cell lines and in primary myeloma cells both at the mRNA and protein level. Exposure to recombinant human EPO (rhEPO reduced viability of INA-6 myeloma cell line and of primary myeloma cells. This effect could be partially reversed by neutralizing antibodies against EPOR. In INA-6 cells and primary myeloma cells, janus kinase 2 (JAK-2 and extracellular signal regulated kinase 1 and 2 (ERK-1/2 were phosphorylated by rhEPO treatment. Knockdown of EPOR expression in INA-6 cells reduced rhEPO-induced phospo-JAK-2 and phospho-ERK-1/2. Co-cultures of primary myeloma cells with bone marrow-derived stroma cells did not protect the myeloma cells from rhEPO-induced cell death. In four different clinical trials, survival data linked to gene expression analysis indicated that high levels of EPOR mRNA were associated with better survival. Conclusions Our results demonstrate for the first time

  16. Erythropoietin (EPO)-receptor signaling induces cell death of primary myeloma cells in vitro.

    Science.gov (United States)

    Våtsveen, Thea Kristin; Sponaas, Anne-Marit; Tian, Erming; Zhang, Qing; Misund, Kristine; Sundan, Anders; Børset, Magne; Waage, Anders; Brede, Gaute

    2016-08-31

    Multiple myeloma is an incurable complex disease characterized by clonal proliferation of malignant plasma cells in a hypoxic bone marrow environment. Hypoxia-dependent erythropoietin (EPO)-receptor (EPOR) signaling is central in various cancers, but the relevance of EPOR signaling in multiple myeloma cells has not yet been thoroughly investigated. Myeloma cell lines and malignant plasma cells isolated from bone marrow of myeloma patients were used in this study. Transcript levels were analysed by quantitative PCR and cell surface levels of EPOR in primary cells by flow cytometry. Knockdown of EPOR by short interfering RNA was used to show specific EPOR signaling in the myeloma cell line INA-6. Flow cytometry was used to assess viability in primary cells treated with EPO in the presence and absence of neutralizing anti-EPOR antibodies. Gene expression data for total therapy 2 (TT2), total therapy 3A (TT3A) trials and APEX 039 and 040 were retrieved from NIH GEO omnibus and EBI ArrayExpress. We show that the EPOR is expressed in myeloma cell lines and in primary myeloma cells both at the mRNA and protein level. Exposure to recombinant human EPO (rhEPO) reduced viability of INA-6 myeloma cell line and of primary myeloma cells. This effect could be partially reversed by neutralizing antibodies against EPOR. In INA-6 cells and primary myeloma cells, janus kinase 2 (JAK-2) and extracellular signal regulated kinase 1 and 2 (ERK-1/2) were phosphorylated by rhEPO treatment. Knockdown of EPOR expression in INA-6 cells reduced rhEPO-induced phospo-JAK-2 and phospho-ERK-1/2. Co-cultures of primary myeloma cells with bone marrow-derived stroma cells did not protect the myeloma cells from rhEPO-induced cell death. In four different clinical trials, survival data linked to gene expression analysis indicated that high levels of EPOR mRNA were associated with better survival. Our results demonstrate for the first time active EPOR signaling in malignant plasma cells. EPO

  17. Effect of erythropoietin on intestinal injury and bacterial translocation in neonatal rat model of necrotizing enterocolitis

    Directory of Open Access Journals (Sweden)

    Xiao-qing CHEN

    2012-05-01

    Full Text Available Objective  To observe the influence of erythropoietin (EPO on intestinal histopathological changes and bacterial translocation (BT in neonatal rat model of necrotizing enterocolitis (NEC, and explore the protective effect of EPO against NEC. Methods  Seventy-five three-day-old SD rat pups were randomly divided into three groups (25 in each group: normal control group, NEC model group and EPO intervention group. The rat pups in normal control group were placed together with their mothers and breast fed, receiving no other intervention. NEC model group rats were separated from their mothers, housed in an incubator, and gavaged with rat-milk substitute, then experienced hypoxia (breathing 100% nitrogen gas for 90s and cold stress (4℃ for 10min three times daily for 3 days. EPO intervention group rats were fed with the substitute of rat-milk supplemented with 0.1U/ml of EPO, and they were also given hypoxia and cold stress similar to that of the NEC model group. Blood samples were obtained via cardiac puncture, and 2-cm-length of terminal ileum proximal to the ileocecal valve were obtained from the animals on the 4th day. The histopathological changes in terminal ileum were scored after hematoxylin-eosin (HE staining, and the scores ≥2 were defined as NEC. To determine the incidence of bacterial translocation, 16S rRNA real-time fluorescence quantitative PCR was used to detect the bacterial DNA in blood samples. Results  Compared with the NEC model group, the mean rank-sum rate of the intestinal histopathological score (39.4583 vs 53.8696, NEC incidence [25%(6/24 vs 57%(13/23] and bacterial translocation rate [17% (4/24 vs 65%(15/23] in EPO intervention group were significantly lowered (P < 0.05, P < 0.01. Conclusion  Enteral EPO administration is not only effective for reduction of the severity and incidence of NEC, but also for decrease of the bacterial translocation rate in neonatal rat models.

  18. Release of erythropoietin and neuron-specific enolase after breath holding in competing free divers

    DEFF Research Database (Denmark)

    Kjeld, Thomas; Jattu, T; Nielsen, Henrik

    2015-01-01

    Free diving is associated with extreme hypoxia. This study evaluated the combined effect of maximal static breath holding and underwater swimming on plasma biomarkers of tissue hypoxemia: erythropoietin, neuron-specific enolase and S100B, C-reactive protein, pro-atrial natriuretic peptide......, and troponin T. Venous blood samples were obtained from 17 competing free divers before and 3 h after sessions of static apnea and underwater swimming. The heart was evaluated by echocardiography. Static apnea for 293 ± 78 s (mean ± SD) and subsequent 88 ± 21 m underwater swimming increased plasma...... = 0.549), and troponin T (P = 0.125) remained unchanged and, as assessed by echocardiography, the heart was not affected. In competitive free divers, bouts of static and dynamic apnea increase plasma erythropoietin and neuron-specific enolase, suggesting that renal and neural tissue, rather than...

  19. Health-related quality of life in the era of erythropoietin.

    Science.gov (United States)

    Weisbord, Steven D; Kimmel, Paul L

    2008-01-01

    Patients with end-stage renal disease treated with maintenance hemodialysis suffer substantial impairments in health-related quality of life (HRQOL). Despite widespread efforts, there are few interventions that improve the overall well-being and quality of life of this patient population. The current review provides a description of HRQOL as an essential, yet arguably overlooked health-related domain in hemodialysis patients, and discusses interventions that have been evaluated to improve the functional status and well-being of this population, with a particular focus on therapy with recombinant human erythropoietin. We review the controversy surrounding recombinant human erythropoietin as it relates to HRQOL, and describe the delicate balance faced by renal providers who seek to reduce hemodialysis patients' morbidity and mortality while simultaneously striving to improve patients' HRQOL.

  20. Recombinant human erythropoietin increases cerebral cortical width index and neurogenesis following ischemic stroke

    Institute of Scientific and Technical Information of China (English)

    Zhongmin Wen; Peiji Wang

    2012-01-01

    The cerebral cortical expansion index refers to the ratio between left and right cortex width and is recognized as an indicator for cortical hyperplasia. Cerebral ischemia was established in CB-17 mice in the present study, and the mice were subsequently treated with recombinant human erythropoietin via subcutaneous injection. Results demonstrated that cerebral cortical width index significantly increased. Immunofluorescence detection showed that the number of nuclear antigen antibody/5-bromodeoxyuridine-positive cells at the infarction edge significantly increased. Correlation analysis revealed a negative correlation between neurological scores and cortical width indices in rats following ischemic stroke. These experimental findings suggested that recombinant human erythropoietin promoted cerebral cortical hyperplasia, increased cortical neurogenesis, and enhanced functional recovery following ischemic stroke.

  1. Erythropoietin resistance in end-stage renal disease patient with gastric antral vascular ectasia

    Directory of Open Access Journals (Sweden)

    Desiree Ji Re Lee

    2015-09-01

    Full Text Available AbstractWe observed a case of recombinant human erythropoietin resistance caused by Gastric Antral Vascular Ectasia in a 40-year-old female with ESRD on hemodialysis. Some associated factors such as autoimmune disease, hemolysis, heart and liver disease were discarded on physical examination and complementary tests. The diagnosis is based on the clinical history and endoscopic appearance of watermelon stomach. The histologic findings are fibromuscular proliferation and capillary ectasia with microvascular thrombosis of the lamina propria. However, these histologic findings are not necessary to confirm the diagnosis. Gastric Antral Vascular Ectasia is a serious condition and should be considered in ESRD patients on hemodialysis with anemia and resistance to recombinant human erythropoietin because GAVE is potentially curable with specific endoscopic treatment method or through surgical procedure.

  2. Radioimmunoassay of haemoglobin F in K 562 cells following induction with renin substrate and erythropoietin

    Energy Technology Data Exchange (ETDEWEB)

    Rosenloef, K.; Fyhrquist, F.; Hortling, L.; Groenhagen-Riska, C. (Helsinki Univ. (Finland). Minerva Inst. for Medical Research; Helsinki Univ. (Finland). 4th Dept. of Medicine)

    1985-06-01

    To test the hypothesis of renin substrate (RS: angiotensinogen) being a precursor of erythropoietin (EP), the capacity of RS and EP to induce Hb synthesis was compared in cultured human erythroid leukaemia cells of the K 562 line after prestimulation with haemin. For this purpose a radioimmunoassay for haemoglobin F (HbF) was developed. This assay was shown to be specific for HbF, reproducible, and sensitive for 0.1 ng of HbF. The cells were induced by RS and EP to increased HbF production. Cells stimulated with RS or EP showed increased benzidine staining. These data support the hypothesis that renin substrate is a likely precursor of erythropoietin.

  3. Comparison among three anion exchange chromatographic supports to capture erythropoietin from cell culture supernatant

    Institute of Scientific and Technical Information of China (English)

    Lourdes HERNNDEZ; Diobel STEWART; Lourdes ZUMALACRREGUI; Daniel AMARO

    2015-01-01

    Affinity and ion exchange conventional chromatography have been used to capture erythropoietin ( EPO)from mammalian cell culture supernatant. Currently,chromatographic adsorbent perfusion is available, however a limited number of applications have been found in the literature. In this work,three anion exchange chromatographic supports( gel,membrane and monolithic)were evaluated in the capture step of the recombi-nant erythropoietin purification process. The influences of load and flow rate on each support performance were analyzed. Also the purity of the EPO molecules was determined. A productivity analysis,as a decision tool for larger scale implementation,was done. As a conclusion,the evaluated supports are technically suitable to cap-ture EPO with adequate recovery and good purity. However,the monolithic column admits high operating velocity,showing the highest adsorption capacity and productivity.

  4. Effects of prolonged recombinant human erythropoietin administration on muscle membrane transport systems and metabolic marker enzymes

    DEFF Research Database (Denmark)

    Juel, C; Thomsen, J J; Rentsch, R L;

    2007-01-01

    Adaptations to chronic hypoxia involve changes in membrane transport proteins. The underlying mechanism of this response may be related to concomitant occurring changes in erythropoietin (Epo) levels. We therefore tested the direct effects of recombinant human erythropoietin (rHuEpo) treatment...... on the expression of muscle membrane transport proteins. Likewise, improvements in performance may involve upregulation of metabolic enzymes. Since Epo is known to augment performance we tested the effect of rHuEpo on some marker enzymes that are related to aerobic capacity. For these purposes eight subjects...... received 5,000 IU rHuEpo every second day for 14 days, and subsequently a single dose of 5,000 IU weekly for 12 weeks. Muscle biopsies were obtained before and after 14 weeks of rHuEpo treatment. The treatment increased hematocrit (from 44.7 to 48.8%), maximal oxygen uptake by 8.1%, and submaximal...

  5. Recombinant human erythropoietin and hemoglobin concentration at operation and during the postoperative period

    DEFF Research Database (Denmark)

    Qvist, N; Boesby, S; Wolff, B

    1999-01-01

    and 750 ml, respectively. The number of blood transfusions given was significantly lower in the erythropoietin group, with a mean of 0.3 (range 0-6) units compared to 1.6 (0-9) units in the control group (p concentration at the time of surgery and during the week......In a double-blind placebo-controlled study we investigated the effect of recombinant human erythropoietin (r-HuEPO), on the perioperative hemoglobin concentration and the use of blood transfusions in patients undergoing elective colorectal surgery with a preoperative hemoglobin level ... for 4 days before surgery. There were no differences between the two groups with regard to sex, height, weight, serum electrolytes, and liver function tests at study entry. The preentry hemoglobin concentration was similar in the two groups, with a median value of 7.9 (range 5.3-8.5) mmol...

  6. Erythropoietin in patients with aneurysmal subarachnoid haemorrhage: a double blind randomised clinical trial

    DEFF Research Database (Denmark)

    Springborg, J B; Møller, C; Gideon, P;

    2007-01-01

    BACKGROUND: Erythropoietin (EPO) is neuroprotective in experimental models of stroke and subarachnoid haemorrhage (SAH) and possibly in patients with thromboembolic stroke. We studied the efficacy and safety of EPO in patients with SAH. METHODS: A larger scale clinical trial was planned but preli......BACKGROUND: Erythropoietin (EPO) is neuroprotective in experimental models of stroke and subarachnoid haemorrhage (SAH) and possibly in patients with thromboembolic stroke. We studied the efficacy and safety of EPO in patients with SAH. METHODS: A larger scale clinical trial was planned...... group but the difference was statistically insignificant. In the EPO-treated patients the CSF concentration of EPO increased 600-fold. Except for a higher extracelullar concentration of glycerol in the EPO group probably caused by the poorer clinical condition of these patients, there were...

  7. THE COMBINATION OF α-LIPOIC ACID INTAKE WITH ECCENTRIC EXERCISE MODULATES ERYTHROPOIETIN RELEASE

    OpenAIRE

    Morawin, B.; Turowski, D; M Naczk; Siatkowski, I.; A. Zembron-Lacny

    2014-01-01

    The generation of reactive nitrogen/oxygen species (RN/OS) represents an important mechanism in erythropoietin (EPO) expression and skeletal muscle adaptation to physical and metabolic stress. RN/OS generation can be modulated by intense exercise and nutrition supplements such as α-lipoic acid, which demonstrates both anti- and pro-oxidative action. The study was designed to show the changes in the haematological response through the combination of α-lipoic acid intake with running eccentric ...

  8. Erythropoietin (EPO)-receptor signaling induces cell death of primary myeloma cells in vitro

    OpenAIRE

    Thea Kristin Våtsveen; Anne-Marit Sponaas; Erming Tian; Qing Zhang; Kristine Misund; Anders Sundan; Magne Børset; Anders Waage; Gaute Brede

    2016-01-01

    Background: Multiple myeloma is an incurable complex disease characterized by clonal proliferation of malignant plasma cells in a hypoxic bone marrow environment. Hypoxia-dependent erythropoietin (EPO)-receptor (EPOR) signaling is central in various cancers, but the relevance of EPOR signaling in multiple myeloma cells has not yet been thoroughly investigated. Methods: Myeloma cell lines and malignant plasma cells isolated from bone marrow of myeloma patients were used in this st...

  9. A Novel Role for Erythropoietin During Fibrin-Induced Wound-Healing Response

    OpenAIRE

    Haroon, Zishan A.; Amin, Khalid; Jiang, XiaoHong; Arcasoy, Murat O.

    2003-01-01

    In this study, we investigated the role of the hematopoietic cytokine erythropoietin (EPO) during wound healing, the physiological response to tissue injury. We used an in vivo wound-healing assay (fibrin Z-chambers) consisting of fibrin-filled chambers implanted subcutaneously in rats. The fibrin inside the chambers is replaced by granulation tissue consisting of new blood vessels, macrophages and fibroblasts as part of the wound-healing response. Local, exogenous recombinant EPO administrat...

  10. A Novel Role for Erythropoietin During Fibrin-Induced Wound-Healing Response

    OpenAIRE

    Haroon, Zishan A.; Amin, Khalid; Jiang, Xiaohong; Arcasoy, Murat O.

    2003-01-01

    In this study, we investigated the role of the hematopoietic cytokine erythropoietin (EPO) during wound healing, the physiological response to tissue injury. We used an in vivo wound-healing assay (fibrin Z-chambers) consisting of fibrin-filled chambers implanted subcutaneously in rats. The fibrin inside the chambers is replaced by granulation tissue consisting of new blood vessels, macrophages and fibroblasts as part of the wound-healing response. Local, exogenous recombinant EPO administrat...

  11. Erythropoietin Promotes Bone Formation through EphrinB2/EphB4 Signaling

    OpenAIRE

    Li, C; Shi, C.; Kim, J; Chen, Y.; Ni, S.; Jiang, L.; Zheng, C.; Li, D; J. Hou; Taichman, R. S.; Sun, H

    2015-01-01

    Recent studies have demonstrated that erythropoietin (EPO) has extensive nonhematopoietic biological functions. However, little is known about how EPO regulates bone formation, although several studies suggested that EPO can affect bone homeostasis. In this study, we investigated the effects of EPO on the communication between osteoclasts and osteoblasts through the ephrinB2/EphB4 signaling pathway. We found that EPO slightly promotes osteoblastic differentiation with the increased expression...

  12. Erythropoietin Modulates the Structure of Bone Morphogenetic Protein 2–Engineered Cranial Bone

    OpenAIRE

    Sun, Hongli; Jung, Younghun; Shiozawa, Yusuke; Taichman, Russell S.; Krebsbach, Paul H.

    2012-01-01

    The ideally engineered bone should have similar structural and functional properties to the native tissue. Although structural integrity is critical for functional bone regeneration, we know less about modulating the structural properties of the engineered bone elicited by bone morphogenetic protein (BMP) than efficacy and safety. Erythropoietin (Epo), a primary erythropoietic hormone, has been used to augment blood transfusion in orthopedic surgery. However, the effects of Epo on bone regene...

  13. The anemia of chronic renal failure in sheep. Response to erythropoietin-rich plasma in vivo.

    OpenAIRE

    Eschbach, J W; Mladenovic, J; Garcia, J F; Wahl, P W; Adamson, J W

    1984-01-01

    The hypoproliferative anemia in chronic renal failure has been assumed to be the result of decreased erythropoietin (Ep) production by the damaged kidney and of the shortening of erythrocyte survival. However, many in vitro studies suggest that erythropoietic inhibitors in uremic plasma may contribute to the anemia. To determine the in vivo relevance of uremic inhibitors, increasing amounts of Ep as Ep-rich plasma were infused into six uremic sheep, and their erythropoietic responses were com...

  14. Changes in erythropoietin levels during space flight or space flight simulation

    Science.gov (United States)

    Dunn, C. D. R.; Hen, J. P.

    1980-01-01

    Two hundred and seventy samples from 24 subjects involved in 3 bedrest studies and from 3 subjects involved in Spacelab Mission Development Test 3 were assayed for erythropoietin (Ep), in an in vitro fetal mouse liver cell assay, and for ferritin using a commercially available immunoradiometric assay kit. No trends or significant changes in serum Ep were observed. Serum ferritin concentrations tended to increases slightly during the 'missions', reflecting a redirection of iron from the suppressed erythron into iron stores.

  15. Increased Levels of Erythropoietin in Nipple Aspirate Fluid and in Ductal Cells from Breast Cancer Patients

    Directory of Open Access Journals (Sweden)

    Ferdinando Mannello

    2008-01-01

    Full Text Available Background: Erythropoietin (Epo is an important regulator of erythropoiesis, and controls proliferation and differentiation of both erythroid and non-erythroid tissues. Epo is actively synthesized by breast cells during lactation, and also plays a role in breast tissues promoting hypoxia-induced cancer initiation. Our aims are to perform an exploratory investigation on the Epo accumulation in breast secretions from healthy and cancer patients and its localization in breast cancer cells.

  16. Therapeutic levels of erythropoietin (EPO) achieved after gene electrotransfer to skin in mice

    DEFF Research Database (Denmark)

    Gothelf, A; Hojman, P; Gehl, Julie

    2010-01-01

    Gene electrotransfer refers to gene transfection by electroporation and is an effective non-viral method for delivering naked DNA into cells and tissues. This study presents data from gene electrotransfer with erythropoietin (EPO) to mouse skin. Nine-week-old female NMRI mice received one, two...... or three intradermal injections of 50 microg EPO plasmid and were subsequently electroporated. With plate electrodes and 100 microg of EPO, a significant increase in hemoglobin (P...

  17. Erythropoietin, a Novel Versatile Player Regulating Energy Metabolism beyond the Erythroid System

    OpenAIRE

    Wang, Li; Di, Lijun; Noguchi, Constance Tom

    2014-01-01

    Erythropoietin (EPO), the required cytokine for promoting the proliferation and differentiation of erythroid cells to stimulate erythropoiesis, has been reported to act as a pleiotropic cytokine beyond hematopoietic system. The various activities of EPO are determined by the widespread distribution of its cell surface EPO receptor (EpoR) in multiple tissues including endothelial, neural, myoblasts, adipocytes and other cell types. EPO activity has been linked to angiogenesis, neuroprotection,...

  18. Decreased plasma soluble erythropoietin receptor in high-altitude excessive erythrocytosis and Chronic Mountain Sickness

    OpenAIRE

    Villafuerte, Francisco C.; Macarlupú, José Luis; Anza-Ramírez, Cecilia; Corrales-Melgar, Daniela; Vizcardo-Galindo, Gustavo; Corante, Noemí; León-Velarde, Fabiola

    2014-01-01

    Excessive erythrocytosis (EE) is the hallmark of chronic mountain sickness (CMS), a prevalent syndrome in high-altitude Andean populations. Although hypoxemia represents its underlying stimulus, why some individuals develop EE despite having altitude-normal blood erythropoietin (Epo) concentration is still unclear. A soluble form of the Epo receptor (sEpoR) has been identified in human blood and competes directly for Epo with its membrane counterpart (mEpoR). Thus, reduced levels of circulati...

  19. The effect of erythropoietin on serum uric acid levels during renal ischemia reperfusion injury in rats

    Science.gov (United States)

    Tsompos, Constantinos; Panoulis, Constantinos; Toutouzas, Konstantinos; Zografos, George; Papalois, Apostolos

    2014-01-01

    Objective: The aim of this experimental study was to assess the effect of erythropoietin on a rat model, particularly under a renal ischemia reperfusion protocol. The beneficial or lack of effects of that molecule on the excreted renal product of serum uric acid were studied biochemically. Material and methods: Forty rats were used with a mean weight of 247.7 gr. Serum uric acid levels were measured measured at 60 min after reperfusion (Groups A and C) and at 120 min after reperfusion (groups B and D). Results: 1) Erythropoietin administration non-significantly decreased the serum uric acid levels non-significantly by 0.02 mg/dL [−0.2415423 mg/dL-0.2015423 mg/dL] (p=0.8560), in accordance with the paired t-test (p=0.8438). Reperfusion time non-significantly increased the serum uric acid levels non-significantly by 0.17 mg/dL [−0.0444933 mg/dL-0.3844933 mg/dL] (p=0.1169), in accordance with the paired t-test (p=0.1648). 3) The interaction of erythropoietin administration and reperfusion time non-significantly increased the serum uric acid levels non-significantly by 0.1 mg/dL [−0.0295564 mg/dL-0.2295564 mg/dL] (p=0.1264). Conclusion: Erythropoietin administration, reperfusion time and their interaction have no significant short-term alterations on serum uric acid levels. Conclusions cannot be extracted by non-significant p-values within 2 hours. Obviously, longer study times may permit safer results. PMID:26328161

  20. Form CMS-2728 data versus erythropoietin claims data: implications for quality of care studies.

    Science.gov (United States)

    Beaubrun, Anne C; Kanda, Eiichiro; Bond, T Christopher; McClellan, William M

    2013-01-01

    Medical Evidence Report Form CMS-2728 data is frequently used to study US dialysis patients, but the validity of these data have been called into question. We compared predialysis erythropoietin use as recorded on Form CMS-2728 with claims data as part of an assessment of quality of care among hemodialysis patients. Medicare claims were linked to Form CMS-2728 data for 18,870 patients. Dialysis patients, 67 years old or older, who started dialysis from 1 June 2005 to 31 May 2007 were eligible. Logistic and multivariate regressions were used to compare the use of either Form CMS-2728 or the corresponding claims data to predict mortality and the probability of meeting target hemoglobin levels. The sensitivity, specificity, and kappa coefficient for the predialysis erythropoietin indicator were 58.0%, 78.4%, and 0.36, respectively. Patients with a predialysis erythropoietin claim were less likely to die compared with patients without a claim (odds ratio = 0.80 and 95% confidence interval = 0.74-0.87), but there was no relationship observed between predialysis care and death using only Form CMS-2728 predictors. At the facility level, a predialysis erythropoietin claim was associated with a 0.085 increase in the rate of meeting target hemoglobin levels compared with patients without a claim (p = 0.041), but no statistically significant relationship was observed when using the Form CMS-2728 indicators. The agreement between Form CMS-2728 and claims data is poor and discordant results are observed when comparing the use of these data sources to predict health outcomes. Facilities with higher agreement between the two data sources may provide greater quality of care.

  1. Expression of GPI anchored human recombinant erythropoietin in CHO cells is devoid of glycosylation heterogeneity.

    Science.gov (United States)

    Singh, Pankaj Kumar; Devasahayam, Mercy; Devi, Sobita

    2015-04-01

    Erythropoietin is a glycohormone involved in the regulation of the blood cell levels. It is a 166 amino acid protein having 3 N-glycosylation and one O-linked glycosylation sites, and is used to treat anaemia related illness. Though human recombinant erythropoietin (rEPO) is produced in CHO cells, the loss in quality control is 80% due to incomplete glycosylation of the rEPO with low levels of fully glycosylated active rEPO. Here, we describe the expression from CHO cells of fully glycosylated human rEPO when expressed as a GPI anchored molecule (rEPO-g). The results demonstrated the production of a homogenous completely glycosylated human rEPO-g as a 42 kD band without any low molecular weight glycoform variants as shown by affinity chromatography followed by SDS-PAGE and anti-human EPO specific western blot. The western blot using specific monoclonal antibody is the available biochemical technique to prove the presence of homogeneity in the expressed recombinant protein. The GPI anchor can be removed during the purification process to yield a therapeutically relevant recombinant erythropoietin molecule cells with a higher in vivo biological activity due to its high molecular weight of 40 kD. This is possibly the first report on the production of a homogenous and completely glycosylated human rEPO from CHO cells for efficient therapy.

  2. Tract-based spatial statistics to assess the neuroprotective effect of early erythropoietin on white matter development in preterm infants.

    Science.gov (United States)

    O'Gorman, Ruth L; Bucher, Hans U; Held, Ulrike; Koller, Brigitte M; Hüppi, Petra S; Hagmann, Cornelia F

    2015-02-01

    Despite improved survival, many preterm infants undergo subsequent neurodevelopmental impairment. To date, no neuroprotective therapies have been implemented into clinical practice. Erythropoietin, a haematopoietic cytokine used for treatment of anaemia of prematurity, has been shown to have neuroprotective and neuroregenerative effects on the brain in many experimental studies. The aim of the study was to assess the effect of recombinant human erythropoietin on the microstructural development of the cerebral white matter using tract-based spatial statistics performed at term equivalent age. A randomized, double-blind placebo-controlled, prospective multicentre study applying recombinant human erythropoietin in the first 42 h after preterm birth entitled 'Does erythropoietin improve outcome in preterm infant' was conducted in Switzerland (NCT00413946). Preterm infants were given recombinant human erythropoietin (3000 IU) or an equivalent volume of placebo (NaCl 0.9%) intravenously before 3 h of age after birth, at 12-18 h and at 36-42 h after birth. High resolution diffusion tensor imaging was obtained at 3 T in 58 preterm infants with mean (standard deviation) gestational age at birth 29.75 (1.44) weeks, and at scanning at 41.1 (2.09) weeks. Imaging was performed at a single centre. Voxel-wise statistical analysis of the fractional anisotropy data was carried out using tract-based spatial statistics to test for differences in fractional anisotropy between infants treated with recombinant human erythropoietin and placebo using a general linear model, covarying for the gestational age at birth and the corrected gestational age at the time of the scan. Preterm infants treated with recombinant human erythropoietin demonstrated increased fractional anisotropy in the genu and splenium of the corpus callosum, the anterior and posterior limbs of the internal capsule, and the corticospinal tract bilaterally. Mean fractional anisotropy was significantly higher in preterm

  3. Orally administrated Juzen-taiho-to/TJ-48 ameliorates erythropoietin (rHuEPO)-resistant anemia in patients on hemodialysis.

    Science.gov (United States)

    Nakamoto, Hidetomo; Mimura, Taku; Honda, Nobuko

    2008-10-01

    Maintenance of the red blood cell volume is a fundamental aspect of ensuring oxygen supply to the tissue. Recombinant human erythropoietin (rHuEPO) was approved for marketing in Japan in 1990 for the treatment of anemia in patients on dialysis. Recombinant human erythropoietin caused a significant increase in hemoglobin (Hb) levels in patients on dialysis. However, not all have a good response to rHuEPO therapy; the causes of rHuEPO failure include iron deficiency, infection, uremia, and interaction of some drugs. Juzen-taiho-to (TJ-48), a mixture of extracts from 10 medicinal herbs, has been used traditionally to treat patients with anemia, anorexia, or fatigue. To clarify the effect of TJ-48 on erythropoietin-resistant anemia, we studied the effect of TJ-48 in patients on hemodialysis with erythropoietin-resistant anemia. We divided 42 end-stage renal disease patients on hemodialysis with erythropoietin-resistant anemia (Hbrenal disease patients. This effect was, at least in part, due to the anti-inflammatory effect of TJ-48 in patients on hemodialysis.

  4. Effects of an 8-weeks erythropoietin treatment on mitochondrial and Whole body fat oxidation capacity during exercise in healthy males

    DEFF Research Database (Denmark)

    Guadalupe Grau, Amelia; Plenge, Ulla; Bønding, Signe Helbo

    2015-01-01

    Abstract The present investigation was performed to elucidate if the non-erythropoietic ergogenic effect of a recombinant erythropoietin treatment results in an impact on skeletal muscle mitochondrial and whole body fatty acid oxidation capacity during exercise, myoglobin concentration and angiog......Abstract The present investigation was performed to elucidate if the non-erythropoietic ergogenic effect of a recombinant erythropoietin treatment results in an impact on skeletal muscle mitochondrial and whole body fatty acid oxidation capacity during exercise, myoglobin concentration......, pyruvate, succinate) with additional electron input from β-oxidation (octanoylcarnitine) (from 60 ± 13 to 87 ± 24 pmol · s(-1) · mg(-1) P ... of recombinant erythropoietin treatment increases mitochondrial fatty acid oxidation capacity and myoglobin concentration without any effect on whole body maximal fat oxidation....

  5. ARA290, a Specific Agonist of Erythropoietin/CD131 Heteroreceptor, Improves Circulating Endothelial Progenitors' Angiogenic Potential and Homing Ability.

    Science.gov (United States)

    Hache, Guillaume; Garrigue, Philippe; Bennis, Youssef; Stalin, Jimmy; Moyon, Anais; Cerami, Anthony; Brines, Michael; Blot-Chabaud, Marcel; Sabatier, Florence; Dignat-George, Francoise; Guillet, Benjamin

    2016-10-01

    Alternate erythropoietin (EPO)-mediated signaling via the EPOR/CD131 heteromeric receptor exerts the tissue-protective actions of EPO in a wide spectrum of injuries, especially ischemic diseases. Circulating endothelial progenitor cells contribute to endothelial repair and post-natal angiogenesis after chronic ischemic injury. This work aims to investigate the effects of ARA290, a specific agonist of EPOR/CD131 complex, on a subpopulation of endothelial progenitor cells named endothelial colony-forming cells (ECFCs) and to characterize its contribution to ECFCs-induced angiogenesis after peripheral ischemia. ARA290 effects on ECFCs properties were studied using cell cultures in vitro. We injected ARA290 to mice undergoing chronic hindlimb ischemia (CLI) in combination with ECFC transplantation. The homing of transplanted ECFC to ischemic tissue in vivo was assessed by SPECT/CT imaging. In vitro, ARA290 enhanced the proliferation, migration, and resistance to H2O2-induced apoptosis of ECFCs. After ECFC transplantation to mice with CLI, a single ARA290 injection enhanced the ischemic/non-ischemic ratio of hindlimb blood flow and capillary density after 28 days and the homing of radiolabeled transplanted cells to the ischemic leg 4 h after transplantation. Prior neutralization of platelet-endothelial cell adhesion molecule-1 (CD31) expressed by the transplanted cells inhibited ARA290-induced improvement of homing. ARA290 induces specific improvement of the biological activity of ECFCs. ARA290 administration in combination with ECFCs has a synergistic effect on post-ischemic angiogenesis in vivo. This potentiation appears to rely, at least in part, on a CD31-dependent increase in homing of the transplanted cells to the ischemic tissue.

  6. Use of high-dose erythropoietin for repair after injury: A comparison of outcomes in heart and kidney.

    Science.gov (United States)

    Gobe, Glenda C; Morais, Christudas; Vesey, David A; Johnson, David W

    2013-07-01

    There is a need to define the exact benefits and contraindications of use of high-dose recombinant human erythropoietin (EPO) for its non-hematopoietic function as a cytokine that enhances tissue repair after injury. This review compares the outcomes from use of EPO in the injured heart and kidney, two organs that are thought, traditionally, to have intrinsically-different repair mechanisms. Directory of Open Access Journals (DOAJ), Google Scholar, Pubmed (NLM), LISTA (EBSCO) and Web of Science have been searched. Ongoing work by us on EPO protection of ischemia-reperfusion-injured kidneys indicated, first, that EPO acutely enhanced kidney repair via anti-apoptotic, pro-regenerative mechanisms, and second, that EPO may promote chronic fibrosis in the long term. Work by others on the ischaemia-injured heart has also indicated that EPO promotes repair. Although myocardial infarcts are made up mostly of necrotic tissue, many publications state EPO is anti-apoptotic in the heart, as well as promoting healing via cell differentiation and stimulation of granulation tissue. In the case of the heart, promotion of fibrosis may be advantageous where an infarct has destroyed a zone of cardiomyocytes, but if EPO stimulates progressive fibrosis in the heart, this may promote cardiac failure. A major concern in relation to the use of EPO in a cytoprotective role is its stimulation of long-term inflammation and fibrosis. EPO usage for cytoprotection is undoubtedly advantageous, but it may need to be offset with an anti-inflammatory agent in some organs, like kidney and heart, where progression to chronic fibrosis after acute injury is often recorded.

  7. Erythropoietin receptor in human skeletal muscle and the effects of acute and long-term injections with recombinant human erythropoietin on the skeletal muscle

    DEFF Research Database (Denmark)

    Lundby, Carsten; Hellsten, Ylva; Jensen, Mie B. F.;

    2008-01-01

    The presence and potential physiological role of the erythropoietin receptor (Epo-R) were examined in human skeletal muscle. In this study we demonstrate that Epo-R is present in the endothelium, smooth muscle cells, and in fractions of the sarcolemma of skeletal muscle fibers. To study...... the potential effects of Epo in human skeletal muscle, two separate studies were conducted: one to study the acute effects of a single Epo injection on skeletal muscle gene expression and plasma hormones and another to study the effects of long-term (14 wk) Epo treatment on skeletal muscle structure. Subjects...... (n = 11) received a single Epo injection of 15,000 IU (double blinded, cross over, placebo). A single Epo injection reduced myoglobin and increased transferrin receptor and MRF-4 mRNA content within 10 h after injection. Plasma hormones remained unaltered. Capillarization and fiber hypertrophy...

  8. Clinical efficacy and safety of recombinant canine erythropoietin in dogs with anemia of chronic renal failure and dogs with recombinant human erythropoietin-induced red cell aplasia.

    Science.gov (United States)

    Randolph, John E; Scarlett, Janet; Stokol, Tracy; MacLeod, James N

    2004-01-01

    The efficacy and safety of recombinant canine erythropoietin (rcEPO) therapy was evaluated in 19 dogs with anemia of chronic renal failure (group 1) and 6 dogs with chronic renal failure and recombinant human erythropoietin (rhEPO)-induced red cell aplasia (group 2). Hematocrit (Hct) and absolute reticulocyte count (ARC) were monitored weekly for the first 8 weeks, CBC (including ARC) and serum iron profiles were evaluated monthly, and serum biochemical analyses were performed every 2 months for 6 (group 2) to 12 (group 1) months. For group 1 dogs, median Hct and ARC increased significantly during the 1st week of rcEPO treatment, and median Hct was sustained at >35% after week 5. In contrast, median Hct and ARC for group 2 did not change significantly with rcEPO treatment, even with doses greater than those used in group 1. Nevertheless, 2 (33%) of the 6 dogs in group 2 developed erythroid hyperplasia, reticulocytosis, and increases in Hct with rcEPO treatment. Although median systolic blood pressure did not change significantly in either group, 5 dogs developed systolic blood pressures > or = 180 mm Hg during the study. Appetite and energy level improved in most group 1 dogs with increases in Hct. Recombinant cEPO stimulated erythrocyte production in dogs with nonregenerative anemia secondary to chronic renal failure without causing the profound erythroid hypoplasia that can occur in rhEPO-treated dogs. Unfortunately, rcEPO was not as effective in restoring erythrocyte production in dogs that had previously developed rhEPO-induced red cell aplasia.

  9. Does recombinant human erythropoietin accelerate correction of post-ulcer-bleeding anaemia? A pilot study

    Institute of Scientific and Technical Information of China (English)

    Spiros D. Ladas; Dimitrios Polymeros; Thomas Pagonis; Konstantinos Triantafyllou; Gregorios Paspatis; Maria Hatziargiriou; Sotirios A.Raptis

    2004-01-01

    AIM: Anaemia caused by acute upper gastrointestinal bleeding is treated with blood transfusion or iron, but patients usually face a two-month recovery period from posthaemorrhage anaemia. This prospective, randomised, open,pilot study was designed to investigate whether recombinant human erythropoietin (Epoetin) therapy accelerate haematocrit increase in the post-bleeding recovery period.METHODS: We studied hospitalised patients admitted because of acute ulcer bleeding or haemorrhagic gastritis,who had a haematocrit of 27-33% and did not receive blood transfusions. One day after the endoscopic confirmation of cessation of bleeding, they were randomised either to erythropoietin (20 000 IU Epoetin alfa subcutaneously, on days 0, 4 and 6) plus iron (100 mg im, on days 1- 6, (G1) or iron only (G2). Haematocrit was measured on days 0, 6, 14,30, 45, and 60, respectively.RESULTS: One patient from G1 and two from G2 were lost to follow-up. Therefore, 14 and 13 patients from G1 and G2respectively were analysed. Demographic characteristics, serum iron, ferritin, total iron binding capacity, reticulocytes, and haematocrit were not significantly different at entry to the study.Median reticulocyte counts were significantly different between groups on day six (G1: 4.0, 3.0-6.4 vsG2: 3.5, 2.1-4.4%,P=0.03) and median haematocrit on day fourteen [G1: 35.9,30.7-41.0 vsG2: 32.5, 29.5-37.0% (median, range), P=0.04].CONCLUSION: Erythropoietin administration significantly accelerates correction of anemia after acute ulcer bleeding.The haematocrit gain is equivalent to one unit of transfused blood two weeks after the bleeding episode.

  10. Historical review on the use of recombinant human erythropoietin in chronic renal failure.

    Science.gov (United States)

    Winearls, C G

    1995-01-01

    The success of maintenance haemodialysis in the 1960s was blighted by the problem of anaemia. Treatment with iron, folic acid, androgens and transfusions did no more than minimize its effects. The need for a renewable source of erythropoietin was appreciated very early but the hope took 25 years to realize. Cloning and expression of the human gene was achieved in 1984 and clinical trials planned even before the descriptions of the recombinant hormone were published. The Amgen material was tested in parallel studies in Seattle and England and by the end of 1986 the efficacy of recombinant human erythropoietin (r-HuEPO) given in large intravenous bolus doses in reversing the anaemia of uraemia was established. The benefits were immediately obvious: relief from transfusion dependence was the unequivocal evidence but the effect on 'wellbeing' though subjective was remarkable. Large clinical trials were completed in Europe and the USA so that r-HuEPO was licensed as a therapeutic drug less than two years later. The pilot studies flagged a number of key issues: hypertension, sometimes with encephalopathy, occurred in patients whose blood pressure was labile before treatment; vascular access failure seemed more frequent and hyperkalaemia was thought to reflect less efficient dialysis. Failure to respond focused attention on iron balance as well as on factors such as infection, aluminium, and hyperparathyroidism. A more clear understanding of the pathogenesis of the anaemia of uraemia was made possible by dissection of the specific effects of the exogenous erythropoietin on erythroid function.(ABSTRACT TRUNCATED AT 250 WORDS)

  11. Use of recombinant human erythropoietin as an antianemic and performance enhancing drug.

    Science.gov (United States)

    Jelkmann, W

    2000-07-01

    The glycoprotein hormone erythropoietin is an essential viability and growth factor for the erythrocytic progenitors in the bone marrow. Tissue hypoxia is the main stimulus for the synthesis of the hormone in the kidneys and the liver. Endogenous erythropoietin and recombinant human erythropoietin (rHu-EPO) are similar with respect to their biological and chemical properties except for some microheterogeneities in their 4 carbohydrate chains. Generic products and alternatives to rHu-EPO are in development. Renal anemia can be corrected by rHu-EPO in a dose-dependent and predictable way without major side effects apart from a possible increase in arterial blood pressure. The optimal target hematocrit still needs to be defined. There are rare reports of antibody formation towards rHu-EPO in humans. Patients suffering from non-renal anemias may also benefit from the prescription of rHu-EPO. The drug has been approved for treatment of tumor patients with platinum-induced anemia. The cost-effectiveness and medical justification of the administration of rHu-EPO in tumor patients with respect to its positive effects on tumor oxygenation, tumor growth inhibition and support of chemo- and radiotherapy is still a matter of debate. In surgical patients, the pharmacological application of rHu-EPO can increase the yield of blood units in autologous blood donation programs and lower the severity and duration of postoperative anemia, if applicated some days prior to surgery. While rHu-EPO is a godsend in medical practice, its abuse as an performance enhancing drug by athletes in endurance sports is an unethical and potentially dangerous procedure. Unequivocal methods for detection of rHu-EPO doping still need to be established.

  12. Erythropoietin may reduce the risk of germ cell loss in boys with cryptorchidism

    DEFF Research Database (Denmark)

    Cortes, D; Visfeldt, J; Thorup, J M

    2001-01-01

    of infertility. In order to increase the number of germ cells, and thereby the fertility potential, additional hormonal therapy has been attempted before surgery. In a study, small doses of the gonadotropin-releasing hormone analogue buserelin before orchiopexy caused higher values. Others have found...... that hormonal treatment with human chorionic gonadotropin or gonadotropin releasing hormone analogue may harm the germ cells in cryptorchidism. The aim of the study is to demonstrate that additional hormonal therapy with erythropoietin has a positive effect on the number of germ cells. MATERIALS AND METHODS...

  13. Erythropoietin improves synaptic transmission during and following ischemia in rat hippocampal slice cultures.

    Science.gov (United States)

    Weber, Astrid; Maier, Rolf F; Hoffmann, Ulrike; Grips, Martin; Hoppenz, Marc; Aktas, Ayse G; Heinemann, Uwe; Obladen, Michael; Schuchmann, Sebastian

    2002-12-27

    Erythropoietin (EPO) prevents neuronal damage following ischemic, metabolic, and excitotoxic stress. In this study evoked extracellular field potentials (FP) were used to investigate the effect of EPO on synaptic transmission in hippocampal slice cultures. EPO treated cultured slices (40 units/ml for 48 h) showed significantly increased FP during and following oxygen and glucose deprivation compared with untreated control slices. The addition of the Jak2 inhibitor AG490 (50 microM for 48 h) blocked the EPO effect. These data suggest that EPO improves synaptic transmission during and following ischemia in hippocampal slice cultures.

  14. New insights for identification of doping with recombinant human erythropoietin micro-doses after high hydration

    DEFF Research Database (Denmark)

    Martin, L.; Ashenden, M; Bejder, Jacob

    2016-01-01

    To minimize the chances of being caught after doping with recombinant human erythropoietins (rhEPO), athletes have turned to new practices using micro-doses and excess fluid ingestion to accelerate elimination and decrease the probability of detection. Our objective was to test the sensitivity...... subjects. After an injection in the evening, urine and plasma samples were collected the following morning. Half of the subjects then drank a bolus of water and new samples were collected 80 min later. Interestingly, rhEPO was detected in 100% of the samples even after water ingestion. A second similar...

  15. Pathogenesis and therapy of anemia in oncohemathology patients with recombinant erythropoietin agents (review

    Directory of Open Access Journals (Sweden)

    N. A. Romanenko

    2014-07-01

    Full Text Available The article presents a literature review on the mechanisms of anemia in patients with hematologic malignancies and a classification of chronic anemia and methods of its correction. It describes in detail the mechanism of action, indications and side effects of rembinant erythropoietin (rEPO. It gives anemia treatment algorithms with rEPO in patients with chronic blood malignancies. The analysis of rEPO efficacy is shown in anemia treatment in patients with various types of cancer. It presents the recommendations of ASCO/ASH for the use of rEPO in various patients categories.

  16. Pathogenesis and therapy of anemia in oncohemathology patients with recombinant erythropoietin agents (review

    Directory of Open Access Journals (Sweden)

    N. A. Romanenko

    2012-01-01

    Full Text Available The article presents a literature review on the mechanisms of anemia in patients with hematologic malignancies and a classification of chronic anemia and methods of its correction. It describes in detail the mechanism of action, indications and side effects of rembinant erythropoietin (rEPO. It gives anemia treatment algorithms with rEPO in patients with chronic blood malignancies. The analysis of rEPO efficacy is shown in anemia treatment in patients with various types of cancer. It presents the recommendations of ASCO/ASH for the use of rEPO in various patients categories.

  17. Recombinant human erythropoietin, and myocardial and cerebral acute ischemia: implications for clinical use.

    Directory of Open Access Journals (Sweden)

    Rafael Alejandro Gómez Baute

    2010-07-01

    Full Text Available Recombinant human erythropoietin has been used for more than two decades in clinical practice with promising results in the treatment of anemia associated with chronic renal insufficiency and in patients with cancer. Recent evidence has uncovered new nonhematopoietic functions of this protein and have brought new hope in the treatment of diseases with ischemic component. In the present review is rife with detail about these new features in the light of new discoveries and explores the therapeutic opportunities offered by these new scientific evidence.

  18. Plasma soluble erythropoietin receptor is decreased during sleep in Andean highlanders with Chronic Mountain Sickness

    OpenAIRE

    Villafuerte, Francisco C.; Corante, Noemí; Anza-Ramírez, Cecilia; Figueroa-Mujíca, Rómulo; Vizcardo-Galindo, Gustavo; Mercado, Andy; Macarlupú, José Luis; León-Velarde, Fabiola

    2016-01-01

    Excessive erythrocytosis (EE) is the main sign of Chronic Mountain Sickness (CMS), a highly prevalent syndrome in Andean highlanders. Low pulse O2 saturation (SpO2) during sleep and serum androgens have been suggested to contribute to EE in CMS patients. However, whether these factors have a significant impact on the erythropoietin (Epo) system leading to EE is still unclear. We have recently shown that morning soluble Epo receptor (sEpoR), an endogenous Epo antagonist, is decreased in CMS pa...

  19. Preterm infant with a late presentation of blueberry muffin lesions secondary to recombinant erythropoietin.

    Science.gov (United States)

    Rajpara, Anand; Blackmon, Joseph; Laarman, Rachel; Skaggs, Robert; Liolios, Ana; Lui, Deede; Fraga, Garth

    2013-09-14

    Our patient is a 26-week-old preterm female infant delivered by caesarean section secondary to severe maternal preeclampsia who had been receiving subcutaneous recombinant erythropoietin (r-EPO) for anemia of prematurity. At 8 weeks of age after 8 doses of r-EPO, the infant developed numerous non-blanching erythematous macules and patches located on the back, posterior shoulder, and posterior arms, concerning for late-onset blueberry muffin lesions. Biopsy of the lesions confirmed dermal hematopoiesis. After r-EPO was discontinued all skin lesions gradually resolved over a period of 2 weeks and never recurred.

  20. Erythropoietin Increases Expression and Function of Transient Receptor Potential Canonical 5 Channels

    DEFF Research Database (Denmark)

    Liu, Ying; Xu, Yunfei; Thilo, Florian;

    2011-01-01

    Hypertension is a common complication in hemodialysis patients during erythropoietin (EPO) treatment. The underlying mechanisms of EPO-induced hypertension still remain to be determined. Increased transient receptor potential canonical (TRPC) channels have been associated with hypertension. Now......, TRPC gene expression was investigated using quantitative real-time RT-PCR and immunoblotting in cultured human endothelial cells and in monocytes from hemodialysis patients. EPO dose-dependently increased TRPC5 mRNA in endothelial cells. EPO increased TRPC5 mRNA stability, that is, EPO prolonged...

  1. Influence of erythropoietin on cognitive performance during experimental hypoglycemia in patients with type 1 diabetes mellitus

    DEFF Research Database (Denmark)

    Kristensen, Peter Lommer; Pedersen-Bjergaard, Ulrik; Kjær, Troels Wesenberg

    2013-01-01

    The incidence of severe hypoglycemia in type 1 diabetes has not decreased over the past decades. New treatment modalities minimizing the risk of hypoglycemic episodes and attenuating hypoglycemic cognitive dysfunction are needed. We studied if treatment with the neuroprotective hormone erythropoi...... erythropoietin (EPO) enhances cognitive function during hypoglycemia.......The incidence of severe hypoglycemia in type 1 diabetes has not decreased over the past decades. New treatment modalities minimizing the risk of hypoglycemic episodes and attenuating hypoglycemic cognitive dysfunction are needed. We studied if treatment with the neuroprotective hormone...

  2. Effects of systemic domestic recombinant human erythropoietin on HIF-1α expression in the retina in a rabbit model of acute high intraocular pressure

    Institute of Scientific and Technical Information of China (English)

    Yan-ping Song; Jian-ming Wang; Mei Zhang; Na Hui; Shi-ping Zhao; Kai Hu

    2009-01-01

    Objective To observe the expression of hypoxia inducible faetor-1α (HIF-1α) in the retina of rabbits with acute high intraocular pressure and to investigate the mechanism of systemic domestic recombinant human erythropoietin (rhEPO) protecting the retina from ischemia-reperfusion injury. Methods First, control group and model group were established in rabbit eyes. The acute high intraocular pressure model was established by saline perfusion into anterior chamber, and then hypodermic injection of domestic rhEPO was made. HIF-1α protein in the retina was observed by immunohistochemical staining method on days 1, 3, 7 and 14 after retinal ischemla-reperfusion, respectively. Results No cells with HIF-la positive expression were observed in the retina of the control group. Ceils with HIF-1α positive expression in the model group outnumbered those in the control group (P < 0. 01). The resemblance pattern occurred in EPO group but its degree was slightly greater than that in the model group from day 3 after ischemia-reperfusion (P<0.05). Conclusion Domestic rhEPO can down-regulate the expression of HIF-1α in the retina with acute high intraocular pressure, which may be one of the mechanisms that rhEPO protects the retina from ischemia-reperfusion injury.

  3. The association between anti-carbamylated protein (anti-CarP) antibodies and radiographic progression in early rheumatoid arthritis: a study exploring replication and the added value to ACPA and rheumatoid factor.

    Science.gov (United States)

    Ajeganova, S; van Steenbergen, H W; Verheul, M K; Forslind, K; Hafström, I; Toes, R E M; Huizinga, T W J; Svensson, B; Trouw, L A; van der Helm-van Mil, A H M

    2017-01-01

    Anti-carbamylated protein (anti-CarP) antibodies are reported to associate with more radiographic progression within the total rheumatoid arthritis (RA) population and anti-citrullinated peptide antibody (ACPA)-negative subgroup. We explored the association of anti-CarP with radiographic progression in RA and aimed to replicate the association and evaluate the added value of anti-CarP antibodies in relation to ACPA and rheumatoid factor (RF). 576 Swedish and 628 Dutch patients with RA (2394 and 3247 sets of radiographs, respectively) were longitudinally studied. Replication was restricted to the Swedish patients. In both cohorts, the association of anti-CarP with radiographic progression was determined in strata of patients with similar ACPA and RF status; results of both cohorts were combined in fixed-effect meta-analyses. The net percentage of patients for whom the radiographic progression in 5 years was additionally correctly classified when adding anti-CarP to a model including ACPA and RF was evaluated. Anti-CarP associated with radiographic progression in the total Swedish RA population (beta=1.11 per year, p=8.75×10(-13)) and in the ACPA-negative subgroup (beta=1.14 per year, p=0.034). Anti-CarP associated with more radiographic progression in the strata of ACPA-positive/RF-negative, ACPA-negative/RF-positive and ACPA-positive/RF-positive patients with RA (respective p values 0.014, 0.019 and 0.0056). A model including ACPA and RF correctly classified 54% and 57% of the patients; adding anti-CarP to this model did not increase these percentages (54% and 56% were correctly classified). Anti-CarP antibodies associated with more severe radiographic progression in the total and ACPA-negative RA population. Anti-CarP-positivity had a statistically significant additive value to ACPA and RF, but did not improve correct classification of patients. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence

  4. White matter changes in patients with Friedreich ataxia after treatment with erythropoietin

    Science.gov (United States)

    Egger, Karl; Clemm von Hohenberg, Christian; Schocke, Michael F; Guttmann, Charles RG; Wassermann, Demian; Wigand, Marlene C; Nachbauer, Wolfgang; Kremser, Christian; Sturm, Brigitte; Scheiber-Mojdehkar, Barbara; Kubicki, Marek; Shenton, Martha E; Boesch, Sylvia

    2013-01-01

    Background and Purpose Erythropoietin (EPO) has received growing attention because of its neuro-regenerative properties. Preclinical and clinical evidence supports its therapeutic potential in brain conditions like stroke, multiple sclerosis and schizophrenia. Also in Friedreich ataxia, clinical improvement after EPO therapy was shown. The aim of the present study was to assess possible therapy-associated brain white-matter changes in these patients. Methods Nine patients with Friedreich ataxia underwent Diffusion Tensor Imaging (DTI) before and after EPO treatment. Tract-based spatial statistics (TBSS) was used for longitudinal comparison. Results We detected widespread longitudinal increase in fractional anisotropy (FA) and axial diffusivity (D||) in cerebral hemispheres bilaterally (p<0.05, corrected), while no changes were observed within the cerebellum, medulla oblongata and pons. Conclusions To the best of our knowledge, this is the first DTI study to investigate the effects of erythropoietin in a neurodegenerative disease. Anatomically, the diffusivity changes appear disease-unspecific, and their biological underpinnings deserve further study. PMID:24015771

  5. Factors related to transfusion in very low birthweight infants treated with erythropoietin.

    Science.gov (United States)

    Maier, R. F.; Obladen, M.; Messinger, D.; Wardrop, C. A.

    1996-01-01

    The need for red cell transfusions is reduced but not eliminated by recombinant human erythropoietin (rhEPO) in very low birthweight (VLBW) infants. To detect factors associated with the decision to transfuse VLBW infants during rhEPO treatment and to explain rhEPO 'non-responders', the subgroup of those 120 VLBW infants who were treated with rhEPO 750 IU/kg per week in the second European Multicentre rhEPO Trial was evaluated. Sixty (50%) infants received at least one transfusion during erythropoietin treatment. Transfusion was frequent in infants with extremely low birthweight (79% for 750-999 g), low gestational age (70% for or = 1 ml/kg per day). The prognostic variables birthweight, initial haematocrit, and gestational age were found to be most predictive for transfusion. To improve rhEPO response in VLBW infants, there is a need to minimise diagnostic blood loss, to prevent iron deficiency, and to develop rational criteria for transfusion in preterm infants. PMID:8777681

  6. Oxpentifylline versus placebo in the treatment of erythropoietin-resistant anaemia: a randomized controlled trial

    Directory of Open Access Journals (Sweden)

    Fassett Robert G

    2008-08-01

    Full Text Available Abstract Background The main hypothesis of this study is that Oxpentifylline administration will effectively treat erythropoietin- or darbepoietin-resistant anaemia in chronic kidney disease patients. Methods/design Inclusion criteria are adult patients with stage 4 or 5 chronic kidney disease (including dialysis patients with significant anaemia (haemoglobin ≤ 110 g/L for at least 3 months for which there is no clear identifiable cause and that is unresponsive to large doses of either erythropoietin (≥ 200 IU/kg/week or darbepoetin (≥ 1 μg/kg/week. Patients will be randomized 1:1 to receive either placebo (1 tablet daily or oxpentifylline (400 mg daily per os for a period of 4 months. During this 4 month study period, haemoglobin measurements will be performed monthly. The primary outcome measure will be the difference in haemoglobin level between the 2 groups at the end of the 4 month study period, adjusted for baseline values. Secondary outcome measures will include erythropoiesis stimulating agent dosage, Key's index (erythropoiesis stimulating agent dosage divided by haemoglobin concentration, and blood transfusion requirement. Discussion This investigator-initiated multicentre study has been designed to provide evidence to help nephrologists and their chronic kidney disease patients determine whether oxpentifylline represents a safe and effective strategy for treating erythropoiesis stimulating agent resistance in chronic kidney disease. Trial Registration Australian New Zealand Clinical Trials Registry Number ACTRN12608000199314.

  7. Erythropoietin therapy after allogeneic hematopoietic cell transplantation: a prospective, randomized trial.

    Science.gov (United States)

    Jaspers, Aurélie; Baron, Frédéric; Willems, Evelyne; Seidel, Laurence; Hafraoui, Kaoutar; Vanstraelen, Gaetan; Bonnet, Christophe; Beguin, Yves

    2014-07-01

    We conducted a prospective randomized trial to assess hemoglobin (Hb) response to recombinant human erythropoietin (rhEPO) therapy after hematopoietic cell transplantation (HCT). Patients (N = 131) were randomized (1:1) between no treatment (control arm) or erythropoietin at 500 U/kg per week (EPO arm). Patients were also stratified into 3 cohorts: patients undergoing myeloablative HCT with rhEPO to start on day (D)28, patients given nonmyeloablative HCT (NMHCT) with rhEPO to start on D28, and patients also given NMHCT but with rhEPO to start on D0. The proportion of complete correctors (ie, Hb ≥13 g/dL) before D126 posttransplant was 8.1% in the control arm (median not reached) and 63.1% in the EPO arm (median, 90 days) (P < .001). Hb levels were higher and transfusion requirements decreased (P < .001) in the EPO arm, but not during the first month in the nonmyeloablative cohort starting rhEPO on D0. There was no difference in rates of thromboembolic events or other complications between the 2 arms. This is the first randomized trial to demonstrate that rhEPO therapy hastens erythroid recovery and decreases transfusion requirements when started one month after allogeneic HCT. There was no benefit to start rhEPO earlier after NMHCT.

  8. Chronic erythropoietin treatment improves diet-induced glucose intolerance in rats

    DEFF Research Database (Denmark)

    Caillaud, Corinne; Mechta, Mie; Ainge, Heidi

    2015-01-01

    Erythropoietin (EPO) ameliorates glucose metabolism through mechanisms not fully understood. In this study, we investigated the effect of EPO on glucose metabolism and insulin signaling in skeletal muscle. A 2-week EPO treatment of rats fed with a high-fat diet (HFD) improved fasting glucose leve...... not directly activate the phosphorylation of AKT in muscle cells. We propose that the reduced systemic inflammation or oxidative stress that we observed after treatment with EPO could contribute to the improvement of whole-body glucose metabolism.......Erythropoietin (EPO) ameliorates glucose metabolism through mechanisms not fully understood. In this study, we investigated the effect of EPO on glucose metabolism and insulin signaling in skeletal muscle. A 2-week EPO treatment of rats fed with a high-fat diet (HFD) improved fasting glucose levels...... cell cultures with EPO failed to induce AKT phosphorylation and had no effect on glucose uptake or glycogen synthesis. We found that the EPO receptor gene was expressed in myotubes, but was undetectable in soleus. Together, our results indicate that EPO treatment improves glucose tolerance but does...

  9. Successful treatment of severe anemia using erythropoietin in a Jehovah Witness with non-Hodgkin lymphoma

    Directory of Open Access Journals (Sweden)

    Alexandra Agapidou

    2014-12-01

    Full Text Available Blood transfusion many times works in a life-saving way when a patient is facing a critical situation. However, some patients, such as Jehovah’s Witnesses, may refuse their administration because it opposes to their religion beliefs. Thus, clinicians are forced to respect patients’ preferences and seek other treatments in order to overcome the obstacle of the transfusion. In 1989, recombinant human erythropoietin (rHuEPO was approved by the United States Food and Drug Administration (FDA for the treatment of anemia associated with chronic renal failure. This is an amino acid glycol-protein that stimulates red blood cell production in the same manner as endogenous erythropoietin. Other treatment indications approved by the FDA include anemia due to chronic kidney disease, anemia secondary to zidovudine therapy in patients with human immunodeficiency virus infection, and anemia secondary to cancer chemotherapy. The drug also has been used for many off-label indications. Many Jehovah’s Witnesses have accepted rHuEPO as a treatment option to maintain and enhance erythropoiesis. This paper reports the case of a 57-year-old Jehovah’s Witness man, who was diagnosed with severe anemia due to aggressive non Hodgkin lymphoma and refused transfusion of blood; thanks to the treatment with rHuEPO he has managed to complete chemotherapy and has survived a life threatening situation.

  10. Comparative structural study of N-linked oligosaccharides of urinary and recombinant erythropoietins

    Energy Technology Data Exchange (ETDEWEB)

    Tsuda, E.; Goto, M.; Murakami, A.; Akia, K.; Ueda, M.; Kawanishi, G.; Takahashi, N.; Sasaki, R.; Chiba, H.; Ishihara, H.; Mori, M.

    1988-07-26

    The structures of the N-linked oligosaccharides of the urinary erythropoietin (u-EPOI) purified from urine of aplastic anemic patients were analyzed and compared with those for recombinant erythropoietin (r-EPO) prepared with baby hamster kidney (BHK) cells. Asparagine-linked neutral oligosaccharides were released from each EPO protein by N-oligosaccharide glycopeptidase (almond) digestion. The reducing ends of the oligosaccharide chains thus obtained were aminated with a fluorescent reagent, 2-aminopyridine, and the mixture of pyridylamino derivatives of the oligosaccharides was separated by high-performance liquid chromatography (HPLC) on an ODS silica column. More than 8 and 13 kinds of oligosaccharide fractions for u-EPO and r-EPO (BHK), respectively, were completely separated by the one-step HPLC procedure. The structure of each oligosaccharide thus isolated was analyzed by a combination of sequential exoglycosidase digestion and another kind of HPLC with an amide-silica column. Furthermore, high-resolution proton nuclear magnetic resonance (/sup 1/H NMR) spectroscopy and methylation analyses were carried out in the case of r-EPO (BHK).

  11. [Infantile pyknocytosis: A cause of noenatal hemolytic anemia. Is recombinant erythropoietin an alternative to transfusion?].

    Science.gov (United States)

    Bagou, M; Rolland, E; Gay, C; Patural, H

    2016-01-01

    Infantile pyknocytosis is a neonatal hemolytic disorder which causes anemia and icterus and is characterized by the presence of an increased number of distorted red blood cells called pyknocytes. Resolution spontaneously occurs in the first semester of life. It has been generally described as a rare entity, with an occasional family history. We report seven cases of infantile pyknocytosis observed in our hospital in 3 years. Most of the infants presented with hemolytic icterus and profound anemia that was reaching its peak by the 3rd week of life. Three neonates received one to three red blood cell transfusions, according to former recommendations. However, the following four received a treatment with recombinant erythropoietin administered subcutaneously. Only one of these four cases required a transfusion. All of them were free of hematological disease 2-3 months after completion of treatment. Infantile pyknocytosis is a recognized cause of neonatal hemolytic anemia, which requires careful examination of red cell morphology on a peripheral blood smear. The cause of this transient disorder remains unknown. Our observations show that recombinant erythropoietin therapy is effective in treating infantile pyknocytosis and increases the reticulocyte response, thus improving the hemoglobin level.

  12. Erythropoietin combined with liposomal amphotericin b improves outcome during disseminated aspergillosis in mice

    Directory of Open Access Journals (Sweden)

    nathalie erousseau

    2014-10-01

    Full Text Available Disseminated aspergillosis is responsible for a high mortality rate despite the use of antifungal drugs. Adjuvant therapies are urgently needed to improve the outcome. The aim of this study was to demonstrate that the cytoprotective effect of erythropoietin combined to amphotericin b can reduce the mortality rate in a murine model of disseminated aspergillosis. After infection with Aspergillus fumigatus, neutropenic mice were randomized to receive vehicle or 7,5 mg/Kg of Liposomal Amphotericin B (LAmB or 7,5 mg/Kg of LAmB combined with 1000 IU/Kg of EPO (16 mice per group. Aspergillus galactomannan and organ cultures were performed to evaluate fungal burden at day 5. Cumulative long-term survival was analyzed at day 12 post-infection according to the Kaplan-Meier method. At day 5, fungal burden was similar between non-treated and treated groups. At day 12, mortality rates were 75 %, 62.5 % and 31 % in control group, LAmB group and EPO/LAmB group, respectively. We observed a significant decreased in mortality using EPO/LAmB combination compared to control group (p < 0.01. LAmB single treatment did not improve the survival rate compared to control group (p = 0.155.Our results provided the first evidence that erythropoietin improved the outcome of mice presenting disseminated aspergillosis when combined with amphotericin b.

  13. Investigation of Genetic Disturbances in Oxygen Sensing and Erythropoietin Signaling Pathways in Cases of Idiopathic Erythrocytosis

    Directory of Open Access Journals (Sweden)

    Carla Luana Dinardo

    2013-01-01

    Full Text Available Background. Idiopathic erythrocytosis is the term reserved for cases with unexplained origins of abnormally increased hemoglobin after initial investigation. Extensive molecular investigation of genes associated with oxygen sensing and erythropoietin signaling pathways, in those cases, usually involves sequencing all of their exons and it may be time consuming. Aim. To perform a strategy for molecular investigation of patients with idiopathic erythrocytosis regarding oxygen sensing and erythropoietin signaling pathways. Methods. Samples of patients with idiopathic erythrocytosis were evaluated for the EPOR, VHL, PHD2, and HIF-2α genes using bidirectional sequencing of their hotspots. Results. One case was associated with HIF-2α mutation. Sequencing did not identify any pathogenic mutation in 4 of 5 cases studied in any of the studied genes. Three known nonpathogenic polymorphisms were found (VHL p.P25L, rs35460768; HIF-2α p.N636N, rs35606117; HIF-2α p.P579P, rs184760160. Conclusion. Extensive molecular investigation of cases considered as idiopathic erythrocytosis does not frequently change the treatment of the patient. However, we propose a complementary molecular investigation of those cases comprising genes associated with erythrocytosis phenotype to meet both academic and genetic counseling purposes.

  14. The effect of erythropoietin on calcium levels during hypoxia reoxygenation injury in rats

    Directory of Open Access Journals (Sweden)

    Constantinos Tsompos

    2016-04-01

    Full Text Available This experimental study examined the effect of erythropoietin (Epo on rat model and particularly in a hypoxia-reoxygenation protocol. The effect of that molecule was studied biochemically using blood mean calcium levels (Ca++. Forty rats of mean weight 247.7 g were used in the study. Ca++ levels were measured at 60 min (groups A and C and at 120 min (groups B and D of reoxygenation. Erythropoietin was administered only in groups C and D. Epo administration non-significantly decreased the Ca++ levels by 0.56%±1.13% (P=0.5761. Reoxygenation time non-significantly increased the Ca++ levels by 0.65%±1.12% (P=0.5281. However, Epo administration and reoxygenation time together non-significantly decreased the Ca++ levels by 0.34%±0.68% (P=0.6095. Epo administration whether it interacted or not with reoxygenation time had non-significant decreasing short-term effects on calcium levels. Perhaps, a longer study time than 2 h or a higher Epo dose may reveal more significant effects.

  15. Recombinant human erythropoietin stimulates angiogenesis and healing of ischemic skin wounds.

    Science.gov (United States)

    Buemi, Michele; Galeano, Mariarosaria; Sturiale, Alessio; Ientile, Riccardo; Crisafulli, Costantino; Parisi, Alessandra; Catania, MariaAntonietta; Calapai, Gioacchino; Impalà, Patrizia; Aloisi, Carmela; Squadrito, Francesco; Altavilla, Domenica; Bitto, Alessandra; Tuccari, Giovanni; Frisina, Nicola

    2004-08-01

    Wound healing in ischemic tissues such as flap margins due to inadequate blood supply is still a source of considerable morbidity in surgical practice. Adequate tissue perfusion is particularly important in wound healing. We investigated the effects of recombinant human erythropoietin (rHuEPO) on wound healing in an ischemic skin wound model. Sixty-three Sprague-Dawley rats were used. Normal incisional wound and H-shaped double flaps were used as the wound models. Animals were treated with rHuEPO (400 IU/kg) or its vehicle. Rats were killed on different days (3, 5, and 10 days after skin injury) and the wounded skin tissues were used for immunohistochemistry and for analysis of vascular endothelial growth factor content and collagen content. Tissue transglutaminase immunostaining of histological specimens was used as a vascular marker to determine the level of microvessel density. The results showed a higher level of vascular endothelial growth factor protein and an increased microvessel density in ischemic wounds with rHuEPO treatment than the normal incisional wounds and ischemic control wounds. Collagen content was higher in the incisional wounds and in the ischemic wounds with rHuEPO treatment compared with the ischemic control wounds. Our results suggest that erythropoietin may be an effective therapeutic approach in improving healing in ischemic skin wounds.

  16. Erythropoietin modulates neural and cognitive processing of emotional information in biomarker models of antidepressant drug action in depressed patients

    DEFF Research Database (Denmark)

    Miskowiak, Kamilla W; Favaron, Elisa; Hafizi, Sepehr

    2010-01-01

    Erythropoietin (Epo) has neuroprotective and neurotrophic effects, and may be a novel therapeutic agent in the treatment of psychiatric disorders. We have demonstrated antidepressant-like effects of Epo on the neural and cognitive processing of facial expressions in healthy volunteers. The current...... study investigates the effects of Epo on the neural and cognitive response to emotional facial expressions in depressed patients....

  17. Captopril Modulates Hypoxia-Inducible Factors and Erythropoietin Responses in a Murine Model of Total Body Irradiation

    Science.gov (United States)

    2011-01-01

    high-dose irradiation may aid in DNA repair, cell survival, and hematopoietic cell recovery [54]. We previously observed that captopril treatment...expression in tumor cells and other tissues. Oncologist. 2004;9(suppl 5):18–30. 28. Lam SY, Tipoe GL, Fung ML. Upregulation of erythropoietin and its

  18. Erythropoietin does not reduce plasma lactate, H+, and K+ during intense exercise

    DEFF Research Database (Denmark)

    Nordsborg, Nikolai Baastrup; Robach, P; Boushel, R

    2015-01-01

    It is investigated if recombinant human erythropoietin (rHuEPO) treatment for 15 weeks (n = 8) reduces extracellular accumulation of metabolic stress markers such as lactate, H(+) , and K(+) during incremental exhaustive exercise. After rHuEPO treatment, normalization of blood volume and composit...

  19. Effects of erythropoietin on emotional processing biases in patients with major depression: an exploratory fMRI study

    DEFF Research Database (Denmark)

    Miskowiak, Kamilla W; Favaron, Elisa; Hafizi, Sepehr

    2009-01-01

    INTRODUCTION: Erythropoietin (Epo) has neurotrophic effects and may be a novel therapeutic agent in the treatment of depression. We have found antidepressant-like effects of Epo on emotional processing and mood in healthy volunteers. OBJECTIVE: The current study aimed to explore the effects of Ep...

  20. Alterations of systemic and muscle iron metabolism in human subjects treated with low-dose recombinant erythropoietin

    DEFF Research Database (Denmark)

    Robach, Paul; Recalcati, Stefania; Girelli, Domenico;

    2009-01-01

    healthy volunteers were treated with recombinant erythropoietin (rhEpo) for 1 month. As expected, the treatment efficiently increased erythropoiesis and stimulated bone marrow iron use. It was also associated with a prompt and considerable decrease in urinary hepcidin and a slight transient increase...

  1. Vascular endothelial growth factor is crucial for erythropoietin-induced improvement of cardiac function in heart failure

    NARCIS (Netherlands)

    Westenbrink, B. Daan; Ruifrok, Willem-Peter T.; Voors, Adriaan A.; Tilton, Ronald G.; van Veldhuisen, Dirk J.; Schoemaker, Regien G.; van Gilst, Wiek H.; de Boer, Rudolf A.

    2010-01-01

    We intended to delineate the mechanisms of erythropoietin (EPO)-induced cardiac vascular endothelial growth factor (VEGF) production and to establish if VEGF is crucial for EPO-induced improvement of cardiac performance. The effects of EPO on VEGF expression were studied in cultured cardiac cells an

  2. Determinants of red cell distribution width (RDW) in cardiorenal patients: RDW is not related to erythropoietin resistance.

    NARCIS (Netherlands)

    Emans, M.E.; Putten, K. van der; Rooijen, K.L. van; Kraaijenhagen, R.J.; Swinkels, D.W.; Solinge, W.W. van; Cramer, M.J.; Doevendans, P.A.; Braam, B.; Gaillard, C.A.J.M.

    2011-01-01

    BACKGROUND: Studies have shown that red cell distribution width (RDW) is related to outcome in chronic heart failure (CHF). The pathophysiological process is unknown. We studied the relationship between RDW and erythropoietin (EPO) resistance, and related factors such as erythropoietic activity, fun

  3. Determinants of Red Cell Distribution Width (RDW) in Cardiorenal Patients : RDW is Not Related to Erythropoietin Resistance

    NARCIS (Netherlands)

    Emans, Mireille E.; van der Putten, Karien; van Rooijen, Karlijn L.; Kraaijenhagen, Rob J.; Swinkels, Dorine; van Solinge, Wouter W.; Cramer, Maarten J.; Doevendans, Pieter A. F. M.; Braam, Branko; Gaillard, Carlo A. J. M.

    2011-01-01

    Background: Studies have shown that red cell distribution width (RDW) is related to outcome in chronic heart failure (CHF). The pathophysiological process is unknown. We studied the relationship between RDW and erythropoietin (EPO) resistance, and related factors such as erythropoietic activity, fun

  4. Vascular endothelial growth factor is crucial for erythropoietin-induced improvement of cardiac function in heart failure

    NARCIS (Netherlands)

    Westenbrink, B. Daan; Ruifrok, Willem-Peter T.; Voors, Adriaan A.; Tilton, Ronald G.; van Veldhuisen, Dirk J.; Schoemaker, Regien G.; van Gilst, Wiek H.; de Boer, Rudolf A.

    2010-01-01

    We intended to delineate the mechanisms of erythropoietin (EPO)-induced cardiac vascular endothelial growth factor (VEGF) production and to establish if VEGF is crucial for EPO-induced improvement of cardiac performance. The effects of EPO on VEGF expression were studied in cultured cardiac cells an

  5. Erythropoietin modulates neural and cognitive processing of emotional information in biomarker models of antidepressant drug action in depressed patients

    DEFF Research Database (Denmark)

    Miskowiak, Kamilla W; Favaron, Elisa; Hafizi, Sepehr

    2010-01-01

    Erythropoietin (Epo) has neuroprotective and neurotrophic effects, and may be a novel therapeutic agent in the treatment of psychiatric disorders. We have demonstrated antidepressant-like effects of Epo on the neural and cognitive processing of facial expressions in healthy volunteers. The curren...

  6. The Anti-Aging Effect of Erythropoietin via the ERK/Nrf2-ARE Pathway in Aging Rats.

    Science.gov (United States)

    Wu, Haiqin; Zhao, Jiaxin; Chen, Mengyi; Wang, Huqing; Yao, Qingling; Fan, Jiaxin; Zhang, Meng

    2017-03-01

    Erythropoietin (EPO) has a neuroprotective effect and can resist aging, which most likely occur through EPO increasing the activity of antioxidant enzymes and scavenging free radicals. In this study, we verified the anti-aging function of EPO and discussed the mechanism occurring through the extracellular signal-regulated kinase (ERK)/NF-E2-related factor 2 (Nrf2)-ARE pathway. A rat model of aging was induced by the continuous subcutaneous injection of 5 % D-galactose for 6 weeks. At the beginning of the sixth week, physiological saline or EPO was administered twice per day through a lateral ventricle system for a total of 7 days. In one group, 2 μl PD98059 was administered 30 min before EPO. Learning and memory ability were analyzed with the Morris water maze system. HE staining was used to observe the morphological changes in the neurons in the hippocampus, and immunohistochemical staining as well as Western blots were carried out to detect the expression of ERK for each group of rats and the expression of phosphorylated-ERK (P-ERK), Nrf2, and superoxide dismutase (SOD). Real-Time PCR was carried out to detect the amount of Nrf2 mRNA and the KEAP1 mRNA expression. EPO can significantly improve learning and memory ability in aging rats and can provide protection against aging by improving the hippocampus morphology. Immunohistochemical staining and Western blots showed P-ERK, Nrf2, and Cu-Zn SOD decreases in aging rats compared to the normal group, while the expression for those proteins increased after EPO intervention. PD98059 inhibited the enhanced expression of P-ERK, Nrf2, and Cu-Zn SOD induced by EPO. Real-Time PCR results suggested that the trend of Nrf2mRNA expression was the same as that for the proteins, which confirmed that the enhancement occurred at the gene level. As such, EPO can significantly resist or delay aging and protect the brain by reducing oxidative stress. The most likely mechanism is that EPO can promote the ERK/Nrf2-ARE pathway in

  7. ASSESSMENT OF DRUG UTILIZATION PATTERN OF ERYTHROPOIETIN IN PATIENTS WITH ANAEMIA OF CHRONIC KIDNEY DISEASE AND ON HAEMODIALYSIS

    Directory of Open Access Journals (Sweden)

    Upal D

    2015-07-01

    Full Text Available OBJECTIVES: To access the efficacy of erythropoietin in patients with chronic kidney disease and on haemodialysis, compare the efficacy via intravenous route relative to the subcutaneous route, Evaluate Adverse Events that occur during the course of therapy, Assess Pa tients Perceptions of Health Related Quality of Life. MATERIAL & METHODS: Patients with Anemia of Chronic Kidney Disease and on haemodialysis were screened and enrolled. These patients were traced retrospectively to the date of initiation of therapy with e rythropoietin and were followed prospectively. The study duration was 12 months. RESULTS: A total of 108 patients were enrolled. Haemoglobin increased to 9.8±1.9g/dl in the erythropoietin group and fell to 8.3±2.2g/dl in the iron only group at end of study. Mean haemoglobin for the IV group was 9.2±1.9g/dl and increased to 10.1±2.1g/dl in the SC group at the end of study. Blood tra nsfusions were required in 17 patients of the Iron Only Group and 3 patients in the epo+iron group. All of the patients were hypertensive with 37 patients treated with multiple drugs. 14 patients in the epo+iron group had IHD related event.6 patients had f ailed AVFs. Quality of life with respect to ESRD targeted scales shows that patients in the erythropoietin group had an improved quality of life. SUMMARY & CONCLUSION: Erythropoietin +Iron were more effective in increasing and maintaining haemoglobin level s than Iron alone. The SC route proves more efficacious. Patients treated with epoetin had increased incidence of an adverse event. Patients not treated with erythropoietin required blood transfusions. Patients with ESRD have higher QOL when treated with e rythropoietin.

  8. The glucocorticoid receptor cooperates with the erythropoietin receptor and c-Kit to enhance and sustain proliferation of erythroid progenitors in vitro

    NARCIS (Netherlands)

    W. Zauner; G. Mellitzer; P. Steinlein (Peter); G. Fritsch; K. Huber; H. Beug (Hartmut); B. Löwenberg (Bob); M.M. von Lindern (Marieke)

    1999-01-01

    textabstractAlthough erythropoietin (Epo) is essential for the production of mature red blood cells, the cooperation with other factors is required for a proper balance between progenitor proliferation and differentiation. In avian erythroid progenitors, steroid hormone

  9. [Neuroprotector effect of human recombinant erythropoietin sorbed on polymer nanoparticles studied on model of intracerebral post-traumatic hematoma (hemorrhagic stroke)].

    Science.gov (United States)

    Balaban'ian, V Iu; Solev, I N; Elizarova, O S; Garibova, T L; Litvinova, S A; Voronina, T A

    2011-01-01

    The neuroprotective activity of recombinant human erythropoietin (r-HuEpo) sorbed on poly(butyl)cyanoacrilate nanoparticles (EPO-PBCA) and on polylactic-co-glycolic acid nanoparticles (EPO-PLGA) has been studied on Wistar rats with intracerebral post-traumatic hematoma (model of hemorrhagic stroke) (IPH-HS) in comparison to native r-HuEpo. It is established that EPO-PBCA produced a protective effect in rats after IPH-HS that was manifested by a decrease in the number of animals with neurological disorders such as circus movement, paresis, and paralysis of hind limbs; the drug also improved coordination (rotating rod test), reduced the number of lost animals, and decreased the loss weight among survived rats. In addition, EPO-PBCA optimized the research behavior of rats with IPH-HS in the open field test and prevented amnesia of passive avoidance reflex (PAR), which was caused by the IPH-HS. These effects were manifested during a two-week observation period. EPO-PLGA has a similar but much less pronounced effect on the major disorders caused by IPH-HS. The efficiency of native r-HuEpo as a neuropotective agent was insignificant and only manifested by decrease in the number of lost animals with IPH-HS.

  10. Role of recombinant human erythropoietin loading chitosan-tripolyphosphate nanoparticles in busulfan-induced genotoxicity: Analysis of DNA fragmentation via comet assay in cultured HepG2 cells.

    Science.gov (United States)

    Ghassemi-Barghi, Nasrin; Varshosaz, Jaleh; Etebari, Mahmoud; Jafarian Dehkordi, Abbas

    2016-10-01

    Busulfan is one of the most effective chemotherapeutic agents used for the treatment of chronic myeloid leukemia. Busulfan is involved in secondary malignancy due to its genotoxic potential in normal tissues. As an alkylating agent busulfan can cause DNA damage by cross-linking DNAs and DNA and proteins, induces senescence in normal cells via transient depletion of intracellular glutathione (GSH) and subsequently by a continuous increase in reactive oxygen species (ROS) production. Erythropoietin, a glycoprotein widely used against drug induced anemia in cancerous patients and regulates hematopoiesis, has been shown to exert an important cyto-protective effect in many tissues. Recombinant human erythropoietin has been demonstrated to directly limit cell injury and ROS generation during oxidative stress. Furthermore, rhEPO decreased levels of pro-apoptotic factor (Bax) and also increased expression of the anti-apoptotic factor Bcl2. According to EPO's short half-life and requirements for the frequently administration, finding the new strategies to attenuate its side effects is important. The aim of this study was to explore whether rhEPO loading chitosan-tripolyphosphate nanoparticles protects against busulfan-induced genotoxicity in HepG2 cells. For this purpose cells were incubated with busulfan alone, regular rhEPO alone and regular rhEPO and CS-TPP-EPO nanoparticles along with busulfan in pre and co-treatment condition. Our results showed that busulfan induced a noticeable genotoxic effects in HepG2 cells (pDNA damage via blocking ROS generation, and enhancement intracellular glutathione levels. CS-TPP-EPO nanoparticles were more effective than regular rhEPO in both pre and co-treatment conditions. In conclusion, our results show that administration of rhEPO and CS-TPP-EPO nanoparticles especially in the pre-treatment conditions, significantly decreased the level of DNA damage induced by busulfan, measured with the comet assay, in HepG2 cells compared to the

  11. Evaluation of the osteogenesis and angiogenesis effects of erythropoietin and the efficacy of deproteinized bovine bone/recombinant human erythropoietin scaffold on bone defect repair.

    Science.gov (United States)

    Li, Donghai; Deng, Liqing; Xie, Xiaowei; Yang, Zhouyuan; Kang, Pengde

    2016-06-01

    Erythropoietin (EPO) could promote the angiogenesis and may also play a role in bone regeneration. This study was conducted to evaluate the osteogenesis and angiogenesis effects of EPO and the efficacy of deproteinized bovine bone/recombinant human EPO scaffold on bone defect repair. Twenty-four healthy adult goats were chosen to build goat defects model and randomly divided into four groups. The goats were treated with DBB/rhEPO scaffolds (group A), porous DBB scaffolds (group B), autogenous cancellous bone graft (group C), and nothing (group D). Animals were evaluated with radiological and histological methods at 4, 8 and 12 weeks after surgery. The grey value of radiographs was used to evaluate the healing of the defects and the outcome revealed that the group A had a better outcome of defect healing compared with group B (P 0.05). The newly formed bone area was calculated from histological sections and the results demonstrated that the amount of new bone in group A increased significantly compared with that in group B (P 0.05) at 4, 8, 12 weeks respectively. In addition, the expression of vascular endothelial growth factor (VEGF) by immunohistochemical testing and real-time polymerase chain reaction at 12 weeks in group A was significantly higher than that in group B (P 0.05). Therefore, EPO has significant effects on bone formation and angiogenesis, and has capacity to promote the repair of bone defects. It is worthy of being recommended to further studies.

  12. Exercise aggravates cardiovascular risks and mortality in rats with disrupted nitric oxide pathway and treated with recombinant human erythropoietin.

    Science.gov (United States)

    Meziri, Fayçal; Binda, Delphine; Touati, Sabeur; Pellegrin, Maxime; Berthelot, Alain; Touyz, Rhian M; Laurant, Pascal

    2011-08-01

    Chronic administration of recombinant human erythropoietin (rHuEPO) can generate serious cardiovascular side effects such as arterial hypertension (HTA) in clinical and sport fields. It is hypothesized that nitric oxide (NO) can protect from noxious cardiovascular effects induced by chronic administration of rHuEPO. On this base, we studied the cardiovascular effects of chronic administration of rHuEPO in exercise-trained rats treated with an inhibitor of NO synthesis (L-NAME). Rats were treated or not with rHuEPO and/or L-NAME during 6 weeks. During the same period, rats were subjected to treadmill exercise. The blood pressure was measured weekly. Endothelial function of isolated aorta and small mesenteric arteries were studied and the morphology of the latter was investigated. L-NAME induced hypertension (197 ± 6 mmHg, at the end of the protocol). Exercise prevented the rise in blood pressure induced by L-NAME (170 ± 5 mmHg). However, exercise-trained rats treated with both rHuEPO and L-NAME developed severe hypertension (228 ± 9 mmHg). Furthermore, in these exercise-trained rats treated with rHuEPO/L-NAME, the acetylcholine-induced relaxation was markedly impaired in isolated aorta (60% of maximal relaxation) and small mesenteric arteries (53%). L-NAME hypertension induced an internal remodeling of small mesenteric arteries that was not modified by exercise, rHuEPO or both. Vascular ET-1 production was not increased in rHuEPO/L-NAME/training hypertensive rats. Furthermore, we observed that rHuEPO/L-NAME/training hypertensive rats died during the exercise or the recovery period (mortality 51%). Our findings suggest that the use of rHuEPO in sport, in order to improve physical performance, represents a high and fatal risk factor, especially with pre-existing cardiovascular risk.

  13. Erythropoietin may reduce the risk of germ cell loss in boys with cryptorchidism

    DEFF Research Database (Denmark)

    Cortes, D; Visfeldt, J; Thorup, J M

    2001-01-01

    of infertility. In order to increase the number of germ cells, and thereby the fertility potential, additional hormonal therapy has been attempted before surgery. In a study, small doses of the gonadotropin-releasing hormone analogue buserelin before orchiopexy caused higher values. Others have found......PURPOSE: In boys with cryptorchidism older than 2 years a testicular biopsy at time of orchiopexy shows lack of germ cells in 10-40% of the cases. The number of spermatogonia per tubule is prognostic for subsequent fertility potential. A biopsy without germ cells is associated with 33-100% risk...... that hormonal treatment with human chorionic gonadotropin or gonadotropin releasing hormone analogue may harm the germ cells in cryptorchidism. The aim of the study is to demonstrate that additional hormonal therapy with erythropoietin has a positive effect on the number of germ cells. MATERIALS AND METHODS...

  14. Glycoengineering of Chinese hamster ovary cells for enhanced erythropoietin N-glycan branching and sialylation

    DEFF Research Database (Denmark)

    Yin, Bojiao; Gao, Yuan; Chung, Cheng-yu

    2015-01-01

    -glycosylation of recombinant erythropoietin (rEPO), a human α2,6-sialyltransferase (ST6Gal1) was expressed in Chinese hamster ovary (CHO-K1) cells. Sialylation increased on both EPO and CHO cellular proteins as observed by SNA lectin analysis, and HPLC profiling revealed that the sialic acid content of total glycans on EPO......EPO from these engineered cells was increased ∼45% higher with tetra-sialylation accounting for ∼10% of total sugar chains compared to ∼3% for the wild-type parental CHO-K1. In this way, coordinated overexpression of these three glycosyltransferases for the first time in model CHO-K1 cell lines provides...

  15. Satellite cell response to erythropoietin treatment and endurance training in healthy young men

    DEFF Research Database (Denmark)

    Hoedt, Andrea; Christensen, Britt; Nellemann, Birgitte

    2016-01-01

    KEY POINT: Erythropoietin (Epo) treatment may induce myogenic differentiation factor (MyoD) expression and prevent apoptosis in satellite cells (SCs) in murine and in vitro models. Endurance training stimulates SC proliferation in vivo in murine and human skeletal muscle. In the present study, we...... show, in human skeletal muscle, that treatment with an Epo-stimulating agent (darbepoetin-α) in vivo increases the content of MyoD(+) SCs in healthy young men. Moreover, we report that Epo receptor mRNA is expressed in adult human SCs, suggesting that Epo may directly target SCs through ligand......-term Epo treatment during disease conditions involving anaemia may impact SCs and warrants further investigation. Satellite cell (SC) proliferation is observed following erythropoitin treatment in vitro in murine myoblasts and endurance training in vivo in human skeletal muscle. The present study aimed...

  16. Erythrocyte incorporation and absorption of 58Fe in premature infants treated with erythropoietin.

    Science.gov (United States)

    Widness, J A; Lombard, K A; Ziegler, E E; Serfass, R E; Carlson, S J; Johnson, K J; Miller, J E

    1997-03-01

    We hypothesized that treatment of very low birth weight premature infants with r-HuEPO would increase erythrocyte incorporation and gastrointestinal absorption of iron. Infants with birth weights absorption of 58Fe was not different between the epo and placebo groups after both early dosing (30 +/- 22% versus 34 +/- 8%) and late dosing (32 +/- 9% versus 31 +/- 6%). Absorption of nonlabeled elemental iron and 58Fe were significantly correlated with one another. The percentage of the absorbed 58Fe dose incorporated into Hb was not different between groups. We conclude that, although erythropoietin treatment stimulates erythrocyte iron incorporation in premature infants, it has no effect on iron absorption at the r-HuEPO dose studied.

  17. Two large preoperative doses of erythropoietin do not reduce the systemic inflammatory response to cardiac surgery

    DEFF Research Database (Denmark)

    Poulsen, Troels Dirch; Andersen, Lars Willy; Steinbrüchel, Daniel

    2009-01-01

    OBJECTIVES: Cardiac surgery and cardiopulmonary bypass (CPB) induce an inflammatory reaction that may lead to tissue injury. Experimental studies suggest that recombinant human erythropoietin (EPO) independent of its erythropoietic effect may be used clinically as an anti-inflammatory drug...... of inflammatory cytokines. In contrast, EPO may augment the TNF-alpha and NT-proBNP response. Although the long-term clinical impact remains unknown, the findings do not support use of EPO as an anti-inflammatory drug in patients undergoing cardiac surgery........ This study tested the hypothesis that 2 large doses of EPO administered shortly before CPB ameliorate the systemic inflammatory response to CPB. DESIGN AND SETTING: A prospective, double-blind, placebo-controlled and randomized study at a single tertiary care hospital. PARTICIPANTS: Patients scheduled...

  18. Can local Erythropoietin administration enhance bone regeneration in osteonecrosis of femoral head?

    Science.gov (United States)

    Bakhshi, Hooman; Rasouli, Mohammad R; Parvizi, Javad

    2012-08-01

    Osteonecrosis of femoral head (ONFH) is a challenging disease. Regardless of underlying causes, the ultimate result in all cases is disruption of femoral head blood supply. Once the disease starts, it is progressive in 80% of cases. Since the majority of the affected individuals are young, every effort should be focused on preserving the patients own femoral head. These years, the role of angiogenic growth factors has been investigated with promising results in animal models of ONFH. Erythropoietin (EPO) is a well known hormone that has been used in treatment of chronic anemia for many years with few side effects. Considering the angiogenic properties of EPO, we hypothesize that local delivery of recombinant human EPO during core decompression will enhance bone regeneration in ONFH. In this way we also can avoid systemic side effects of EPO.

  19. Role of cytochrome P sub 450 in the control of the production of erythropoietin

    Energy Technology Data Exchange (ETDEWEB)

    Fandrey, J.; Seydel, F.P.; Siegers, C.P.; Jelkmann, W. (Medical Univ. of Luebeck (West Germany))

    1990-01-01

    Effects of agents affecting cytochrome P{sub 450} were studied on the production of erythropoietin (Epo) in cultures of the human hepatoma cell line HepG2. Epo was measured by radioimmunoassay of the culture media after 24 h of incubation. The addition of phenobarbital or 3-methylcholanthrene, which induce cytochrome P{sub 450}, significantly enhanced the formation of Epo. Likewise, the thyroid hormones T{sub 3} and T{sub 4} stimulated the rate of the production of Epo. On the other hand, the formation of Epo was lowered following the addition of diethyl-dithiocarbamate or cysteamine chloride, which inhibit cytochrome P{sub 450}. These findings support the idea that O{sub 2} sensitive hemoproteins of the microsomal mixed-functional oxidases play a role in the control of the synthesis of Epo.

  20. Chemical synthesis of erythropoietin glycoforms for insights into the relationship between glycosylation pattern and bioactivity

    Science.gov (United States)

    Murakami, Masumi; Kiuchi, Tatsuto; Nishihara, Mika; Tezuka, Katsunari; Okamoto, Ryo; Izumi, Masayuki; Kajihara, Yasuhiro

    2016-01-01

    The role of sialyloligosaccharides on the surface of secreted glycoproteins is still unclear because of the difficulty in the preparation of sialylglycoproteins in a homogeneous form. We selected erythropoietin (EPO) as a target molecule and designed an efficient synthetic strategy for the chemical synthesis of a homogeneous form of five EPO glycoforms varying in glycosylation position and the number of human-type biantennary sialyloligosaccharides. A segment coupling strategy performed by native chemical ligation using six peptide segments including glycopeptides yielded homogeneous EPO glycopeptides, and folding experiments of these glycopeptides afforded the correctly folded EPO glycoforms. In an in vivo erythropoiesis assay in mice, all of the EPO glycoforms displayed biological activity, in particular the EPO bearing three sialyloligosaccharides, which exhibited the highest activity. Furthermore, we observed that the hydrophilicity and biological activity of the EPO glycoforms varied depending on the glycosylation pattern. This knowledge will pave the way for the development of homogeneous biologics by chemical synthesis. PMID:26824070

  1. Effects of Erythropoietin on Hippocampal Volume and Memory in Mood Disorders

    DEFF Research Database (Denmark)

    Miskowiak, Kamilla Woznica; Vinberg, Maj; Macoveanu, Julian

    2015-01-01

    BACKGROUND: Persistent cognitive dysfunction in depression and bipolar disorder (BD) impedes patients' functional recovery. Erythropoietin (EPO) increases neuroplasticity and reduces cognitive difficulties in treatment-resistant depression (TRD) and remitted BD. This magnetic resonance imaging...... assessment with the Rey Auditory Verbal Learning Test, and mood ratings with the Beck Depression Inventory, Hamilton Depression Rating Scale, and Young Mania Rating Scale at baseline and week 14. Hippocampus segmentation and analysis of hippocampal volume, shape, and gray matter density were conducted...... with subfield hippocampal volume increase independent of mood change. CONCLUSIONS: EPO-associated memory improvement in TRD and BD may be mediated by reversal of brain matter loss in a subfield of the left hippocampus. EPO may provide a therapeutic option for patients with mood disorders who have impaired...

  2. Chemical synthesis of erythropoietin glycoforms for insights into the relationship between glycosylation pattern and bioactivity.

    Science.gov (United States)

    Murakami, Masumi; Kiuchi, Tatsuto; Nishihara, Mika; Tezuka, Katsunari; Okamoto, Ryo; Izumi, Masayuki; Kajihara, Yasuhiro

    2016-01-01

    The role of sialyloligosaccharides on the surface of secreted glycoproteins is still unclear because of the difficulty in the preparation of sialylglycoproteins in a homogeneous form. We selected erythropoietin (EPO) as a target molecule and designed an efficient synthetic strategy for the chemical synthesis of a homogeneous form of five EPO glycoforms varying in glycosylation position and the number of human-type biantennary sialyloligosaccharides. A segment coupling strategy performed by native chemical ligation using six peptide segments including glycopeptides yielded homogeneous EPO glycopeptides, and folding experiments of these glycopeptides afforded the correctly folded EPO glycoforms. In an in vivo erythropoiesis assay in mice, all of the EPO glycoforms displayed biological activity, in particular the EPO bearing three sialyloligosaccharides, which exhibited the highest activity. Furthermore, we observed that the hydrophilicity and biological activity of the EPO glycoforms varied depending on the glycosylation pattern. This knowledge will pave the way for the development of homogeneous biologics by chemical synthesis.

  3. Gel electrophoretic methods for the analysis of biosimilar pharmaceuticals using the example of recombinant erythropoietin.

    Science.gov (United States)

    Reichel, Christian; Thevis, Mario

    2013-03-01

    Due to their versatility and cost-effectiveness, gel electrophoretic methods provide an important set of tools for the analysis of therapeutic proteins. As an increasing number of biosimilar pharmaceuticals are entering the market, techniques are required that allow reliable demonstration of comparability of these products with the reference products. Isoelectric focusing, SDS-PAGE, native PAGE and 2D electrophoresis (2D-PAGE) have been frequently applied for this purpose. Supplementary techniques are fluorophore-assisted carbohydrate electrophoresis and sarcosyl-PAGE. Of additional importance is the comparison of recombinant with endogenously synthesized glycoproteins. Reagent array analysis combined with SDS-PAGE and western blotting proved especially useful for this purpose. As an example for the application of these methods, the analysis of recombinant originator erythropoietins and some of their biosimilar counterparts is described.

  4. Antiepoetin antibody-related pure red cell aplasia: successful remission with cessation of recombinant erythropoietin alone.

    Science.gov (United States)

    Katagiri, Daisuke; Shibata, Maki; Katsuki, Takashi; Masumoto, Shoichi; Katsuma, Ai; Minami, Eri; Hoshino, Taro; Inoue, Tsuyoshi; Tada, Manami; Hinoshita, Fumihiko

    2010-10-01

    An elderly patient with pure red cell aplasia (PRCA) with antierythropoietin (anti-EPO) antibodies is described. PRCA due to alloimmunization is a rare and severe complication of recombinant human erythropoietin (rHu-EPO) therapy. Most reported patients with PRCA were cured primarily by immunosuppressive drug therapy. The patient in this case, however, did not want to receive any immunosuppressive drugs. Therefore, rHu-EPO injection was simply discontinued, the severe anemia gradually improved, and the hemoglobin approached normal range. This case is very rare and significant in that there have been few such elderly patients with rHu-EPO-induced PRCA in whom PRCA remission was achieved, with decreasing antibody titers, after cessation of rHu-EPO alone. Further cases are needed to assess how PRCA should be treated in patients with anti-EPO antibodies.

  5. Erythropoietin may reduce the risk of germ cell loss in boys with cryptorchidism

    DEFF Research Database (Denmark)

    Cortes, D; Visfeldt, J; Thorup, J M

    2001-01-01

    of infertility. In order to increase the number of germ cells, and thereby the fertility potential, additional hormonal therapy has been attempted before surgery. In a study, small doses of the gonadotropin-releasing hormone analogue buserelin before orchiopexy caused higher values. Others have found......PURPOSE: In boys with cryptorchidism older than 2 years a testicular biopsy at time of orchiopexy shows lack of germ cells in 10-40% of the cases. The number of spermatogonia per tubule is prognostic for subsequent fertility potential. A biopsy without germ cells is associated with 33-100% risk...... that hormonal treatment with human chorionic gonadotropin or gonadotropin releasing hormone analogue may harm the germ cells in cryptorchidism. The aim of the study is to demonstrate that additional hormonal therapy with erythropoietin has a positive effect on the number of germ cells. MATERIALS AND METHODS...

  6. HIGH SERUM ERYTHROPOIETIN AND FERRITIN LEVELS ASSOCIATED WITH ANEMIA RESPONSE IN MALIGNANT LYMPHOMA

    Directory of Open Access Journals (Sweden)

    Sofia Omari

    2011-05-01

    Full Text Available Anemia is a common finding in lymphoma. There are few data available regarding the erythropoietin (EPO levels in conjunction with ferritin in lymphoma patients. We prospectively evaluated 55 patients diagnosed with malignant lymphoma during the period between November 2006 and March 2008 at King Abdullah University Teaching Hospital, Jordan. Our data showed that 74.4% of lymphoma patients were anemic. Furthermore, serum EPO and ferritin levels were higher in lymphoma patients compared with the healthy controls (P=0.001. The observed versus predicted EPO ratio showed also significantly higher levels in anemic lymphoma patients compared to healthy controls (p=0.03. There was an improvement in Hb level in lymphoma patients who were treated with at least 3-cycles of chemotherapy as compared with newly-diagnosed patients. An adequate increase of EPO levels was observed in anemic lymphoma patients and notably associated with higher ferritin levels and improvement of Hb (p

  7. Autologous blood collection in anemic patients using low-dose erythropoietin therapy.

    Science.gov (United States)

    Mott, L S; Bechinski, J; Jones, M J

    1997-06-01

    Autologous donation of blood for use during elective surgery is being recommended and used more frequently. Autologous donation and transfusion represent the safest way to handle elective surgical blood requirements because they eliminate the risk of transfusion-transmitted disease and alloimmunization, and significantly reduce the other risks associated with homologous transfusion. Many individuals, particularly women and the elderly, do not have sufficient initial hemoglobin concentration or hemopoietic reserve to effectively use autologous donation. Use of standard-dose recombinant human erythropoietin (rHuEPO) (600 units/kg) to mitigate these limitations is costly. The optimal dose, interval, and route of administration for rHuEPO therapy has yet to be perfected. This article describes a program using low-dose (effectiveness, cost savings, and clinical indications for the use of low-dose rHuEPO.

  8. Expression of human erythropoietin directed by mWAP promoter in mammary gland of transgenic mice

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    The present work has generated transgenic mice with a hybrid gene construct consisting of genomic sequences encoding human erythropoietin (hEPO) and governed by regulatory sequences of mouse whey acidic protein (mWAP). The construct proved effective by transient expression in lactating animal. After introducing hybrid gene construct into single-cell embryo via pronuclear microinjection, surviving embryo are reimplanted into pseudopregnant foster mother mouse. 58 mice of 86 generation zero mice obtained were identified to be positive by PCR-Southern blot and genomic DNA Southern blot methods. The integration rate is 67%. hEPO was expressed in the milk of 16 mice of 39 mice measured by hEPO ELISA kit .The expression level gets over 15 m g/mL.

  9. Erythropoietin may reduce the risk of germ cell loss in boys with cryptorchidism

    DEFF Research Database (Denmark)

    Cortes, Dina; Visfeldt, J; Thorup, J M

    2001-01-01

    In boys with cryptorchidism older than 2 years a testicular biopsy at time of orchiopexy shows lack of germ cells in 10-40% of the cases. The number of spermatogonia per tubule is prognostic for subsequent fertility potential. A biopsy without germ cells is associated with 33-100% risk...... of infertility. In order to increase the number of germ cells, and thereby the fertility potential, additional hormonal therapy has been attempted before surgery. In a study, small doses of the gonadotropin-releasing hormone analogue buserelin before orchiopexy caused higher values. Others have found...... that hormonal treatment with human chorionic gonadotropin or gonadotropin releasing hormone analogue may harm the germ cells in cryptorchidism. The aim of the study is to demonstrate that additional hormonal therapy with erythropoietin has a positive effect on the number of germ cells....

  10. Human erythropoietin response to hypocapnic hypoxia, normocapnic hypoxia, and hypocapnic normoxia

    DEFF Research Database (Denmark)

    Klausen, T; Christensen, H; Hansen, J M

    1996-01-01

    This study investigated the human erythropoietin (EPO) response to short-term hypocapnic hypoxia, its relationship to a normoxic or hypoxic increase of the haemoglobin oxygen affinity, and its suppression by the addition of CO2 to the hypoxic gas. On separate days, eight healthy male subjects were...... (10% Co2 with 10% O2) to the hypoxic gas mixture. This elicited an increased ventilation, unaltered arterial pH and haemoglobin oxygen affinity, a lower degree of hypoxia than during hypocapnic hypoxia, and no significant changes in serum-EPO (ANOVA P > 0.05). Hypocapnic normoxia, produced...... by hyperventilation of room air, elicited a normoxic increase in the haemoglobin oxygen affinity without changing serum-EPO. Among the measured blood gas and acid-base parameters, only the partial pressures of oxygen in arterial blood during hypocapnic hypoxia were related to the peak values of serum-EPO (r = -0...

  11. Erythropoietin and thrombopoietin mimetics: Natural alternatives to erythrocyte and platelet disorders.

    Science.gov (United States)

    Gutti, Usha; Pasupuleti, Satya Ratan; Sahu, Itishri; Kotipalli, Aneesh; Undi, Ram Babu; Kandi, Ravinder; Venakata Saladi, Raja Gopal; Gutti, Ravi Kumar

    2016-12-01

    Erythropoietin (EPO) and thrombopoietin (TPO) plays a major role in the regulation of hematopoietic development. Though, blood transfusion was the most widely used method to treat low blood count, over the years with advancements in recombinant technology and drug designing, the EPO and TPO mimetics are dominating the therapeutics industry. On the other hand, the recombinant human EPO and TPO are associated either with reduced half-life or immune reactions. The restoration of alternate medicine in recent years has the hope to overcome limitations associated with recombinant technology, to treat various disorder including blood diseases, with low to no side effects. The work in recent years on plant derived mimetics suggests a paradigm shift in the way diseases are treated. Here, we are providing a comprehensive review on the EPO and TPO recombinant counterparts and synthetic mimetics studied till date with a focus on the need for more natural alternatives.

  12. Common variants of the genes encoding erythropoietin and its receptor modulate cognitive performance in schizophrenia

    DEFF Research Database (Denmark)

    Kästner, Anne; Grube, Sabrina; El-Kordi, Ahmed

    2012-01-01

    -term memory readouts, with one particular combination of genotypes superior to all others (p 800), these associations were confirmed. A matching preclinical study with mice demonstrated cognitive processing speed and memory enhanced upon transgenic......Erythropoietin (EPO) improves cognitive performance in clinical studies and rodent experiments. We hypothesized that an intrinsic role of EPO for cognition exists, with particular relevance in situations of cognitive decline, which is reflected by associations of EPO and EPO receptor (EPOR......) genotypes with cognitive functions. To prove this hypothesis, schizophrenic patients (N > 1000) were genotyped for 5' upstream-located gene variants, EPO SNP rs1617640 (T/G) and EPORSTR(GA)(n). Associations of these variants were obtained for cognitive processing speed, fine motor skills and short...

  13. Effects of erythropoietin on memory-relevant neurocircuitry activity and recall in mood disorders

    DEFF Research Database (Denmark)

    Miskowiak, K W; Macoveanu, J; Vinberg, M

    2016-01-01

    OBJECTIVE: Erythropoietin (EPO) improves verbal memory and reverses subfield hippocampal volume loss across depression and bipolar disorder (BD). This study aimed to investigate with functional magnetic resonance imaging (fMRI) whether these effects were accompanied by functional changes in memory...... cohort. The effects of EPO were not correlated with change in mood, red blood cells, blood pressure, or medication. CONCLUSION: The findings highlight enhanced encoding-related dlPFC and temporo-parietal activity as key neuronal underpinnings of EPO-associated memory improvement.......MRI at 3T, mood ratings, and blood tests at baseline and week 14. During fMRI, participants performed a picture encoding task followed by postscan recall. RESULTS: Sixty-two patients had complete data (EPO: N = 32, saline: N = 30). EPO improved picture recall and increased encoding-related activity...

  14. Recombinant human erythropoietin stimulates angiogenesis and wound healing in the genetically diabetic mouse.

    Science.gov (United States)

    Galeano, Mariarosaria; Altavilla, Domenica; Cucinotta, Domenico; Russo, Giuseppina T; Calò, Margherita; Bitto, Alessandra; Marini, Herbert; Marini, Rolando; Adamo, Elena B; Seminara, Paolo; Minutoli, Letteria; Torre, Valerio; Squadrito, Francesco

    2004-09-01

    The effects of recombinant human erythropoietin (rHuEPO) in diabetes-related healing defects were investigated by using an incisional skin-wound model produced on the back of female diabetic C57BL/KsJ-m(+/+)Lept(db) mice (db(+)/db(+)) and their normoglycemic littermates (db(+/+)m). Animals were treated with rHuEPO (400 units/kg in 100 microl s.c.) or its vehicle alone (100 microl). Mice were killed on different days (3, 6, and 12 days after skin injury) for measurement of vascular endothelial growth factor (VEGF) mRNA expression and protein synthesis, for monitoring angiogenesis by CD31 expression, and for evaluating histological changes. Furthermore, we evaluated wound-breaking strength at day 12. At day 6, rHuEPO injection in diabetic mice resulted in an increase in VEGF mRNA expression (vehicle = 0.33 +/- 0.1 relative amount of mRNA; rHuEPO = 0.9 +/- 0.09 relative amount of mRNA; P < 0.05) and protein wound content (vehicle = 23 +/- 5 pg/wound; rHuEPO = 92 +/- 12 pg/wound; P < 0.05) and caused a marked increase in CD31 gene expression (vehicle = 0.18 +/- 0.05 relative amount of mRNA; rHuEPO = 0.98 +/- 0.21 relative amount of mRNA; P < 0.05) and protein synthesis. Furthermore, rHuEPO injection improved the impaired wound healing and, at day 12, increased the wound-breaking strength in diabetic mice (vehicle = 12 +/- 2 g/mm; rHuEPO 21 +/- 5 g/mm; P < 0.05). Erythropoietin may have a potential application in diabetes-related wound disorders.

  15. Isolation and characterization of renal erythropoietin-producing cells from genetically produced anemia mice.

    Directory of Open Access Journals (Sweden)

    Xiaoqing Pan

    Full Text Available Understanding the nature of renal erythropoietin-producing cells (REPs remains a central challenge for elucidating the mechanisms involved in hypoxia and/or anemia-induced erythropoietin (Epo production in adult mammals. Previous studies have shown that REPs are renal peritubular cells, but further details are lacking. Here, we describe an approach to isolate and characterize REPs. We bred mice bearing an Epo gene allele to which green fluorescent protein (GFP reporter cDNA was knocked-in (Epo(GFP with mice bearing an Epo gene allele lacking the 3' enhancer (Epo(Δ3'E. Mice harboring the mutant Epo(GFP/Δ3'E gene exhibited anemia (average Hematocrit 18% at 4 to 6 days after birth, and this perinatal anemia enabled us to identify and purify REPs based on GFP expression from the kidney. Light and confocal microscopy revealed that GFP immunostaining was confined to fibroblastic cells that reside in the peritubular interstitial space, confirming our previous observation in Epo-GFP transgenic reporter assays. Flow cytometry analyses revealed that the GFP fraction constitutes approximately 0.2% of the whole kidney cells and 63% of GFP-positive cells co-express CD73 (a marker for cortical fibroblasts and Epo-expressing cells in the kidney. Quantitative RT-PCR analyses confirmed that Epo expression was increased by approximately 100-fold in the purified population of REPs compared with that of the unsorted cells or CD73-positive fraction. Gene expression analyses showed enrichment of Hif2α and Hif3α mRNA in the purified population of REPs. The genetic approach described here provides a means to isolate a pure population of REPs, allowing the analysis of gene expression of a defined population of cells essential for Epo production in the kidney. This has provided evidence that positive regulation by HIF2α and negative regulation by HIF3α might be necessary for correct renal Epo induction.

  16. Erythropoietin assay: present status of methods, pitfalls, and results in polycythemic disorders.

    Science.gov (United States)

    Popovic, W J; Adamson, J W

    1978-01-01

    Mammalian erythropoiesis is regulated primarily by the hormone erythropoietin (ESP). Studies of ESF have provided information about its biochemistry and its role in regulating hemoglobin synthesis. Such studies rely on assays for erythropoietic activity in biological fluid. The assay which has proven most valuable and is used most widely is based upon the incorporation of radioactive iron into newly-formed red cells of polycythemic mice. While this assay has gained wide acceptance, it is expensive, cumbersome, imprecise, and insensitive, capable of reliably detecting no less than 50 milliunits of erythropoietin. Improvements in assay techniques will require new methodology relying primarily on immunologic recognition for the determination of hormone activity. Currently under development and in experimental use are radioimmunoassays and a hemagglutination inhibition assay. While work has progressed in these areas, these assays are not of proven value at present and meaningful physiological correlations have not emerged from their use. Alternatively, assays for hormone activity using suspensions of hematopoietic cells and the measurement of incorporation of radioactive isotopes into hemoglobin have provided both improvement in sensitivity and precision. The disadvantage of these types of assays is that they are sensitive to factors other than ESF and may give misleading information, depending on whether the factors present stimulate or inhibit cellular proliferation and hemoglobin synthesis. While such techniques may provide a temporary solution to some problems associated with assaying ESF for purification or physiological studies, they are not the best answer to the overall problem of hormone detection and characterization. The most important contribution to this field will be the availability of large amounts of highly purified and well-characterized ESF.

  17. Effect of protein-energy malnutrition on erythropoietin requirement in maintenance hemodialysis patients.

    Science.gov (United States)

    Akgul, Arzu; Bilgic, Ayse; Sezer, Siren; Ozdemir, Fatma Nurhan; Olcay, Irem; Arat, Zubeyde; Haberal, Mehmet

    2007-04-01

    Possible interactions between inflammatory and nutritional markers and their impact on recombinant human erythropoietin (rHuEPO) hyporesponsiveness are not well understood. We investigated the role of nutritional status in rHuEPO requirement in maintenance hemodialysis (MHD) patients without evidence of inflammation. This cross-sectional study included 88 MHD patients. The associations between required rHuEPO dose and malnutrition-inflammation score (MIS) and several laboratory values known to be related to nutrition and/or inflammation were analyzed. Anthropometric measures including body mass index, triceps skinfold thickness, and midarm circumferences were also measured. Twenty-three patients with serum C-reactive protein levels >10 mg/L were excluded from the analysis. The remaining 65 patients (male/female, 41/24; age 49.1+/-11.4 years; dialysis duration 99.7+/-63.0 months) were studied. These patients had moderate malnutrition and the average MIS was 7.4 (range 3-17). The average weekly dose of administered rHuEPO was 69.1+/-63.1 U/kg. Malnutrition-inflammation score had a positive correlation with the serum concentration of tumor necrosis factor-alpha, whereas it had a negative correlation with anthropometric measures, total iron-binding capacity, prealbumin, phosphorus, creatinine, and triglyceride. According to Pearson's correlation analysis, significant relationships of increased MIS with increased required rHuEPO dose and rHuEPO responsiveness index (EPO divided by hematocrit) were observed (p=0.008, r=-0.326; p=0.017, r=-0.306, respectively). Recombinant human erythropoietin dose requirement is correlated with MIS and adverse nutritional status in MHD patients without evidence of inflammation. Further research should focus on reversing the undergoing microinflammation for a better outcome in dialysis patients.

  18. Recombinant erythropoietin differently affects proliferation of mesothelioma cells but not sensitivity to cisplatin and pemetrexed.

    Science.gov (United States)

    Palumbo, Camilla; Battisti, Sonia; Carbone, Daniela; Albonici, Loredana; Alimandi, Maurizio; Bei, Roberto; Modesti, Andrea

    2008-04-01

    The combination of cisplatin and pemetrexed represents the newly established standard of care for patients with unresectable malignant mesothelioma (MM). However, this chemotherapy regimen appears to be associated with an increased prevalence of higher grade anemia as compared to treatment with cisplatin alone. Human recombinant erythropoietin (rHuEpo) is currently used for the treatment of anemia in cancer patients. Still, following the finding that the erythropoietin receptor (EpoR) is expressed by several tumor cells types and after the trials reporting that the recombinant cytokine can adversely affect tumor progression and patient survival, the clinical safety of rHuEpo administration to neoplastic patients has recently been questioned. The observation that the expression of EpoR, variably associated with the expression of the cognate ligand, is a common feature of MM cells prompted us to investigate whether treatment with rHuEpo could elicit proliferative and cytoprotective signals in EpoR-positive MM cell lines. Biochemical responsiveness of MM cells to rHuEpo was demonstrated by the time-course activation of both ERK1/2 and AKT following treatment with the recombinant cytokine. A moderately increased mitogenic activity was observed in two out of five MM cell lines treated with pharmacologically relevant concentrations of rHuEpo. On the other hand, the recombinant cytokine, administered either before or after cisplatin and pemetrexed, failed to interfere with the cytotoxic effects exerted by the chemotherapeutic drugs on the five MM cell lines. According to the presented findings, rHuEpo appears to have an overall limited impact on cell growth and no effect on MM sensitivity to chemotherapy.

  19. Erythropoietin receptor expression is a potential prognostic factor in human lung adenocarcinoma.

    Directory of Open Access Journals (Sweden)

    Anita Rózsás

    Full Text Available Recombinant human erythropoietins (rHuEPOs are used to treat cancer-related anemia. Recent preclinical studies and clinical trials, however, have raised concerns about the potential tumor-promoting effects of these drugs. Because the clinical significance of erythropoietin receptor (EPOR signaling in human non-small cell lung cancer (NSCLC also remains controversial, our aim was to study whether EPO treatment modifies tumor growth and if EPOR expression has an impact on the clinical behavior of this malignancy. A total of 43 patients with stage III-IV adenocarcinoma (ADC and complete clinicopathological data were included. EPOR expression in human ADC samples and cell lines was measured by quantitative real-time polymerase chain reaction. Effects of exogenous rHuEPOα were studied on human lung ADC cell lines in vitro. In vivo growth of human ADC xenografts treated with rHuEPOα with or without chemotherapy was also assessed. In vivo tumor and endothelial cell (EC proliferation was determined by 5-bromo-2'-deoxy-uridine (BrdU incorporation and immunofluorescent labeling. Although EPOR mRNA was expressed in all of the three investigated ADC cell lines, rHuEPOα treatment (either alone or in combination with gemcitabine did not alter ADC cell proliferation in vitro. However, rHuEPOα significantly decreased tumor cell proliferation and growth of human H1975 lung ADC xenografts. At the same time, rHuEPOα treatment of H1975 tumors resulted in accelerated tumor endothelial cell proliferation. Moreover, in patients with advanced stage lung ADC, high intratumoral EPOR mRNA levels were associated with significantly increased overall survival. This study reveals high EPOR level as a potential novel positive prognostic marker in human lung ADC.

  20. Recombinant human erythropoietin reduces plasminogen activator inhibitor and ameliorates pro-inflammatory responses following trauma

    Directory of Open Access Journals (Sweden)

    M Mojtahedzadeh

    2011-05-01

    Full Text Available "n  "n Background and the purpose of the study: Besides its hematopoietic effects, erythropoietin (EPO by mobilization of iron and modulation of some inflammatory cytokines has antioxidant and anti-inflammatory properties. The purpose of this study was to evaluate these effects of erythropoietin and its impact on organ function in traumatized patients. "n Methods: Twenty-six ICU-admitted traumatized patients within 24 hrs after trauma were randomly assigned to the EPO (received EPO, 300 units/Kg/day and Control (not received EPO groups. The inflammatory biomarkers including Tumor Necrosis Factor alpha (TNF-α, Interleukin 1 (IL-1, Plasminogen Activator Inhibitor 1 (PAI-1 and Nitrotyrosine were recorded at the admission, 3, 6 and 9 days thereafter. Acute Physiology and Chronic Health Evaluation (APACHE II and Sequential Organ Failure Assessment (SOFA scores were also recorded. "n Results: Among 12 patients (EPO group TNF-α level at the day of 9 (P=0.046, and within EPO group at the days of 3 (P=0.026 ameliorate, 6 (P=0.016, and 9 (P=0.052 were significantly lowered. Level of IL-1 and PAI-1 decreased significantly at days of 3, 6 and 9 post intervention. Also there were significant differences between two groups in the SOFA score during three measured time intervals (the first, third and seventh days. "n Conclusion: From the results of this study it seems that injection of erythrocyte stimulating agent is well tolerated and inhibits the inflammatory response and oxidative stress following trauma.

  1. Erythropoietin reduces ischemia-reperfusion injury after liver transplantation in rats.

    Science.gov (United States)

    Schmeding, Maximilian; Hunold, Gerhard; Ariyakhagorn, Veravoorn; Rademacher, Sebastian; Boas-Knoop, Sabine; Lippert, Steffen; Neuhaus, Peter; Neumann, Ulf P

    2009-07-01

    Human recombinant Erythropoietin (rHuEpo) has recently been shown to be a potent protector of ischemia- reperfusion injury in warm-liver ischemia. Significant enhancement of hepatic regeneration and survival after large volume partial hepatic resection has also been demonstrated. It was the aim of this study to evaluate the capacities of rHuEpo in the setting of rat liver transplantation. One-hundred-and-twenty Wistar rats were used: 60 recipients received liver transplantation following donor organ treatment (60 donors) with either 1000 IU rHuEpo or saline injection (controls) into portal veins (cold ischemia 18 h, University of Wisconsin (UW) solution). Recipients were allocated to two groups, which either received 1000 IU rHuEpo at reperfusion or an equal amount of saline (control). Animals were sacrificed at defined time-points (2, 4.5, 24, 48 h and 7 days postoperatively) for analysis of liver enzymes, histology [hematoxylin-eosin (HE) staining, periodic acid Schiff staining (PAS)], immunostaining [terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), Hypoxyprobe] and real-time polymerase chain reaction (RT-PCR) of cytokine mRNA (IL-1, IL-6). Lactate dehydrogenase (LDH) and alanine aminotransferase (ALT) values were significantly reduced among the epo-treated animals 24 and 48 h after liver transplantation (LT). The TUNEL and Hypoxyprobe analyses as well as necrotic index evaluation displayed significant reduction of apoptosis and necrosis in rHuEpo-treated graft livers. Erythropoietin reduces ischemia-reperfusion injury after orthotopic liver transplantation in rats.

  2. Serum immunoreactive erythropoietin levels and associated factors amongst HIV-infected children.

    Science.gov (United States)

    Allen, U D; King, S M; Gomez, M P; Lapointe, N; Forbes, J C; Thorne, A; Kirby, M A; Bowker, J; Raboud, J; Singer, J; Mukwaya, G; Tobin, J; Read, S E

    1998-10-01

    To determine the spectrum of serum immunoreactive erythropoietin (SIE) levels amongst HIV-infected children aged renal failure; to examine the relationship between clinical and laboratory parameters and SIE levels. A cross-sectional study with a descriptive non-interventional format. HIV-infected Canadian subjects were recruited through four tertiary Canadian and one Bahamian centre. Children with renal failure and healthy children were recruited from one of the Canadian centres. Study subjects had clinical and laboratory profiles determined at baseline and at each of five follow-up periods over 1 year. SIE levels were measured by radioimmunoassay with a normal range of 12-28 IU/I. Data handling and statistical functions were performed by the Canadian HIV Trials Network. The study enrolled 133 HIV-infected subjects and 38 controls. Of these, 117 HIV-infected subjects, 24 healthy controls, and 11 controls with renal failure were eligible for analysis. The median age of infected subjects was 44 months, whereas that of healthy controls was 56 months, and 95 months for controls with renal failure. The median SIE levels were 14 and 11 IU/I for subjects with renal failure and healthy subjects, respectively. The median SIE level was 61 IU/I among zidovudine (ZDV)-treated subjects and 22 IU/I among ZDV-naive HIV-infected subjects. HIV-infected children almost invariably had SIE levels 100 g/l (median, 58 and 15 IU/l, respectively; P exogenous recombinant human erythropoietin in HIV-infected children with anemia.

  3. The role of erythropoietin stimulating agents in anemic patients with heart failure: solved and unresolved questions

    Directory of Open Access Journals (Sweden)

    Palazzuoli A

    2014-08-01

    Full Text Available Alberto Palazzuoli, Gaetano Ruocco, Marco Pellegrini, Carmelo De Gori, Gabriele Del Castillo, Nicola Giordano, Ranuccio NutiDepartment of Internal Medicine and Metabolic Diseases, Cardiology Section, Le Scotte Hospital, University of Siena, Siena, ItalyAbstract: Anemia is a common finding in congestive heart failure (CHF and is associated with an increased mortality and morbidity. Several conditions can cause depression of erythroid progenitor cells: reduction of iron absorption and reuptake, decreased bone marrow activity, reduced endogenous erythropoietin production, and chronic inflammatory state. Anemia’s etiology in CHF is complex and partially understood; it involves several systems including impaired hemodynamic condition, reduced kidney and bone perfusion, increased inflammatory activity, and neurohormonal overdrive. The use of erythropoiesis stimulating agents (ESAs such as erythropoietin and its derivatives is recently debated; the last interventional trial seems to demonstrate a neutral or negative effect in the active arm with darbepoetin treatment. The current data is opposite to many single blind studies and previous meta-analysis showing an improvement in quality of life, New York Heart Association class, and exercise tolerance using ESA therapy. These contrasting data raise several concerns regarding the target of hemoglobin levels needing intervention, the exact anemia classification and categorization, and the standardization of hematocrit cutoffs. Some cardiac and systemic conditions (ie, hypertension, atrial fibrillation, prothrombotic status may predispose to adverse events, and ESA administration should be avoided. To prevent the negative effects, high-dosage and chronic administration should be avoided. Clarification of these items could probably identify patients that may benefit from additional iron or ESA treatment. In this review, we discuss the interventional trials made in anemic heart failure patients, the

  4. Association of I/D angiotensin-converting enzyme genotype with erythropoietin stimulation in kidney failure

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    Savin Marina

    2017-01-01

    Full Text Available Angiotensin-converting enzyme (ACE-gene polymorphism is a possible predisposing factor of erythropoietin response under hypoxic conditions. However, it is not completely clear whether the ACE insertion/deletion (I/D genotype has an impact on anemia in patients with permanent kidney failure. A 9-month prospective trial was conducted on 53 patients on hemodialysis aimed at determining the beneficial effect of oral vs intravenous iron in anemia management with recombinant human erythropoietin (rHuEpo, and identifying a possible association of the ACE gene I/D polymorphism with the response to rHuEpo. Patients were randomly allocated to receive 50-100 mg daily of ferrous gluconate orally (N=26 or intravenously every two weeks (N=27, together with rHuEpo-beta (200 IU/kg subcutaneously, to achieve a hemoglobin increase to 105 g/L; subsequently the rHuEpo dose was adjusted at one or two week intervals. In 34 patients who regularly received ACE-inhibitor (ACEi medication, genotyping for ACE-gene I/D polymorphism was performed using PCR, gel analysis and appropriate restriction digestion. After prolonged rHuEpo treatment, 24.5% of patients attained the targeted 9th-month hemoglobin concentration (105 g/L. Of these, 6/26 of patients received elemental iron orally and 7/27 received it intravenously. We observed an association between homozygous DD (deletion of the ACE gene and a remarkable early increase in blood hemoglobin (p=0.028, erythrocyte count (p=0.020 and hematocrit (p=0.043 after reduction of the dose of rHuEpo (F=3.95; p=0.029, irrespective of the iron repletion mode (p=0.960. This is the first report on DD genotype as a linkage marker for the optimization of rHuEpo dose for anemia management in hemodialysis patients.

  5. Hypoproduction of erythropoietin contributes to anemia in chronic cadmium intoxication: clinical study on Itai-itai disease in Japan

    Energy Technology Data Exchange (ETDEWEB)

    Horiguchi, Hyogo (Dept. of Public Health, Faculty of Medicine, Toyama Medical and Pharmaceutical Univ. (Japan)); Teranishi, Hidetoyo (Dept. of Public Health, Faculty of Medicine, Toyama Medical and Pharmaceutical Univ. (Japan)); Niiya, Kenji (Dept. of Clinical Lab. Medicine, Faculty of Medicine, Toyama Medical and Pharmaceutical Univ. (Japan)); Aoshima, Keiko (Dept. of Public Health, Faculty of Medicine, Toyama Medical and Pharmaceutical Univ. (Japan)); Katoh, Terutaka (Dept. of Public Health, Faculty of Medicine, Toyama Medical and Pharmaceutical Univ. (Japan)); Sakuragawa, Nobuo (Dept. of Clinical Lab. Medicine, Faculty of Medicine, Toyama Medical and Pharmaceutical Univ. (Japan)); Kasuya, Minoru (Dept. of Public Health, Faculty of Medicine, Toyama Medical and Pharmaceutical Univ. (Japan))

    1994-10-01

    Itai-itai disease is a condition caused by longterm exposure of the inhabitants of Toyama prefecture, Japan, to cadmium intoxication. The characteristic clinical features of this disease include renal tubular dysfunction, osteomalacia, and anemia. In order to clarify the pathogenesis of the anemia, the red blood cell count, hemoglobin concentration, hematocrit, serum iron level, total iron-binding capacity, serum ferritin level, serum erythropoietin level, creatinine clearance, fractional excretion of [beta][sub 2]-microglobulin, and bone marrow morphology were determined in ten patients with Itai-itai disease. Low serum iron or ferritin levels were not observed, and bone marrow aspiration did not reveal any specific hematological disorders. A close relationship was observed between the decrease in the hemoglobin level and the progression of renal dysfunction. Low serum erythropoietin levels were detected despite the presence of severe anemia. These results suggest an important role of renal damage in the anemia which develops in Itai-itai disease. (orig.)

  6. Erythropoietin test

    Science.gov (United States)

    ... by: Charles Silberberg, DO, private practice specializing in nephrology, affiliated with New York Medical College, Division of Nephrology, Valhalla, NY. Review provided by VeriMed Healthcare Network. ...

  7. Localized and Sustained Delivery of Erythropoietin from PLGA Microspheres Promotes Functional Recovery and Nerve Regeneration in Peripheral Nerve Injury

    OpenAIRE

    Wei Zhang; Yuan Gao; Yan Zhou; Jianheng Liu; Licheng Zhang; Anhua Long; Lihai Zhang; Peifu Tang

    2015-01-01

    Erythropoietin (EPO) has been demonstrated to exert neuroprotective effects on peripheral nerve injury recovery. Though daily intraperitoneal injection of EPO during a long period of time was effective, it was a tedious procedure. In addition, only limited amount of EPO could reach the injury sites by general administration, and free EPO is easily degraded in vivo. In this study, we encapsulated EPO in poly(lactide-co-glycolide) (PLGA) microspheres. Both in vitro and in vivo release assays sh...

  8. Pure red cell aplasia associated with recombinant erythropoietin: a case report and brief review of the literature.

    Science.gov (United States)

    Mohd Slim, M Atif; Shaik, Riaz

    2013-11-22

    Pure red cell aplasia (PRCA) is a rare adverse effect of recombinant erythropoietin (rEPO). Affected patients rapidly become transfusion-dependent, with many requiring immunosuppressive therapy for remission. We report a confirmed case in an elderly female, possibly the first of its kind in New Zealand, who was started on rEPO for anaemia of chronic kidney disease. We also briefly review current literature on rEPO-associated PRCA.

  9. The combined effect of erythropoietin and granulocyte macrophage colony stimulating factor on liver regeneration after major hepatectomy in rats

    OpenAIRE

    Frangou Matrona; Fragulidis George; Dafnios Nikolaos; Theodosopoulos Theodosios; Tympa Aliki; Nastos Constantinos; Lolis Evangelos; Vassiliou Ioannis; Kondi-Pafiti Agathi; Smyrniotis Vassilios

    2010-01-01

    Abstract Background The liver presents a remarkable capacity for regeneration after hepatectomy but the exact mechanisms and mediators involved are not yet fully clarified. Erythropoietin (EPO) and Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) have been shown to promote liver regeneration after major hepatectomy. Aim of this experimental study is to compare the impact of exogenous administration of EPO, GM-CSF, as well as their combination on the promotion of liver regeneration af...

  10. Der Einfluss von Erythropoietin auf den Ischämie-/Reperfusionsschaden der Leber im Modell der orthotopen Rattenlebertransplantation

    OpenAIRE

    Hunold, Gerhard

    2010-01-01

    Human recombinant Erythropoietin (rHuEpo) has recently been shown to be a potent protector of ischemia- reperfusion injury in warm-liver ischemia. Significant enhancement of hepatic regeneration and survival after large volume partial hepatic resection has also been demonstrated. It was the aim of this study to evaluate the capacities of rHuEpo in the setting of rat liver transplantation. Sixty-eight Wistar rats were used: 39 rats received liver transplantation following donor organ treatment...

  11. Rechallenge with intravenous recombinant human erythropoietin can be successful following the treatment of anti-recombinant erythropoietin associated pure red cell aplasia.

    Science.gov (United States)

    Praditpornsilpa, Kearkiat; Tiranathanakul, Khajohn; Jootar, Saengsuree; Tungsanga, Kriang; Eiam-Ong, Somchai

    2014-05-01

    Anti recombinant human erythropoietin (r-HuEpo) associated pure red cell aplasia (PRCA) is an immunologic adverse effect of using subcutaneous r-HuEpo. Immunosuppressive agents have been suggested as treatment of this serious complication. After the reversal of anti-r-HuEpo antibody, the patients continue to have renal anemia and require long-term blood transfusion, albeit less frequently than when the antibody is positive. It is controversial whether re-challenging the patients with r-HuEpo is appropriate because re-challenging may cause the reappearance of the antibody. To balance the risk of antir-HuEpo antibody reappearance and longterm blood transfusion complications, we re-challenged r-HuEpo in five anti-r-HuEpo associated PRCA cases after a successful reversal of antibody using prednisolone in combination with cyclophosphamide. The rechallenge was performed intravenously since there were no reports of anti-r-HuEpo associated PRCA cases using this administration route. The duration after the reversal of antibody was 2.4 months before the re-challenge. Two patients were immediately re-challenged as soon as the antibodies reversed. After rechallenge with intravenous r-HuEpo, all patients responded to r-HuEpo: target level of Hb was maintained, blood transfusion was not required, and anti-r-HuEpo was consistently negative. All patients were followed for at least 6 months after re-challenge. Our data suggest that re-challenge with intravenous r-HuEpo can successfully treat anti- r-HuEpo associated PRCA.

  12. Erythropoietin attenuates renal and pulmonary injury in polymicrobial induced-sepsis through EPO-R, VEGF and VEGF-R2 modulation.

    Science.gov (United States)

    Heitrich, Mauro; García, Daiana Maria de Los Ángeles; Stoyanoff, Tania Romina; Rodríguez, Juan Pablo; Todaro, Juan Santiago; Aguirre, María Victoria

    2016-08-01

    Sepsis remains the most important cause of acute kidney injury (AKI) and acute lung injury (ALI) in critically ill patients. The cecal ligation and puncture (CLP) model in experimental mice reproduces most of the clinical features of sepsis. Erythropoietin (EPO) is a well-known cytoprotective multifunctional hormone, which exerts anti-inflammatory, anti-oxidant, anti-apoptotic and pro-angiogenic effects in several tissues. The aim of this study was to evaluate the underlying mechanisms of EPO protection through the expression of the EPO/EPO receptor (EPO-R) and VEGF/VEF-R2 systems in kidneys and lungs of mice undergoing CLP-induced sepsis. Male inbred Balb/c mice were divided in three experimental groups: Sham, CLP, and CLP+EPO (3000IU/kg sc). Assessment of renal functional parameters, survival, histological examination, immunohistochemistry and/or Western blottings of EPO-R, VEGF and VEGF-R2 were performed at 18h post-surgery. Mice demonstrated AKI by elevation of serum creatinine and renal histologic damage. EPO treatment attenuates renal dysfunction and ameliorates kidney histopathologic changes. Additionally, EPO administration attenuates deleterious septic damage in renal cortex through the overexpression of EPO-R in tubular interstitial cells and the overexpression of the pair VEGF/VEGF-R2. Similarly CLP- induced ALI, as evidenced by parenchymal lung histopathologic alterations, was ameliorated through pulmonary EPO-R, VEGF and VEGF-R2 over expression suggesting and improvement in endothelial survival and functionality. This study demonstrates that EPO exerts protective effects in kidneys and lungs in mice with CLP-induced sepsis through the expression of EPO-R and the regulation of the VEGF/VEGF-R2 pair.

  13. Radiation Protection

    Science.gov (United States)

    ... EPA United States Environmental Protection Agency Search Search Radiation Protection Share Facebook Twitter Google+ Pinterest Contact Us Radiation Protection Document Library View and download EPA radiation ...

  14. A Simple Three-Step Method for Design and Affinity Testing of New Antisense Peptides: An Example of Erythropoietin

    Directory of Open Access Journals (Sweden)

    Nikola Štambuk

    2014-05-01

    Full Text Available Antisense peptide technology is a valuable tool for deriving new biologically active molecules and performing peptide–receptor modulation. It is based on the fact that peptides specified by the complementary (antisense nucleotide sequences often bind to each other with a higher specificity and efficacy. We tested the validity of this concept on the example of human erythropoietin, a well-characterized and pharmacologically relevant hematopoietic growth factor. The purpose of the work was to present and test simple and efficient three-step procedure for the design of an antisense peptide targeting receptor-binding site of human erythropoietin. Firstly, we selected the carboxyl-terminal receptor binding region of the molecule (epitope as a template for the antisense peptide modeling; Secondly, we designed an antisense peptide using mRNA transcription of the epitope sequence in the 3'→5' direction and computational screening of potential paratope structures with BLAST; Thirdly, we evaluated sense–antisense (epitope–paratope peptide binding and affinity by means of fluorescence spectroscopy and microscale thermophoresis. Both methods showed similar Kd values of 850 and 816 µM, respectively. The advantages of the methods were: fast screening with a small quantity of the sample needed, and measurements done within the range of physicochemical parameters resembling physiological conditions. Antisense peptides targeting specific erythropoietin region(s could be used for the development of new immunochemical methods. Selected antisense peptides with optimal affinity are potential lead compounds for the development of novel diagnostic substances, biopharmaceuticals and vaccines.

  15. Assessing the need for transfusion of premature infants and role of hematocrit, clinical signs, and erythropoietin level.

    Science.gov (United States)

    Keyes, W G; Donohue, P K; Spivak, J L; Jones, M D; Oski, F A

    1989-09-01

    There are no clear criteria for administration of blood to premature infants. In the past, indications for transfusion have included tachypnea, tachycardia, poor weight gain, apnea, bradycardia, pallor, lethargy, decreased activity, or poor feeding. Some have suggested that erythropoietin levels may also be useful in determining the need for transfusion. Data were studied from 11 premature infants with birth weights less than 1500 g collected throughout 469 hospital days. During that period the infants received a total of 37 blood transfusions. No overall relationship was found between hematocrit of 19% to 64% and heart rate, respiratory rate, or the occurrence of bradycardia; ie, these variables proved to be clinically unreliable as indicators of hematocrit. Furthermore, no predictable effect of transfusion could be identified on heart rate, respiratory rate, or on the incidence of apnea or bradycardia. It was anticipated that frequent episodes of apnea or bradycardia might increase serum erythropoietin concentration. To the contrary, more frequent bradycardia was associated with the low erythropoietin levels because those infants tended to receive transfusions for "symptomatic" anemia. The data are consistent with the concept that "anemia of prematurity" is not predictably associated with symptoms classically attributed to anemia. Possible reasons for this are that the premature infant has a different inherent response to anemia; that it is inappropriate to extrapolate symptoms of severe acute anemia to persons with mild or moderate chronic anemia; or, most likely, that other determinants of heart rate, respiratory rate, and apnea/bradycardia are of more importance than mild or moderate anemia.

  16. Comparison of real time RT-PCR and flow cytometry methods for evaluation of biological activity of recombinant human erythropoietin

    Directory of Open Access Journals (Sweden)

    Sepehrizadeh Z

    2008-05-01

    Full Text Available Background: Evaluation of bioactivity of recombinant erythropoietin is essential for pharmaceutical industry, quality control authorities and researchers. The purpose of this study was to compare real time RT-PCR and flow cytometry for the assay of biological activity of recombinant erythropoietin. Methods: Three concentrations of recombinant erythropoietin BRP (80, 40 and 20 IU/ml were injected subcutaneously to mice. After 4 days the blood was collected and used for reticulocyte counts by flow cytometry and also for the RNA extraction. Real time RT-PCR amplification was carried out for β-globin. Results and conclusion: There was a significant correlation between the total RNA amounts (R2= 0.9995, relative quantity of β-globin mRNA (R2= 0.984 and reticulocyte counts (R2= 0.9742 with rhEpo concentrations. Total RNA and quantitative RT-PCR showed significant dose dependent results as well the reticulocyte counts by flow cytometry for the biological activity assay of rhEpo and so these methods could be considered as alternatives for flow cytometry.

  17. Use of recombinant erythropoietin for the management of severe hemolytic disease of the newborn of a K0 phenotype mother.

    Science.gov (United States)

    Manoura, Antonia; Korakaki, Eftychia; Hatzidaki, Eleftheria; Saitakis, Emmanuel; Maraka, Sofia; Papamastoraki, Isabella; Matalliotakis, Emmanuel; Foundouli, Kaliopi; Giannakopoulou, Christine

    2007-01-01

    Very few people do not express any Kell antigens on their red blood cells (K0 phenotype). They can be immunized by transfusion or pregnancy and develop antibodies against Kell system antigens. These maternal antibodies can cause severe hemolytic disease of the fetus/newborn, as a result of the suppression of erythropoiesis and hemolysis. Multiple intrauterine transfusions in the management of severe hemolytic disease have been shown to cause erythropoietic suppression as well. Recombinant erythropoietin has been successfully used in the management of late anemia of infants with Rh hemolytic disease and in 1 case of KEL1 (Kell)-associated hemolytic disease. The authors present the case of severe hemolytic disease of a newborn due to KEL5 (Ku) isoimmunization of his K0 phenotype mother. Regular intrauterine transfusions were performed to manage the severe fetal anemia (Hb 3 g/dL). A male infant was born at the 36th week of gestation having normal hemoglobin (15.8 g/dL) and developed only mild hyperbilirubinemia. On the 15th day of life, the infant's hematocrit had fallen to 27.3%, with low reticulocyte count and low erythropoietin level. The infant was managed successfully with recombinant erythropoietin.

  18. EFFECT OF ERYTHROPOIETIN ON THE CLINICAL COURSE OF CHRONIC HEART FAILURE IN PATIENTS WITH ANEMIA: RESULTS OF NOT COMPARATIVE STUDY

    Directory of Open Access Journals (Sweden)

    V. M. Provotorov

    2011-01-01

    Full Text Available Aim. To study the clinical efficacy of corrective therapy of anemia in patients with chronic heart failure (CHF and ischemic heart disease (IHD. Material and methods. Patients (n=58; 32 female, 26 male; aged 47-85 years with IHD and CHF with left ventricular ejection fraction (LVEF <45% were included into the study. They received basic CHF therapy. Patients (n=12 with iron deficiency anemia also received erythropoietin and iron containing drugs during 12 weeks. Clinic and instrumental examination was performed before and after the treatment. Exercise tolerance was evaluated by 6-minute walk test. Results. The anemia was revealed in 14 (24.8% patients, including 12 patients with iron deficiency anemia. By the end of 12 week therapy with erythropoietin and iron containing drugs significant increase (+36% in 6-minute walk distance and LVEF (+32.5%, improvement of CHF NYHA functional class were observed. Besides increase in hemoglobin (+12.5%; p<0.001 and hematocrit (+5.8%; p<0.001 levels, as well as increase in red blood cells number (+8%; p<0.001 were found. Conclusion. In patients with CHF and IHD correction of anemia with erythropoietin and iron containing drugs additionally to the basic CHF/IHD therapy leads to a significant clinical and functional improvement.

  19. The effects of erythropoietin signaling on telomerase regulation in non-erythroid malignant and non-malignant cells

    Energy Technology Data Exchange (ETDEWEB)

    Uziel, Orit, E-mail: Oritu@clalit.org.il [Felsenstein Medical Research Center, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Kanfer, Gil [Felsenstein Medical Research Center, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Dep. of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Beery, Einat [Felsenstein Medical Research Center, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Yelin, Dana; Shepshelovich, Daniel [Medicine A, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Bakhanashvili, Mary [Unit of Infectious Diseases, Sheba Medical Center, Tel-Hashomer (Israel); Nordenberg, Jardena [Felsenstein Medical Research Center, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Dep. of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Endocrinology Laboratory, Beilinson Medical Center, Petah-Tikva (Israel); Lahav, Meir [Felsenstein Medical Research Center, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Medicine A, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel)

    2014-07-18

    Highlights: • We assumed that some of erythropoietin adverse effects may be mediated by telomerase activity. • EPO administration increased telomerase activity, cells proliferation and migration. • The inhibition of telomerase modestly repressed the proliferative effect of erythropoietin. • Telomere shortening caused by long term inhibition of the enzyme totally abolished that effect. • This effect was mediated via the Lyn–AKT axis and not by the canonical JAK2–STAT pathway. - Abstract: Treatment with erythropoietin (EPO) in several cancers is associated with decreased survival due to cancer progression. Due to the major importance of telomerase in cancer biology we hypothesized that some of these effects may be mediated through EPO effect on telomerase. For this aim we explored the possible effects of EPO on telomerase regulation, cell migration and chemosensitivity in non-erythroid malignant and non-malignant cells. Cell proliferation, telomerase activity (TA) and cell migration increased in response to EPO. EPO had no effect on cancer cells sensitivity to cisplatinum and on the cell cycle status. The inhibition of telomerase modestly repressed the proliferative effect of EPO. Telomere shortening caused by long term inhibition of the enzyme abolished the effect of EPO, suggesting that EPO effects on cancer cells are related to telomere dynamics. TA was correlated with the levels of Epo-R. The increase in TA was mediated post-translationally through the Lyn-Src and not the canonical JAK2 pathway.

  20. State-of-the-art biosimilar erythropoietins in the management of renal anemia: lessons learned from Europe and implications for US nephrologists.

    Science.gov (United States)

    Covic, Adrian; Abraham, Ivo

    2015-09-01

    The European Medicines Agency (EMA), under a strictly regulated pathway, has approved several biosimilar products since 2005, including biosimilar versions of the erythropoiesis-stimulating agent (ESA) epoetin alfa since 2007. Subsequent to these approvals, the use of biosimilar epoetin alfa in the management of renal anemia has grown steadily throughout Europe. With the enactment of the US Biologics Price Competition and Innovation Act of 2009, a US Food and Drug Administration regulatory approval process for biosimilars was legalized. Thus, biosimilar erythropoietin products are expected to be available for prescription in the USA by mid-decade, presumably at a price that is competitive with the originator brand-name reference products. In this paper, we describe the status of originator and biosimilar ESAs, review the clinical development and regulatory approval of biosimilar erythropoietins in Europe, and summarize relevant efficacy and safety information of biosimilar erythropoietins in relation to their reference products to provide a background for US nephrologists as they appraise biosimilar erythropoietins as treatment options for renal anemia. Key lessons learned from Europe are that (a) EMA-approved biosimilar erythropoietins have comparable efficacy and safety profiles to their reference product erythropoietin; (b) pharmacovigilance preapproval and postapproval are critical, especially with regard to immunogenicity and vascular thromboembolic events; (c) strict preapproval and postapproval requirements must guide the regulatory pathway for biosimilars; and (d) high-quality manufacturing and production processes must be established to ensure quality biosimilar products. The availability of biosimilar erythropoietins in the USA will provide nephrologists with alternative effective, and potentially more affordable, treatment options for patients with renal anemia.