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  1. Recombinant human erythropoietin pretreatment alleviates renal glomerular injury induced by cardiopulmonary bypass by reducing transient receptor potential channel 6-nuclear factor of activated T-cells pathway activation.

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    Liu, Xiaoming; Zhang, Tingting; Xia, Weiliang; Wang, Yingwei; Ma, Ke

    2013-09-01

    Acute renal injury after cardiopulmonary bypass is common and associated with high mortality. We aimed to demonstrate the glomerular protective effects of recombinant human erythropoietin using an in vivo rat cardiopulmonary bypass model and to explore the possible mechanism. Dose-related renal protective effects of recombinant human erythropoietin were studied in phase I. Male Sprague Dawley rats were randomly divided into 5 groups: sham group, cardiopulmonary bypass group, and 3 recombinant human erythropoietin-treated cardiopulmonary bypass groups (bolus doses of 500, 3000, and 5000 U/kg 24 hours before surgery). Blood and urine samples were collected just before surgery and at 2, 4, 24, 48, and 72 hours after surgery. In phase II, rats were divided into 3 groups: sham group, cardiopulmonary bypass group, and 5000 U/kg recombinant human erythropoietin group. Kidneys were harvested at 4, 24, 48, and 72 hours after surgery. Ultra-organization of glomeruli was observed. Glomerular transient receptor potential channel 6 (TRPC6) expression was studied by immunofluorescence and Western blot. Nuclei nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1) activity was analyzed by enzyme-linked immunosorbent assays and electrophoretic mobility shift assay. Pretreatment of 5000 U/kg recombinant human erythropoietin decreased the urine protein (72 hours: 7.82 ± 1.13 g/L vs 11.28 ± 1.73 g/L), serum creatinine (72 hours: 35.0 ± 3.5 μmol/L vs 60.7 ± 7.6 μmol/L), and cystatin-C (2 hours: 336.5 ± 28.2 μg/L vs 452.6 ± 63.8 μg/L) compared with the control group (P Cardiopulmonary bypass induced morphologic abnormalities of podocyte foot processes and slit diaphragms, which was improved by recombinant human erythropoietin. Furthermore, recombinant human erythropoietin significantly relieved glomerular TRPC6 increase and NFATc1 activation induced by cardiopulmonary bypass. Pretreatment of 5000 U/kg recombinant human erythropoietin elicited

  2. Erythropoietin

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    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...... models of acute and chronic neurodegenerative conditions and in patients with cognitive decline....

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

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    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.

  4. Does erythropoietin augment noise induced hearing loss?

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

    2007-01-01

    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......, rats were exposed to 105dB SPL, 4-20kHz WBN for 8h. EPO was administered by single dose middle ear instillation 1 or 14h after noise exposure. In trial 3, rats were exposed to 105dB SPL, 4-20kHz WBN for 8 or 3x8h. EPO was injected intraperitoneally 1h before noise exposure. Oto-acoustic emissions...... and auditory brainstem responses (at 16kHz) were recorded before and after noise exposure in all trials. The noise exposure induced a hearing loss in all animals. In trial 1, no recovery and no improvement of hearing occurred in any treatment group. In trial 2 and 3, a partial hearing recovery was seen...

  5. Role of NF-κB, PI3K, MAPK/ERK 1/2, and p38 in Erythropoietin Production by Bone Marrow Nuclears under Conditions of Immobilization Stress.

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    Miroshnichenko, L A; Zhdanov, V V; Udut, E V; Polyakova, T Yu; Zyuz'kov, G N; Simanina, E V; Sherstoboev, E Yu; Stavrova, L A; Agafonov, V I; Minakova, M Yu; Chaikovskii, A V; Dygai, A M

    2017-07-01

    The involvement of the studied signal cascades in the regulation of erythropoietin production by bone marrow nuclears under conditions of immobilization stress depends on the type of the hemopoiesis-inducing microenvironment cells and the period of blood system reaction to stress exposure. Secretory activity of monocytes is regulated mainly by PI3K improving cell resistance to disturbances. The functional role of signal cascades involved in the production of erythropoietin by T cells is determined by the stage of the common adaptation syndrome.

  6. Testosterone Induces Erythrocytosis via Increased Erythropoietin and Suppressed Hepcidin: Evidence for a New Erythropoietin/Hemoglobin Set Point

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    Travison, Thomas G.; Basaria, Shehzad; Davda, Maithili N.; Guo, Wen; Li, Michelle; Connor Westfall, John; Bae, Harold; Gordeuk, Victor; Bhasin, Shalender

    2014-01-01

    Background. The mechanisms by which testosterone increases hemoglobin and hematocrit remain unclear. Methods. We assessed the hormonal and hematologic responses to testosterone administration in a clinical trial in which older men with mobility limitation were randomized to either placebo or testosterone gel daily for 6 months. Results. The 7%–10% increase in hemoglobin and hematocrit, respectively, with testosterone administration was associated with significantly increased erythropoietin (EPO) levels and decreased ferritin and hepcidin levels at 1 and 3 months. At 6 months, EPO and hepcidin levels returned toward baseline in spite of continued testosterone administration, but EPO levels remained nonsuppressed even though elevated hemoglobin and hematocrit higher than at baseline, suggesting a new set point. Consistent with increased iron utilization, soluble transferrin receptor (sTR) levels and ratio of sTR/log ferritin increased significantly in testosterone-treated men. Hormonal and hematologic responses were similar in anemic participants. The majority of testosterone-treated anemic participants increased their hemoglobin into normal range. Conclusions. Testosterone-induced increase in hemoglobin and hematocrit is associated with stimulation of EPO and reduced ferritin and hepcidin concentrations. We propose that testosterone stimulates erythropoiesis by stimulating EPO and recalibrating the set point of EPO in relation to hemoglobin and by increasing iron utilization for erythropoiesis. PMID:24158761

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

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    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. Protective effects of erythropoietin against cuprizone-induced oxidative stress and demyelination in the mouse corpus callosum

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    Iraj Ragerdi Kashani

    2017-08-01

    Full Text Available Objective(s: Increasing evidence in both experimental and clinical studies suggests that oxidative stress plays a major role in the pathogenesis of multiple sclerosis. The aim of the present work is to investigate the protective effects of erythropoietin against cuprizone-induced oxidative stress. Materials and Methods: Adult male C57BL/6J mice were fed a chow containing 0.2 % cuprizone for 6 weeks. After 3 weeks, mice were simultaneously treated with erythropoietin (5,000 IU/ kg body weight by daily intraperitoneal injections. Results: Our results showed that cuprizone induced oxidative stress accompanied with down-regulation of subunits of the respiratory chain complex and demyelination of corpus callosum. Erythropoietin antagonized these effects. Biochemical analysis showed that oxidative stress induced by cuprizone was regulated by erythropoietin. Similarly, erythropoietin induced the expression of subunits of the respiratory chain complex over normal control values reflecting a mechanism to compensate cuprizone-mediated down-regulation of these genes. Conclusion: The data implicate that erythropoietin abolishes destructive cuprizone effects in the corpus callosum by decreasing oxidative stress and restoring mitochondrial respiratory enzyme activity.

  9. Activating mitochondrial function and haemoglobin expression with EH-201, an inducer of erythropoietin in neuronal cells, reverses memory impairment.

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    Horng, Lin-Yea; Hsu, Pei-Lun; Chen, Li-Wen; Tseng, Wang-Zou; Hsu, Kai-Tin; Wu, Chia-Ling; Wu, Rong-Tsun

    2015-10-01

    Memory impairment can be progressive in neurodegenerative diseases, and physiological ageing or brain injury, mitochondrial dysfunction and oxidative stress are critical components of these issues. An early clinical study has demonstrated cognitive improvement during erythropoietin treatment in patients with chronic renal failure. As erythropoietin cannot freely cross the blood-brain barrier, we tested EH-201 (2,3,5,4'-tetrahydroxystilbene-2-O-β-d-glucoside, also known as TSG), a low MW inducer of erythropoietin, for its therapeutic effects on memory impairment in models of neurodegenerative diseases, physiological ageing or brain injury. The effects of EH-201 were investigated in astrocytes and PC12 neuronal-like cells. In vivo, we used sleep-deprived (SD) mice as a stress model, amyloid-β (Aβ)-injected mice as a physiological ageing model and kainic acid (KA)-injected mice as a brain damage model to assess the therapeutic effects of EH-201. EH-201 induced expression of erythropoietin, PPAR-γ coactivator 1α (PGC-1α) and haemoglobin in astrocytes and PC12 neuronal-like cells. In vivo, EH-201 treatment restored memory impairment, as assessed by the passive avoidance test, in SD, Aβ and KA mouse models. In the hippocampus of mice given EH-201 in their diet, levels of erythropoietin, PGC-1α and haemoglobin were increased The induction of endogenous erythropoietin in neuronal cells by inducers such as EH-201 might be a therapeutic strategy for memory impairment in neurodegenerative disease, physiological ageing or traumatic brain injury. © 2015 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.

  10. Erythropoietin protects newborn rat against sevoflurane-induced neurotoxicity.

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    Pellegrini, Lionel; Bennis, Youssef; Velly, Lionel; Grandvuillemin, Isabelle; Pisano, Pascale; Bruder, Nicolas; Guillet, Benjamin

    2014-07-01

    Recent data on newborn animals exposed to anesthetics have raised safety concerns regarding anesthesia practices in young children. Indeed, studies on rodents have demonstrated a widespread increase in brain apoptosis shortly after exposure to sevoflurane, followed by long-term neurologic impairment. In this context, we aimed to evaluate the protective effect of rh-EPO, a potent neuroprotective agent, in rat pups exposed to sevoflurane. At postnatal day 7, 75 rat pups were allocated into three groups: SEVO + EPO (n = 27) exposed to sevoflurane 2 vol% (0.5 MAC) for 6 h in an air/O2 mixture (60/40) + 5000 UI.kg(-1) rh-EPO IP; SEVO (n = 27) exposed to sevoflurane + vehicle IP; and CONTROL (n = 21) exposed to the mixture without sevoflurane + vehicle IP. Three days after anesthesia (D10), apoptosis was quantified on brain extract with TUNEL method and caspase 3. NGF and BDNF expression was determined by Western blotting. Rats reaching adulthood were evaluated in terms of exploration capacities (object exploration duration) together with spatial and object learning (water maze and novel object test). Sevoflurane exposure impaired normal behavior in adult rats by reducing the exploratory capacities during the novel object test and impaired both spatial and object learning capacities in adult rats (water maze, ratio time to find platform 3rd trial/1st trial: 1.1 ± 0.2 vs 0.4 ± 0.1; n = 9, SEVO vs CONTROL; P = 0.01). Rh-EPO reduced sevoflurane-induced behavior and learning abnormalities in adult rats (water maze, ratio time to find platform 3rd trial/1st trial: 0.3 ± 0.1 vs 1.1 ± 0.2; n = 9, SEVO + EPO vs SEVO; P = 0.01). Three days after anesthesia, rh-EPO prevented sevoflurane-induced brain apoptosis (5 ± 3 vs 35 ± 6 apoptotic cells·mm(-2) ; n = 6, SEVO + EPO vs SEVO; P = 0.01) and elevation of caspase three level and significantly increased the brain expression of BDNF and NGF (n = 6, SEVO + EPO vs SEVO; P = 0.01). Six hours of sevoflurane anesthesia in newborn

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

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    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 ...... 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.......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...... in a human in vivo model of acute systemic low-grade inflammation, we measured circulating inflammatory mediators after intravenous administration of Escherichia coli endotoxin (LPS) bolus injection (0.1 ng/kg of body weight) in young healthy male subjects. The subjects were divided into three groups...

  12. Post-treatment Effects of Erythropoietin and Nordihydroguaiaretic Acid on Recovery from Cisplatin-induced Acute Renal Failure in the Rat

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    Lee, Dong Won; Kwak, Ihm Soo; Lee, Soo Bong; Song, Sang Heon; Seong, Eun Young; Yang, Byeong Yun; Lee, Min Young; SOL, MEE YOUNG

    2009-01-01

    5-Lipoxygenase inhibitor and human recombinant erythropoietin might accelerate renal recovery in cisplatin-induced acute renal failure rats. Male Sprague-Dawley rats were randomized into four groups: 1) normal controls; 2) Cisplatin group-cisplatin induced acute renal failure (ARF) plus vehicle treatment; 3) Cisplatin+nordihydroguaiaretic acid (NDGA) group-cisplatin induced ARF plus 5-lipoxygenase inhibitor treatment; 4) Cisplatin+erythropoietin (EPO) group-cisplatin induced ARF plus erythrop...

  13. Nitric oxide prevents axonal degeneration by inducing HIF-1-dependent expression of erythropoietin.

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    Keswani, Sanjay C; Bosch-Marcé, Marta; Reed, Nicole; Fischer, Angela; Semenza, Gregg L; Höke, Ahmet

    2011-03-22

    Nitric oxide (NO) is a signaling molecule that can trigger adaptive (physiological) or maladaptive (pathological) responses to stress stimuli in a context-dependent manner. We have previously reported that NO may signal axonal injury to neighboring glial cells. In this study, we show that mice deficient in neuronal nitric oxide synthase (nNOS-/-) are more vulnerable than WT mice to toxin-induced peripheral neuropathy. The administration of NO donors to primary dorsal root ganglion cultures prevents axonal degeneration induced by acrylamide in a dose-dependent manner. We demonstrate that NO-induced axonal protection is dependent on hypoxia-inducible factor (HIF)-1-mediated transcription of erythropoietin (EPO) within glial (Schwann) cells present in the cultures. Transduction of Schwann cells with adenovirus AdCA5 encoding a constitutively active form of HIF-1α results in amelioration of acrylamide-induced axonal degeneration in an EPO-dependent manner. Mice that are partially deficient in HIF-1α (HIF-1α+/-) are also more susceptible than WT littermates to toxic neuropathy. Our results indicate that NO→HIF-1→EPO signaling represents an adaptive mechanism that protects against axonal degeneration.

  14. Protective effect of erythropoietin on renal injury induced in rats by four weeks of exhaustive exercise.

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    Lin, Xixiu; Jiang, Chonghe; Luo, Ziqiang; Qu, Shulin

    2013-06-24

    The protective effect of Erythropoietin (EPO) analogue rHuEPO on acute renal injury induced by exhaustive exercise had been reported. The purpose of this study is to probe into the protective effect of EPO on chronic renal injury induced by repeated exhaustive exercise for four weeks. Eighty adult male Sprague-Dawley rats were used in this experiment. The animals were randomly allocated to one of four groups: control (C), exhaustive exercise test (ET), ET plus EPO pre-treatement (ET+EPO) and ET+EPO plus LY294002 pretreatment (ET+EPO+LY). Compared with the rats in control group, there was considerable damage in kidney cells in rats of ET group as revealed by histological and ultrastructural examinations. However, treatment with EPO during the training, the exhaustive running distance was significant increased (P protective effect of EPO on chronic renal injury induced by repeated exhaustive exercise was demonstrated in the present study. We proposed that the effect could be due to inhibiting the cell apoptosis and blocking the formation of interstitial fibrosis via activation of the PI3K/Akt pathway, thus plays role in the endogenous protection of the kidney injury.

  15. Erythropoietin protects the in vitro blood-brain barrier against VEGF-induced permeability.

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    Martínez-Estrada, Ofelia María; Rodríguez-Millán, Elisabeth; González-De Vicente, Esther; Reina, Manuel; Vilaró, Senén; Fabre, Myriam

    2003-11-01

    The blood-brain barrier (BBB) ensures the homeostasis of the brain microenvironment, mostly through complex tight junctions between brain endothelial cells that prevent the passage of hydrophilic molecules from blood to brain and vice versa. A recent study has shown in vivo that systemic administration of erythropoietin (Epo) protects against brain injury. Using an in vitro model of the bovine BBB, we observed that the expression of the Epo receptor is modulated by its ligand and hypoxic stimuli such as vascular endothelial growth factor (VEGF) treatment. In addition, Epo protects against the VEGF-induced permeability of the BBB, decreases the levels of endothelial nitric oxide synthase and restores junction proteins. The kinetic transport experiments revealed the capacity of Epo to cross the in vitro BBB in a saturable and specific way. Our results suggest a new mechanism for Epo-induced neuroprotection, in which circulating Epo controls and maintains the BBB through an Epo receptor signalling pathway and the re-establishment of cell junctions.

  16. Long-term cadmium exposure induces anemia in rats through hypoinduction of erythropoietin in the kidneys

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    Horiguchi, Hyogo [Department of Public Health, Fukushima Medical College, Fukushima (Japan); Sato, Masao [Department of Biomolecular Sciences, Institute of Biomedical Sciences, Fukushima Medical College, Fukushima (Japan); Konno, Nobuhiro [Department of Public Health, Fukushima Medical College, Fukushima (Japan); Fukushima, Masaaki [Department of Public Health, Fukushima Medical College, Fukushima (Japan)

    1996-11-01

    Cadmium (Cd), a highly toxic heavy metal, is distributed widely in the general environment of today. The characteristic clinical manifestations of chronic Cd intoxication include renal proximal tubular dysfunction, general osteomalacia with severe pains, and anemia. We have recently reported that the serum level of erythropoietin (EPO) remained low despite the severe anemia in patients with Itai-itai disease, the most severe form of chronic Cd intoxication. In order to prove that the anemia observed in chronic Cd intoxication arises from low production of EPO in the kidneys following the renal injury, we administered Cd to rats for a long period and performed the analysis of EPO mRNA inducibility in the kidneys. The rats administered Cd for 6 and 9 months showed anemia with low levels of plasma EPO as well as biochemical and histological renal tubular damage, and also hypoinduction of EPO mRNA in the kidneys. The results indicate that chronic Cd intoxication causes anemia by disturbing the EPO-production capacity of renal cells. (orig.). With 4 figs., 4 tabs.

  17. The Effects of Erythropoietin Dose Titration during High-Fat Diet-Induced Obesity

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    Amanda Foskett

    2011-01-01

    Full Text Available Erythropoietin (Epo is a pleotropic cytokine with several nonhematopoietic tissue effects. High-dose Epo treatment-mediated effects on body weight, fat mass and glucose tolerance have recently been reported, thus extending its pleotropic effects to fat and glucose metabolism. However, the exact dose range of Epo treatment required for such effects remains unidentified to date. We investigated Epo dosage effect (up to 1000 U/kg on hematocrit, body weight, body composition, glucose metabolism, food intake, and physical activity, during high-fat diet-induced obesity. We report that Epo doses (1000, 600, 300, and 150 U/kg significantly reduced body weight gain and fat mass, while, only Epo doses of 300 U/kg and higher significantly affected glucose tolerance. None of the tested Epo doses showed any detectable effects on food intake, and only 1000 U/kg dose significantly increased physical activity, suggesting that these parameters may only be partially responsible for the metabolic effects of Epo treatment.

  18. The effects of erythropoietin dose titration during high-fat diet-induced obesity.

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    Foskett, Amanda; Alnaeeli, Mawadda; Wang, Li; Teng, Ruifeng; Noguchi, Constance T

    2011-01-01

    Erythropoietin (Epo) is a pleotropic cytokine with several nonhematopoietic tissue effects. High-dose Epo treatment-mediated effects on body weight, fat mass and glucose tolerance have recently been reported, thus extending its pleotropic effects to fat and glucose metabolism. However, the exact dose range of Epo treatment required for such effects remains unidentified to date. We investigated Epo dosage effect (up to 1000 U/kg) on hematocrit, body weight, body composition, glucose metabolism, food intake, and physical activity, during high-fat diet-induced obesity. We report that Epo doses (1000, 600, 300, and 150 U/kg) significantly reduced body weight gain and fat mass, while, only Epo doses of 300 U/kg and higher significantly affected glucose tolerance. None of the tested Epo doses showed any detectable effects on food intake, and only 1000 U/kg dose significantly increased physical activity, suggesting that these parameters may only be partially responsible for the metabolic effects of Epo treatment.

  19. Erythropoietin as an adjunctive treatment for methanol-induced toxic optic neuropathy.

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    Pakravan, Mohammad; Esfandiari, Hamed; Sanjari, Nasrin; Ghahari, Elham

    2016-11-01

    Methanol-induced optic neuropathy (MTON) is frequently seen in countries where alcohol consumption is banned or poorly regulated. MTON frequently results in blindness and there is no empirically validated treatment. To evaluate the effect of erythropoietin (EPO) as an adjunctive treatment for MTON. In this nonrandomized interventional comparative study, all participants were diagnosed with MTON and received the steroid methylprednisolone. Eleven participants received intravenous EPO (10000 IU twice a day) for three days as an adjuvant to methylprednisolone (EPO group); 11 participants in a historical control group received methylprednisolone only (control group). Main outcomes were best-corrected visual acuity (BCVA), peripapillary retinal nerve fiber layer thickness (PRNFLT), and visual field mean deviation (MD). Mean BCVA improved significantly in both groups: from 2.93 ± 0.55 to 1.75 ± 1.16 LogMAR at month 3 (p < 0.001) in the EPO group, and from 2.65 ± 0.68 to 2.19 ± 0.75 at final visit in the control group (p = 0.001). The final BCVA was significantly better in the EPO group (p = 0.012). The mean PRNFLT decreased in both groups. However, at the final follow-up, PRNFLT was significantly thinner in the control group (53 ± 6 vs. 77 ± 26 microns, respectively; p < 0.001). Intravenous EPO plus high-dose intravenous steroid may be an effective combination therapy for the patients with MTON.

  20. The extract of Ziziphus jujuba fruit (jujube) induces expression of erythropoietin via hypoxia-inducible factor-1α in cultured Hep3B cells.

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    Chen, Jianping; Lam, Candy T W; Kong, Ava Y Y; Zhang, Wendy L; Zhan, Janis Y X; Bi, Cathy W C; Chan, Gallant K L; Lam, Kelly Y C; Yao, Ping; Dong, Tina T X; Tsim, Karl W K

    2014-11-01

    The fruit of Ziziphus jujuba Mill., known as jujube or Chinese date, is commonly consumed as health supplement or herbal medicine worldwide. To study the beneficial role of jujube in enhancing hematopoietic function, we investigated its roles on the expression of erythropoietin in cultured Hep3B human hepatocellular carcinoma cells. Application of chemically standardized jujube water extract stimulated erythropoietin expression in a dose-dependent manner, with the highest response by ~ 100 % of increase. A plasmid containing hypoxia response element, a critical regulator for erythropoietin transcription, was transfected into Hep3B cells. Application of jujube water extract onto the transfected cells induced the transcriptional activity of the hypoxia response element. To account for its transcriptional activation, the expression of hypoxia-inducible factor-1α was increased after treatment with jujube water extract: the increase was in both mRNA and protein levels. These results confirmed the hematopoietic function of jujube in the regulation of erythropoietin expression in liver cells. Georg Thieme Verlag KG Stuttgart · New York.

  1. Erythropoietin during hypoglycaemia in type 1 diabetes

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    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...

  2. Lenalidomide induces lipid raft assembly to enhance erythropoietin receptor signaling in myelodysplastic syndrome progenitors.

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    Kathy L McGraw

    Full Text Available Anemia remains the principal management challenge for patients with lower risk Myelodysplastic Syndromes (MDS. Despite appropriate cytokine production and cellular receptor display, erythropoietin receptor (EpoR signaling is impaired. We reported that EpoR signaling is dependent upon receptor localization within lipid raft microdomains, and that disruption of raft integrity abolishes signaling capacity. Here, we show that MDS erythroid progenitors display markedly diminished raft assembly and smaller raft aggregates compared to normal controls (p = 0.005, raft number; p = 0.023, raft size. Because lenalidomide triggers raft coalescence in T-lymphocytes promoting immune synapse formation, we assessed effects of lenalidomide on raft assembly in MDS erythroid precursors and UT7 cells. Lenalidomide treatment rapidly induced lipid raft formation accompanied by EpoR recruitment into raft fractions together with STAT5, JAK2, and Lyn kinase. The JAK2 phosphatase, CD45, a key negative regulator of EpoR signaling, was displaced from raft fractions. Lenalidomide treatment prior to Epo stimulation enhanced both JAK2 and STAT5 phosphorylation in UT7 and primary MDS erythroid progenitors, accompanied by increased STAT5 DNA binding in UT7 cells, and increased erythroid colony forming capacity in both UT7 and primary cells. Raft induction was associated with F-actin polymerization, which was blocked by Rho kinase inhibition. These data indicate that deficient raft integrity impairs EpoR signaling, and provides a novel strategy to enhance EpoR signal fidelity in non-del(5q MDS.

  3. Aconitase regulation of erythropoiesis correlates with a novel licensing function in erythropoietin-induced ERK signaling.

    Directory of Open Access Journals (Sweden)

    Anne-Laure Talbot

    Full Text Available BACKGROUND: Erythroid development requires the action of erythropoietin (EPO on committed progenitors to match red cell output to demand. In this process, iron acts as a critical cofactor, with iron deficiency blunting EPO-responsiveness of erythroid progenitors. Aconitase enzymes have recently been identified as possible signal integration elements that couple erythropoiesis with iron availability. In the current study, a regulatory role for aconitase during erythropoiesis was ascertained using a direct inhibitory strategy. METHODOLOGY/PRINCIPAL FINDINGS: In C57BL/6 mice, infusion of an aconitase active-site inhibitor caused a hypoplastic anemia and suppressed responsiveness to hemolytic challenge. In a murine model of polycythemia vera, aconitase inhibition rapidly normalized red cell counts, but did not perturb other lineages. In primary erythroid progenitor cultures, aconitase inhibition impaired proliferation and maturation but had no effect on viability or ATP levels. This inhibition correlated with a blockade in EPO signal transmission specifically via ERK, with preservation of JAK2-STAT5 and Akt activation. Correspondingly, a physical interaction between ERK and mitochondrial aconitase was identified and found to be sensitive to aconitase inhibition. CONCLUSIONS/SIGNIFICANCE: Direct aconitase inhibition interferes with erythropoiesis in vivo and in vitro, confirming a lineage-selective regulatory role involving its enzymatic activity. This inhibition spares metabolic function but impedes EPO-induced ERK signaling and disturbs a newly identified ERK-aconitase physical interaction. We propose a model in which aconitase functions as a licensing factor in ERK-dependent proliferation and differentiation, thereby providing a regulatory input for iron in EPO-dependent erythropoiesis. Directly targeting aconitase may provide an alternative to phlebotomy in the treatment of polycythemia vera.

  4. Expression of hypoxia-inducible factor-1α and erythropoietin at corneal neovascularization in rats

    Directory of Open Access Journals (Sweden)

    Ji-Min Wang

    2014-12-01

    Full Text Available AIM: To describe the expression of hypoxia-inducible factor-1α(HIF-1αand erythropoietin(EPOin rats' corneal and evaluate its potential effect on corneal neovascularization(CNVgrowth. METHODS: The young SD rats(3mowas chosen and randomly divided into 2 groups, which were experimental group and normal control group. CNV model was established by alkali burn, and the length and area of CNV was observed everyday after operation by slit lamp. After that, the expression of HIF-1α and EPO was measured by SABC and RT-PCR methods at 1, 3, 5, 7, and 14d after alkali burn. The data was analyzed by SPSS 20.0. RESULTS: The area of CNV was increasing at 1, 3, 5, 7, and 14d after alkali burn, and the peak point appear at 7d. The growth speed was decreased after 14d. SABC method told us that no HIF-1α and very tiny amount EPO was detected at normal rats' corneal. The expression of the two factors increased at 1d after alkali burn in corneal epithelium and endoderm. The results of RT-PCR showed that a few amounts of HIF-1α and EPO mRNA were detected at normal group. The expression of the two factors was increased at 3d after alkali burn, and the peak value was found at 7d, however, it was decreased at 14d. Statistical difference was found at different time(PCONCLUSION: HIF-1α and EPO is closely related to CNV.

  5. 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...

  6. Erythropoietin Restores Long-Term Neurocognitive Function Involving Mechanisms of Neuronal Plasticity in a Model of Hyperoxia-Induced Preterm Brain Injury

    Directory of Open Access Journals (Sweden)

    Daniela Hoeber

    2016-01-01

    Full Text Available Cerebral white and grey matter injury is the leading cause of an adverse neurodevelopmental outcome in prematurely born infants. High oxygen concentrations have been shown to contribute to the pathogenesis of neonatal brain damage. Here, we focused on motor-cognitive outcome up to the adolescent and adult age in an experimental model of preterm brain injury. In search of the putative mechanisms of action we evaluated oligodendrocyte degeneration, myelination, and modulation of synaptic plasticity-related molecules. A single dose of erythropoietin (20,000 IU/kg at the onset of hyperoxia (24 hours, 80% oxygen in 6-day-old Wistar rats improved long-lasting neurocognitive development up to the adolescent and adult stage. Analysis of white matter structures revealed a reduction of acute oligodendrocyte degeneration. However, erythropoietin did not influence hypomyelination occurring a few days after injury or long-term microstructural white matter abnormalities detected in adult animals. Erythropoietin administration reverted hyperoxia-induced reduction of neuronal plasticity-related mRNA expression up to four months after injury. Thus, our findings highlight the importance of erythropoietin as a neuroregenerative treatment option in neonatal brain injury, leading to improved memory function in adolescent and adult rats which may be linked to increased neuronal network connectivity.

  7. Pure red cell aplasia induced by anti-erythropoietin antibodies, well-controlled with tacrolimus.

    Science.gov (United States)

    Hashimoto, Koji; Harada, Makoto; Kamijo, Yuji

    2016-10-01

    Anti-erythropoietin (anti-EPO) antibody-related pure red cell aplasia (PRCA) is a rare but serious complication that can occur during the administration of erythropoiesis-stimulating agents. Treatment with the calcineurin inhibitor cyclosporine has shown benefits in patients with anti-EPO PRCA. The efficacy of tacrolimus, another calcineurin inhibitor, in patients with anti-EPO PRCA has not been determined. The present report is the first our knowledge to describe the successful treatment of a patient with anti-EPO PRCA using tacrolimus. A 73-year-old man was markedly anemic 8 months after starting epoetin beta treatment. He was diagnosed with anti-EPO PRCA. Cyclosporine was started, but he experienced side effects. He was switched from cyclosporine to tacrolimus. No side effects were observed, and his anti-EPO PRCA was improved 6 months later, despite the persistence of anti-EPO antibodies. Tacrolimus was continued until the disappearance of the antibodies. Following the cessation of tacrolimus, PRCA did not relapse. Antibody remained detectable at the time of clinical remission, indicating that immunosuppressive therapy should be continued while monitoring the antibody titer. When the antibody titer decreases to the negative range, cessation of the immunosuppressive therapy does not result in disease relapse.

  8. Polycythemia in transgenic mice expressing the human erythropoietin gene

    Energy Technology Data Exchange (ETDEWEB)

    Semenza, G.L.; Traystman, M.D.; Gearhart, J.D.; Antonarakis, S.E. (Johns Hopkins Univ. School of Medicine, Baltimore, MD (USA))

    1989-04-01

    Erythropoietin is a glycoprotein hormone that regulates mammalian erythropoiesis. To study the expression of the human erythropoietin gene, EPO, 4 kilobases of DNA encompassing the gene with 0.4 kilobase of 5{prime} flanking sequence and 0.7 kilobase of 3{prime} flanking sequence was microinjected into fertilized mouse eggs. Transgenic mice were generated that are polycythemic, with increased erythrocytic indices in peripheral blood, increased numbers of erythroid precursors in hematopoietic tissue, and increased serum erythropoietin levels. Transgenic homozygotes show a greater degree of polycythemia than do heterozygotes as well as striking extramedullary erythropoiesis. Human erythropoietin RNA was found not only in fetal liver, adult liver, and kidney but also in all other transgenic tissues analyzed. Anemia induced increased human erythropoietin RNA levels in liver but not kidney. These transgenic mice represent a unique model of polycythemia due to increased erythropoietin levels.

  9. Erythropoietin promotes oligodendrogenesis and myelin repair following lysolecithin-induced injury in spinal cord slice culture

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Yun Kyung; Kim, Gunha; Park, Serah; Sim, Ju Hee; Won, You Jin [Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736 (Korea, Republic of); Hwang, Chang Ho [Department of Physical Medicine and Rehabilitation, Ulsan University Hospital, University of Ulsan College of Medicine, 290-3 Jeonha-dong, Dong-gu, Ulsan 682-714 (Korea, Republic of); Yoo, Jong Yoon, E-mail: jyyoo@amc.seoul.kr [Department of Rehabilitation Medicine, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736 (Korea, Republic of); Hong, Hea Nam, E-mail: hnhong@amc.seoul.kr [Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736 (Korea, Republic of)

    2012-01-13

    Highlights: Black-Right-Pointing-Pointer Lysolecithin-induced demyelination elevated EpoR expression in OPCs. Black-Right-Pointing-Pointer In association with elevated EpoR, EPO increased OPCs proliferation. Black-Right-Pointing-Pointer EPO enhanced the oligodendrogenesis via activation of JAK2 pathway. Black-Right-Pointing-Pointer EPO promoted myelin repair following lysolecithin-induced demyelination. -- Abstract: Here, we sought to delineate the effect of EPO on the remyelination processes using an in vitro model of demyelination. We report that lysolecithin-induced demyelination elevated EPO receptor (EpoR) expression in oligodendrocyte progenitor cells (OPCs), facilitating the beneficial effect of EPO on the formation of oligodendrocytes (oligodendrogenesis). In the absence of EPO, the resultant remyelination was insufficient, possibly due to a limiting number of oligodendrocytes rather than their progenitors, which proliferate in response to lysolecithin-induced injury. By EPO treatment, lysolecithin-induced proliferation of OPCs was accelerated and the number of myelinating oligodendrocytes and myelin recovery was increased. EPO also enhanced the differentiation of neural progenitor cells expressing EpoR at high level toward the oligodendrocyte-lineage cells through activation of cyclin E and Janus kinase 2 pathways. Induction of myelin-forming oligodendrocytes by high dose of EPO implies that EPO might be the key factor influencing the final differentiation of OPCs. Taken together, our data suggest that EPO treatment could be an effective way to enhance remyelination by promoting oligodendrogenesis in association with elevated EpoR expression in spinal cord slice culture after lysolecithin-induced demyelination.

  10. 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.

  11. Captopril Modulates Hypoxia-Inducible Factors and Erythropoietin Responses in a Murine Model of Total Body Irradiation

    Science.gov (United States)

    2011-01-01

    erythroid cell loss/imbalance and erythroid demand with captopril- treatment. ACE inhibitors are being used extensively for treatment of breast cancer ...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...ers KE. Synergistic effects of co-administration of angiotensin 1-7 and Neupogen on hematopoietic recovery in mice. Cancer Chemother Pharmacol

  12. 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.

  13. Laser induced nuclear waste transmutation

    CERN Document Server

    Hirlimann, Charles

    2016-01-01

    When producing electricity that collects the mass energy that is available at the time of the induced disintegration of radioactive elements, other unstable elements are produced with half-life span durations ranging from less than one second to hundreds of thousands of years and which are considered as waste. Managing nuclear waste with a half-life of less than 30 years is an easy task, as our societies clearly know how to keep buildings safe for more than a century, the time it takes for the activity to be divided by a factor of 8. High-activity, long-lasting waste that can last for thousands of years or even longer, up to geological time laps, cannot be taken care of for such long durations. Therefore, these types of waste are socially unacceptable; nobody wants to leave a polluted planet to descendants.

  14. Erythropoietin increases bioavailability of tetrahydrobiopterin and protects cerebral microvasculature against oxidative stress induced by eNOS uncoupling.

    Science.gov (United States)

    Santhanam, Anantha Vijay R; d'Uscio, Livius V; Katusic, Zvonimir S

    2014-11-01

    This study was designed to determine whether treatment with erythropoietin (EPO) could protect cerebral microvasculature against the pathological consequences of endothelial nitric oxide (NO) synthase uncoupling. Wild-type and GTP cyclohydrolase I (GTPCH-I)-deficient hph1 mice were administered EPO (1000 U/kg/day, s.c., 3 days). Cerebral microvessels of hph1 mice demonstrated reduced tetrahydrobiopterin (BH4) bioavailability, increased production of superoxide anions and impaired endothelial NO signaling. Treatment of hph1 mice with EPO attenuated the levels of 7,8-dihydrobiopterin, the oxidized product of BH4, and significantly increased the ratio of BH4 to 7,8-dihydrobiopterin. Moreover, EPO decreased the levels of superoxide anions and increased NO bioavailability in cerebral microvessels of hph1 mice. Attenuated oxidation of BH4 and inhibition of endothelial NO synthase uncoupling were explained by the increased expression of antioxidant proteins, manganese superoxide dismutase, and catalase. The protective effects of EPO observed in cerebral microvessels of hph1 mice were also observed in GTPCH-I siRNA-treated human brain microvascular endothelial cells exposed to EPO (1 U/mL or 10 U/mL; 3 days). Our results suggest that EPO might protect the neurovascular unit against oxidative stress by restoring bioavailability of BH4 and endothelial NO in the cerebral microvascular endothelium. We demonstrate that treatment with erythropoietin (EPO) could protect cerebral microvasculature against the pathological consequences of endothelial nitric oxide (NO) synthase uncoupling. Our results suggest that EPO might protect the neurovascular unit against oxidative stress by restoring bioavailability of tetrahydrobiopterin (BH4) and endothelial nitric oxide. © 2014 International Society for Neurochemistry.

  15. 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

    , 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...... attenuated seizures, decreased mortality and reduced neurodegeneration in an in vivo model of kainic acid-induced neurotoxicity. In contrast to erythropoietin, Epotris did not stimulate erythropoiesis upon chronic administration. Thus, Epotris is a novel neuroprotective non-haematopoietic erythropoietin...

  16. Erythropoietin (EPO) ameliorates obesity and glucose homeostasis by promoting thermogenesis and endocrine function of classical brown adipose tissue (BAT) in diet-induced obese mice.

    Science.gov (United States)

    Kodo, Kazuki; Sugimoto, Satoru; Nakajima, Hisakazu; Mori, Jun; Itoh, Ikuyo; Fukuhara, Shota; Shigehara, Keiichi; Nishikawa, Taichiro; Kosaka, Kitaro; Hosoi, Hajime

    2017-01-01

    Erythropoietin (EPO), clinically used as a hematopoietic drug, has received much attention due to its nonhematopoietic effects. EPO reportedly has beneficial effects on obesity and diabetes mellitus. We investigated whether interscapular brown adipose tissue (iBAT: main part of classical BAT) could play a role in EPO's anti-obesity and anti-diabetic effects in diet-induced obese mice. Four-week-old male C57BL/6J mice were fed a high-fat diet (HFD-Con), and half were additionally given an intraperitoneal injection of recombinant human EPO (200 IU/kg) (HFD-EPO) thrice a week for four weeks. At 8 weeks, EPO-injected mice showed significantly reduced body weight with reduced epididymal and subcutaneous white fat mass and unchanged caloric intake and locomotor activity. HOMA-IR (insulin resistance index) and glucose levels during intraperitoneal glucose tolerance test (IPGTT) were significantly lower in HFD-EPO mice than in HFD-Con mice. EPO-injected mice also showed increased oxygen consumption, indicative of metabolic rate, and skin temperature around iBAT tissue masses. EPO significantly upregulated the PRD1-BF1-RIZ1 homologous domain containing 16 (PRDM16), a transcriptional factor with a crucial role in brown adipocyte differentiation. EPO significantly increased phosphorylated signal transducer and activator of transcription 3 (STAT3), which is downstream of erythropoietin receptor (EpoR) and known to stabilize PRDM16. EPO's suppression of myocyte enhancer factor 2c (Mef2c) and microRNA-133a (miR-133a) via β3-adrenergic receptor caused PRDM16 upregulation. EPO-mediated enhancement of EpoR/STAT3 and β-adrenergic receptor/Mef2c/miR-133 pathways dramatically increases total uncoupling protein 1 (UCP1), an essential enzyme for BAT thermogenesis. Furthermore, EPO activated BAT's endocrine functions. EPO facilitated fibroblast growth factor 21 (FGF21) production and excretion in iBAT, associated with reduction of liver gluconeogenesis-related genes. Thus, EPO

  17. The use of laser-induced fluorescence or ultraviolet detectors for sensitive and selective analysis of tobramycin or erythropoietin in complex samples

    Science.gov (United States)

    Ahmed, Hytham M.; Ebeid, Wael B.

    2015-05-01

    Complex samples analysis is a challenge in pharmaceutical and biopharmaceutical analysis. In this work, tobramycin (TOB) analysis in human urine samples and recombinant human erythropoietin (rhEPO) analysis in the presence of similar protein were selected as representative examples of such samples analysis. Assays of TOB in urine samples are difficult because of poor detectability. Therefore laser induced fluorescence detector (LIF) was combined with a separation technique, micellar electrokinetic chromatography (MEKC), to determine TOB through derivatization with fluorescein isothiocyanate (FITC). Borate was used as background electrolyte (BGE) with negative-charged mixed micelles as additive. The method was successively applied to urine samples. The LOD and LOQ for Tobramycin in urine were 90 and 200 ng/ml respectively and recovery was >98% (n = 5). All urine samples were analyzed by direct injection without sample pre-treatment. Another use of hyphenated analytical technique, capillary zone electrophoresis (CZE) connected to ultraviolet (UV) detector was also used for sensitive analysis of rhEPO at low levels (2000 IU) in the presence of large amount of human serum albumin (HSA). Analysis of rhEPO was achieved by the use of the electrokinetic injection (EI) with discontinuous buffers. Phosphate buffer was used as BGE with metal ions as additive. The proposed method can be used for the estimation of large number of quality control rhEPO samples in a short period.

  18. ERYTHROPOIETIN AS DOPING AGENT

    Directory of Open Access Journals (Sweden)

    Nina Đukanović

    2012-09-01

    Full Text Available Doping is the use of prohibited substances and/or methods that improve the abilities of athletes. Erythropoietin (EPO, the kidney hormone, belongs to a group of substances that are classified as blood doping, and it can be found on the list of banned substances from 1990. year. Its application leads to an increase in the number of red blood cells, which enables better supply of oxygen, and thus improve the aerobic performance of athletes. Because of that, EPO is very popular in sports where the endurance is predominantly required like a marathon, cycling, triathlon, nordic skiing. Erythropoietin can cause some adverse events, primarily to increase blood viscosity, which is associated with a higher risk of various thromboembolic complications. In detection of EPO use two groups of tests are available, through a urine sample (direct method and blood sample (indirect method.

  19. Nuclear data in the proton induced reactions

    Energy Technology Data Exchange (ETDEWEB)

    Bhang, H. C. [Seoul National Univ., Seoul (Korea); Cha, D. W. [Inha Univ., Incheon (Korea); Yu, K. H. [Daebul Eng. College, Youngam (Korea); Kim, Y. D. [Sejong Univ., Seoul (Korea); Chai, J. S. [Korea Atomic Energy Research Institute, Taejeon (Korea)

    2001-04-01

    Nuclear data in the intermediate energy nuclear reaction are much needed in many research areas like nuclear transmutation, burning of the long lived nuclear waste materials, accelerator driven subcritical nuclear reactor engineering, nuclear medical physics and cosmic sciences. Currently available nuclear data for the intermediate energy nuclear reaction are not sufficient enough for the basic research and development in these areas. Though many of the required data are generated from the theoretical model calculations, there are limits for such applications and the real data produced in the laboratory experiments are very much needed. In Korea the capability to produce such nuclear data from laboratory experiments are primitive. So far no infrastructure has been established for the measurements of nuclear data in such energy regions. In the current research we have developed an intranuclear cascade code, from the scratch, for the production and the propagation of nucleons in the intermediate energy nuclear reaction region, whose data are more uncertain compared to those of the intermediate energy nuclear reaction region, whose data are more uncertain compared to those of the statistical region and the direct reaction region. We have also performed a few proton induced nuclear reaction experiments, for instance, (p,p), (p,n), and (p,a), using the 50 MeV and 35 MeV protons from the MC-50 cyclotron of KCCH. Through these experiments we have developed a Csl high energy charged particle detector, a neutron TOF system, and the {delta}-E-E telescope for the wide dynamic charged particle measurements. Two papers from these experiments have been published and one in the process or refreeing in the SCI journal, JKPS. 26 refs., 23 figs., 3 tabs. (Author)

  20. Subretinal delivery of erythropoietin alleviates the N-methyl-N-nitrosourea-induced photoreceptor degeneration and visual functional impairments: an in vivo and ex vivo study.

    Science.gov (United States)

    Tao, Ye; Wang, Yue; Ma, Zhao; Wang, Liqiang; Qin, Limin; Wang, Lu; Huang, Yi Fei; Zhang, Shizhong

    2017-11-01

    Retinitis pigmentosa (RP) is a heterogeneous group hereditary retinal disease that is characterized by photoreceptor degeneration. The present study sought to explore the therapeutic effects of erythropoietin (EPO) on the N-methyl-N-nitrosourea (MNU)-induced photoreceptor degeneration. The MNU-administered mouse or normal control received a subretinal injection of EPO (at the dose of 10U). Twenty-four hours after EPO injection, the retinal EPO levels of experimental animals were quantified. Subsequently, the experimental animals were subjected to optokinetic tests, ERG examination, SD-OCT examination, histology assessment, and immunohistochemistry evaluation. The retinal superoxide dismutase (SOD) activity, malondialdehyde (MDA) content, and expression levels of several apoptotic factors were also quantified. The subretinal injection of EPO up-regulated the retinal EPO level in the retinas of MNU-administered mice. The optokinetic tests and ERG examination suggested the visual functional impairments in MNU-administered mice were ameliorated after EPO treatment. The SD-OCT and histological examination suggested the morphological devastations in MNU-administered mice were alleviated after EPO treatment. The cone photoreceptors in MNU-administered mice were protected from the MNU-induced detrimental effects. Moreover, the EPO treatment rectified the apoptotic abnormalities in MNU-administered mice, and enhanced the expression level of Foxo3, a critical mediator of autophagy. The EPO treatment also mitigated the MDA concentration and enhanced the retinal SOD activity, thereby counteracting the retinal oxidative stress in MNU administered mice. In ophthalmological practice, the subretinal delivery of EPO is a feasible therapeutic strategy to alleviate photoreceptor degeneration. These findings would enrich our pharmacological knowledge about EPO and shed light on the development of an effective therapy against RP.

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

    Science.gov (United States)

    Nasri, Hamid

    2014-01-01

    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). Approximately 90% of systemic erythropoietin in adults is produced by peritubular interstitial fibroblasts in the renal cortex and outer medulla of the kidney (3-5). A feedback mechanism involving oxygen delivery to the tissues seems to regulate erythropoietin production. Hypoxia-inducible factor regulates transcription of the erythropoietin gene in the kidney, which determines erythropoietin synthesis (3-5). Erythropoietin is an essential glycoprotein that accelerates red blood cell maturation from erythroid progenitors and mediates erythropoiesis in the bone marrow (4-6). Kidney fibrosis is the last common pathway in chronic renal failure irrespective of the initial etiology (5,6). Constant inflammatory cell infiltration and pericyte-myofibroblast transition lead to renal fibrosis and insufficiency which result in decreased production of erythropoietin (4-7). Thus far, therapeutic efforts to treat patients with chronic renal failure by administering erythropoietin have been made only to correct anemia and putative hypoxic tissue damage. The introduction of recombinant human erythropoietin has marked a significant advance in the management of anemia associated with chronic renal failure (6-9). With an increasing number of patients with chronic renal failure receiving erythropoietin treatment, emerging evidence suggests that erythropoietin not only has an erythropoietic function, but also has renoprotective potential. In fact, in recent years, the additional non

  2. Immuno-magnetic beads-based extraction-capillary zone electrophoresis-deep UV laser-induced fluorescence analysis of erythropoietin.

    Science.gov (United States)

    Wang, Heye; Dou, Peng; Lü, Chenchen; Liu, Zhen

    2012-07-13

    Erythropoietin (EPO) is an important glycoprotein hormone. Recombinant human EPO (rhEPO) is an important therapeutic drug and can be also used as doping reagent in sports. The analysis of EPO glycoforms in pharmaceutical and sports areas greatly challenges analytical scientists from several aspects, among which sensitive detection and effective and facile sample preparation are two essential issues. Herein, we investigated new possibilities for these two aspects. Deep UV laser-induced fluorescence detection (deep UV-LIF) was established to detect the intrinsic fluorescence of EPO while an immuno-magnetic beads-based extraction (IMBE) was developed to specifically extract EPO glycoforms. Combined with capillary zone electrophoresis (CZE), CZE-deep UV-LIF allows high resolution glycoform profiling with improved sensitivity. The detection sensitivity was improved by one order of magnitude as compared with UV absorbance detection. An additional advantage is that the original glycoform distribution can be completely preserved because no fluorescent labeling is needed. By combining IMBE with CZE-deep UV-LIF, the overall detection sensitivity was 1.5 × 10⁻⁸ mol/L, which was enhanced by two orders of magnitude relative to conventional CZE with UV absorbance detection. It is applicable to the analysis of pharmaceutical preparations of EPO, but the sensitivity is insufficient for the anti-doping analysis of EPO in blood and urine. IMBE can be straightforward and effective approach for sample preparation. However, antibodies with high specificity were the key for application to urine samples because some urinary proteins can severely interfere the immuno-extraction. Copyright © 2012 Elsevier B.V. All rights reserved.

  3. [Erythropoietin administration in diabetic patients].

    Science.gov (United States)

    Zukowska-Szczechowska, Ewa; Tomaszewski, Maciej; Sedkowska, Agnieszka; Grzeszczak, Władysław

    2003-01-01

    This paper presents the role of erythropoietin application in diabetic patients with accompanying renal failure. The main cause of anemia in diabetics are: nephropathy, structural lesions of erythrocyte membrane and blood loss connected with diagnostic and therapeutic actions. There are publications which demonstrate that in patients with diabetes type 1 or 2 with accompanying nephropathy, anemia appears more frequently than in the group of patients with chronic renal failure caused by other factors. It is supposed, that the impaired erythropoietin synthesis in diabetics can be caused by autonomic neuropathy. Erythropoietin administration in case of diabetic nephropathy has a beneficial influence on fat metabolism, immune response and reduction of insuline resistance. Erythropoietin because of reduction of vascular endothelial growth factor synthesis blocks the development of diabetic retinopathy and macroangiopathy. Erythropoietin reduces the risk of the left-ventricular hypertrophy caused by anemia. Very important is that the erythropoietin resistance is lower in diabetics. Scientists who are adverse to erythropoietin administration in patients with diabetic nephropathy maintain, that it can lead to vascular complications and the deterioration of glycemia control.

  4. Erythropoietin-induced serine 727 phosphorylation of STAT3 in erythroid cells is mediated by a MEK-, ERK-, and MSK1-dependent pathway

    NARCIS (Netherlands)

    Wierenga, Albertus T.J.; Vogelzang, Irma; Eggen, BJL; Vellenga, E

    Objective. Erythropoietin (EPO) is a key regulator of erythropoiesis, playing a role in both the proliferation and differentiation of erythroid cells. One of the signal transduction molecules activated upon EPO stimulation is signal transducer and activator of transcription (STAT) 3. Besides

  5. 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.

  6. Erythropoietin protects adult retinal ganglion cells against NMDA-, trophic factor withdrawal-, and TNF-α-induced damage.

    Directory of Open Access Journals (Sweden)

    Zhi-Yang Chang

    Full Text Available PURPOSE: This study aimed to evaluate the neuroprotective effect of EPO in the presence of N-methyl-d-aspartate (NMDA-, trophic factor withdrawal (TFW-, and tumor necrosis factor-alpha (TNF-α-induced toxicity on total, small, and large retinal ganglion cells (RGCs. METHODS: Retinal cells from adult rats were cultured in a medium containing brain-derived neurotrophic factor (BDNF, ciliary neurotrophic factor (CNTF, basic fibroblast growth factor (bFGF, and forskolin. Expression of RGC markers and EPOR was examined using immunocytochemistry. RGCs were classified according to their morphological properties. Cytotoxicity was induced by NMDA, TFW, or TNF-α. RGC survival was assessed by counting thy-1 and neurofilament-l double-positive cells. RESULTS: EPO offered dose-dependent (EC₅₀ = 5.7 ng/mL protection against NMDA toxicity for small RGCs; protection was not significant for large RGCs. Time-course analysis showed that the presence of EPO either before or after NMDA exposure gave effective protection. For both small and large RGCs undergoing trophic factor withdrawal, EPO at concentrations of 1, 10, or 100 ng/mL improved survival. However, EPO had to be administered soon after the onset of injury to provide effective protection. For TNF-α-induced toxicity, survival of small RGCs was seen only for the highest examined concentration (100 ng/mL of EPO, whereas large RGCs were protected at concentrations of 1, 10, or 100 ng/mL of EPO. Time-course analysis showed that pretreatment with EPO provided protection only for large RGCs; early post-treatment with EPO protected both small and large RGCs. Inhibitors of signal transduction and activators of transcription such as (STAT-5, mitogen-activated protein kinases (MAPK/extracellular-regulated kinase (ERK, and phosphatidyl inositol-3 kinase (PI3K/Akt impaired the protective effect of EPO on RGCs exposed to different insults. CONCLUSION: EPO provided neuroprotection to cultured adult rat RGCs

  7. 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

    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 (Pobese mice; thus the mice weighed 21.9+/-0.8 g (control, normal diet,) 21.9+/-1.4 g (EPO, normal diet), 35...... 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....

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

    Directory of Open Access Journals (Sweden)

    Matthew E Hardee

    important angiogenic factor that regulates the induction of tumor cell-induced neovascularization and growth during the initial stages of tumorigenesis. The suppression of tumor angiogenesis and progression by erythropoietin blockade suggests that erythropoietin may constitute a potential target for the therapeutic modulation of angiogenesis in cancer.

  9. 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

  10. Gene therapy with an erythropoietin enhancer-mediated, hypoxia-inducible gene expression system in the corpus cavernosum of mice with high-cholesterol diet-induced erectile dysfunction.

    Science.gov (United States)

    Ryu, Ji-Kan; Lee, Minhyung; Choi, Min Ji; Kim, Hyun Ah; Jin, Hai-Rong; Kim, Woo Jean; Yin, Guo Nan; Song, Kang-Moon; Kwon, Mi-Hye; Suh, Jun-Kyu

    2012-01-01

    Cavernous hypoxia is an important factor in the pathogenesis of vasculogenic erectile dysfunction (ED). Therefore, the hypoxia-inducible gene expression system can be exploited as gene therapy for vasculogenic ED. This study was undertaken to examine the effectiveness of a hypoxia-inducible gene expression system, namely, the RTP801 promoter or the erythropoietin enhancer, in a mouse model of hypercholesterolemic ED in vivo and in primary cultured mouse cavernous endothelial cells in vitro. Two-month-old male C57BL/6 mice were fed a diet containing 4% cholesterol and 1% cholic acid, and age-matched control animals were fed a normal diet for 3 months. Mouse cavernous endothelial cells were isolated and cultured under normoxic or hypoxic conditions. After treatment of animals or endothelial cells with pSV-Luc, pRTP801-Luc, or pEpo-SV-Luc vector, gene expression was evaluated by luciferase assay, and the gene expression area was evaluated by immunohistochemistry. Plasmids pRTP801-Luc and pEpo-SV-Luc induced gene expression significantly in the hypercholesterolemic mice and in cavernous endothelial cells under hypoxia, and the highest gene expression was noted in the group treated with pEpo-SV-Luc. Gene expression was higher for more than 7 days in the hypercholesterolemic mice injected with pEpo-SV-Luc than in mice injected with pSV-Luc. As shown by immunohistochemistry, the gene expression area was also greater in the pEpo-SV-Luc group than in the pSV-Luc group, but the difference was not as great as that in luciferase activity. The hypoxia-specific gene expression system could be a valuable tool for facilitating gene delivery into ischemic corpus cavernosum tissue resulting from vascular causes.

  11. The volatile anesthetic isoflurane differentially suppresses the induction of erythropoietin synthesis elicited by acute anemia and systemic hypoxemia in mice in an hypoxia-inducible factor-2-dependent manner.

    Science.gov (United States)

    Kai, Shinichi; Tanaka, Tomoharu; Matsuyama, Tomonori; Suzuki, Kengo; Hirota, Kiichi

    2014-06-05

    Erythropoietin (EPO) is a glycoprotein hormone essential for the regulation of erythroid homeostasis. Although EPO production is prominent in the kidney and liver, its production in the central nervous system has also been detected. Tissue hypoxia due to systemic or local hypoxemia and acute anemia due to blood loss occurs frequently during various clinical settings, leading to a high possibility of elevated plasma EPO levels. However, it is largely unknown whether volatile anesthetic agents affect EPO production elicited by acute hypoxia in vivo. Male C57BL/6N CrSlc mice were exposed to a hypoxic insult as a result of bleeding-related anemia or hypoxemia while they were under anesthetized using various concentrations of isoflurane. EPO protein concentrations were assessed by enzyme-linked immunosorbent assay and mRNA levels were measured by quantitative real-time reverse transcriptase-polymerase chain reaction. Plasma EPO concentration was induced as early as 3h following acute anemic and hypoxemic hypoxia and suppressed by clinically relevant doses of isoflurane in a dose-dependent manner. Anemic hypoxia induced EPO mRNA and protein synthesis in the kidney. In the kidney, isoflurane inhibited EPO induction caused by anemia but not that caused by hypoxemia. On the other hand, in the brain hypoxemia-induced EPO production was suppressed by isoflurane. Finally, qRT-PCR studies demonstrate that isoflurane differentially inhibit HIF-1α and HIF-2α mRNA expression in brain and kidney, indicating the involvement of HIF-2 in the hypoxia-induced EPO expression and inhibition of the induction by isoflurane. Copyright © 2014 Elsevier B.V. All rights reserved.

  12. 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.

  13. DNA damage-induced inflammation and nuclear architecture.

    Science.gov (United States)

    Stratigi, Kalliopi; Chatzidoukaki, Ourania; Garinis, George A

    2017-07-01

    Nuclear architecture and the chromatin state affect most-if not all- DNA-dependent transactions, including the ability of cells to sense DNA lesions and restore damaged DNA back to its native form. Recent evidence points to functional links between DNA damage sensors, DNA repair mechanisms and the innate immune responses. The latter raises the question of how such seemingly disparate processes operate within the intrinsically complex nuclear landscape and the chromatin environment. Here, we discuss how DNA damage-induced immune responses operate within chromatin and the distinct sub-nuclear compartments highlighting their relevance to chronic inflammation. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  14. 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

  15. Cross-section measurements and nuclear model calculation for proton induced nuclear reaction on zirconium

    Energy Technology Data Exchange (ETDEWEB)

    Al-Abyad, M., E-mail: alabyad_m@yahoo.com [Experimental Nuclear Physics Department (Cyclotron Facility), Nuclear Research Center, AEA, Postal Code 13759, Cairo (Egypt); Abdel-Hamid, A.S. [Experimental Nuclear Physics Department (Cyclotron Facility), Nuclear Research Center, AEA, Postal Code 13759, Cairo (Egypt); Tarkanyi, F.; Ditroi, F.; Takacs, S. [Institute of Nuclear Research, Hungarian Academy of Sciences, H-4026 Debrecen (Hungary); Seddik, U. [Experimental Nuclear Physics Department (Cyclotron Facility), Nuclear Research Center, AEA, Postal Code 13759, Cairo (Egypt); Bashter, I.I. [Physics Department, Faculty of Science, Zagazig University, Zagazig (Egypt)

    2012-01-15

    Proton induced nuclear reactions were measured with stacked-foil technique on natural zirconium targets up to 16.7 MeV. Excitation functions were measured for the production of {sup 90,92m,95m,95g,96}Nb and {sup 88}Y. Cumulative cross-section, thick target yields and activation functions were deduced and compared with the available experimental data, as well as with the nuclear models codes; ALICE-IPPE, EMPIRE and TALYS. The integral yields for thick targets were deduced from the measured excitation function of the produced radionuclides. - Highlights: Black-Right-Pointing-Pointer We measured the excitation functions for proton induced reactions on Zr for the production of {sup 90.92m,95m,95g,96}Nb and {sup 88}Y. Black-Right-Pointing-Pointer Results compared with the experimental data, as well as with nuclear models codes. Black-Right-Pointing-Pointer Integral yields for thick targets were deduced .

  16. A primer for electroweak induced low-energy nuclear reactions

    Indian Academy of Sciences (India)

    Under special circumstances, electromagnetic and weak interactions can induce low-energy nuclear reactions to occur with observable rates for a variety of processes. A common element in all these applications is that the electromagnetic energy stored in many relatively slow-moving electrons can – under appropriate ...

  17. 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.

  18. Cross-section measurements and nuclear model calculation for proton induced nuclear reaction on zirconium.

    Science.gov (United States)

    Al-Abyad, M; Abdel-Hamid, A S; Tárkányi, F; Ditrói, F; Takács, S; Seddik, U; Bashter, I I

    2012-01-01

    Proton induced nuclear reactions were measured with stacked-foil technique on natural zirconium targets up to 16.7MeV. Excitation functions were measured for the production of (90,92m,95m,95g,96)Nb and (88)Y. Cumulative cross-section, thick target yields and activation functions were deduced and compared with the available experimental data, as well as with the nuclear models codes; ALICE-IPPE, EMPIRE and TALYS. The integral yields for thick targets were deduced from the measured excitation function of the produced radionuclides. Copyright © 2011 Elsevier Ltd. All rights reserved.

  19. 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.

  20. Effects of Induced Surface Tension in Nuclear and Hadron Matter

    Directory of Open Access Journals (Sweden)

    Sagun V.V.

    2017-01-01

    Full Text Available Short range particle repulsion is rather important property of the hadronic and nuclear matter equations of state. We present a novel equation of state which is based on the virial expansion for the multicomponent mixtures with hard-core repulsion. In addition to the hard-core repulsion taken into account by the proper volumes of particles, this equation of state explicitly contains the surface tension which is induced by another part of the hard-core repulsion between particles. At high densities the induced surface tension vanishes and the excluded volume treatment of hard-core repulsion is switched to its proper volume treatment. Possible applications of this equation of state to a description of hadronic multiplicities measured in A+A collisions, to an investigation of the nuclear matter phase diagram properties and to the neutron star interior modeling are discussed.

  1. 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.

  2. Induced Stokes or anti-Stokes nuclear transitions

    Energy Technology Data Exchange (ETDEWEB)

    Eliezer, S. [Madrid Polytechnical Univ. (Spain)]|[SOREQN, Yavne (Israel); Martinez-Val, J.M.; Velarde, G. [Madrid Polytechnical Univ. (Spain)] [and others

    1995-11-01

    It is suggested that laser-generated soft x rays can be used to induce Stokes or anti-Stokes nuclear transitions. Isomeric transitions in {sup 99}Tc and {sup 179}Hf are considered as Stokes and anti-Stokes transitions, respectively. It is shown that success of the proposed scheme may open the way for a gamma-ray laser. 18 refs., 2 figs.

  3. Nuclear reactions induced by high-energy alpha particles

    Science.gov (United States)

    Shen, B. S. P.

    1974-01-01

    Experimental and theoretical studies of nuclear reactions induced by high energy protons and heavier ions are included. Fundamental data needed in the shielding, dosimetry, and radiobiology of high energy particles produced by accelerators were generated, along with data on cosmic ray interaction with matter. The mechanism of high energy nucleon-nucleus reactions is also examined, especially for light target nuclei of mass number comparable to that of biological tissue.

  4. Role of Erythropoietin in Renal Anemia Therapy

    African Journals Online (AJOL)

    Larramendi CH, Marco FM, Garcia-Abujeta JL, Mateo M, de la Vega A and Sempere JM. Acute allergic reaction to an iron compound in a milk-allergic patient. Pediatr. Allergy Immunol 2006; 17: 230-233. 18. Ksiazek A. Effect of recombinant human erythropoietin (r-. Hu EPO) therapy on blood pressure in dialysis patients.

  5. Modificaciones hematológicas inducidas por eritropoyetina frente a hipoxia normobárica intermitente Hematologic changes induced by erythropoietin versus intermittent normobaric hypoxia

    Directory of Open Access Journals (Sweden)

    F. Sanchis-Gomar

    2010-12-01

    currently exclude athletes, who show aberrant values of these parameters, from competition.
    Twenty-four young male Wistar rats (3 months and ~300g weight were randomly divided in 3 experimental groups: normobaric intermittent hypoxic group  (12h pO2 12% /12h pO2 21% (n=8; the group treated with 300 UI of rHuEpo (n=8 and the group treated with 500 UI of rHuEpo (n=8.The rHuEpo was administered subcutaneously 3 times/week. All the treatments lasted 15 days. Two blood samples were obtained in every experimental group. The first one before the treatments and the second one 15 days after the treatments.
    Our results show similar and statistically significant increments in the hemoglobin, hematocrit and reticulocytes values after 15 days of treatment with 300 UI of rHuEpo or NIH. The treatment with 500 UI of rHuEpo induced a higher increase in the hematological parameters determined in our study when compared with the other treatments (NIH and rHuEpo 300 UI.
    The main conclusion of our study is that the hematological modifications achieved with a NIH protocol were comparable with those that imply a treatment with 300 UI of rHuEpo.
    Key Words: Hemoglobin, hematocrit, reticulocytes, doping

  6. Parvovirus induced alterations in nuclear architecture and dynamics.

    Directory of Open Access Journals (Sweden)

    Teemu O Ihalainen

    2009-06-01

    Full Text Available The nucleus of interphase eukaryotic cell is a highly compartmentalized structure containing the three-dimensional network of chromatin and numerous proteinaceous subcompartments. DNA viruses induce profound changes in the intranuclear structures of their host cells. We are applying a combination of confocal imaging including photobleaching microscopy and computational methods to analyze the modifications of nuclear architecture and dynamics in parvovirus infected cells. Upon canine parvovirus infection, expansion of the viral replication compartment is accompanied by chromatin marginalization to the vicinity of the nuclear membrane. Dextran microinjection and fluorescence recovery after photobleaching (FRAP studies revealed the homogeneity of this compartment. Markedly, in spite of increase in viral DNA content of the nucleus, a significant increase in the protein mobility was observed in infected compared to non-infected cells. Moreover, analysis of the dynamics of photoactivable capsid protein demonstrated rapid intranuclear dynamics of viral capsids. Finally, quantitative FRAP and cellular modelling were used to determine the duration of viral genome replication. Altogether, our findings indicate that parvoviruses modify the nuclear structure and dynamics extensively. Intranuclear crowding of viral components leads to enlargement of the interchromosomal domain and to chromatin marginalization via depletion attraction. In conclusion, parvoviruses provide a useful model system for understanding the mechanisms of virus-induced intranuclear modifications.

  7. Experimental study and nuclear model calculations of {sup 3}He-induced nuclear reactions on zinc

    Energy Technology Data Exchange (ETDEWEB)

    Al-Abyad, M.; Mohamed, Gehan Y. [Nuclear Research Centre, Atomic Energy Authority, Physics Department (Cyclotron Facility), Cairo (Egypt); Ditroi, F.; Takacs, S.; Tarkanyi, F. [Hungarian Academy of Sciences (ATOMKI), Institute for Nuclear Research, Debrecen (Hungary)

    2017-05-15

    Excitation functions of {sup 3}He-induced nuclear reactions on natural zinc were measured using the standard stacked-foil technique and high-resolution gamma-ray spectrometry. From their threshold energies up to 27 MeV, the cross-sections for {sup nat}Zn ({sup 3}He,xn) {sup 69}Ge, {sup nat}Zn({sup 3}He,xnp) {sup 66,67,68}Ga, and {sup nat}Zn({sup 3}He,x){sup 62,65}Zn reactions were measured. The nuclear model codes TALYS-1.6, EMPIRE-3.2 and ALICE-IPPE were used to describe the formation of these products. The present data were compared with the theoretical results and with the available experimental data. Integral yields for some important radioisotopes were determined. (orig.)

  8. Experimental study and nuclear model calculations of 3He-induced nuclear reactions on zinc

    Science.gov (United States)

    Al-Abyad, M.; Mohamed, Gehan Y.; Ditrói, F.; Takács, S.; Tárkányi, F.

    2017-05-01

    Excitation functions of 3He -induced nuclear reactions on natural zinc were measured using the standard stacked-foil technique and high-resolution gamma-ray spectrometry. From their threshold energies up to 27MeV, the cross-sections for natZn (3He, xn) 69Ge, natZn(3He, xnp) 66,67,68Ga, and natZn(3He, x)62,65Zn reactions were measured. The nuclear model codes TALYS-1.6, EMPIRE-3.2 and ALICE-IPPE were used to describe the formation of these products. The present data were compared with the theoretical results and with the available experimental data. Integral yields for some important radioisotopes were determined.

  9. 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  

  10. 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.

  11. 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....... rhEpo treatment increased OXPHOS (from 92 ± 5 to 113 ± 7 pmol·s(-1)·mg(-1)) and ETS (107 ± 4 to 143 ± 14 pmol·s(-1)·mg(-1), p muscle....

  12. Effects of recombinant humant erythropoietin in normal humans

    DEFF Research Database (Denmark)

    Lundby, Carsten; Olsen, Niels Vidiendal

    2011-01-01

    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......, 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...

  13. The ergogenic effect of recombinant human erythropoietin on VO2max depends on the severity of arterial hypoxemia

    DEFF Research Database (Denmark)

    Robach, Paul; Calbet, Jose A L; Thomsen, Jonas J

    2008-01-01

    Treatment with recombinant human erythropoietin (rhEpo) induces a rise in blood oxygen-carrying capacity (CaO(2)) that unequivocally enhances maximal oxygen uptake (VO(2)max) during exercise in normoxia, but not when exercise is carried out in severe acute hypoxia. This implies that there should ...

  14. 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

    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...

  15. 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.

  16. Detecting special nuclear material using muon-induced neutron emission

    Energy Technology Data Exchange (ETDEWEB)

    Guardincerri, Elena; Bacon, Jeffrey; Borozdin, Konstantin; Matthew Durham, J.; Fabritius II, Joseph [Los Alamos National Laboratory, Los Alamos, NM 87545 (United States); Hecht, Adam [University of New Mexico, Albuquerque, NM 87131 (United States); Milner, Edward C. [Southern Methodist University, Dallas, TX 75205 (United States); Miyadera, Haruo; Morris, Christopher L. [Los Alamos National Laboratory, Los Alamos, NM 87545 (United States); Perry, John [Los Alamos National Laboratory, Los Alamos, NM 87545 (United States); University of New Mexico, Albuquerque, NM 87131 (United States); Poulson, Daniel [Los Alamos National Laboratory, Los Alamos, NM 87545 (United States)

    2015-07-21

    The penetrating ability of cosmic ray muons makes them an attractive probe for imaging dense materials. Here, we describe experimental results from a new technique that uses neutrons generated by cosmic-ray muons to identify the presence of special nuclear material (SNM). Neutrons emitted from SNM are used to tag muon-induced fission events in actinides and laminography is used to form images of the stopping material. This technique allows the imaging of SNM-bearing objects tagged using muon tracking detectors located above or to the side of the objects, and may have potential applications in warhead verification scenarios. During the experiment described here we did not attempt to distinguish the type or grade of the SNM.

  17. Particle induced nuclear reaction calculations of Boron target nuclei

    Directory of Open Access Journals (Sweden)

    Tel Eyyup

    2017-01-01

    Full Text Available Boron is usable element in many areas such as health, industry and energy. Especially, Boron neutron capture therapy (BNCT is one of the medical applications. Boron target is irradiated with low energy thermal neutrons and at the end of reactions alpha particles occur. After this process recoiling lithium-7 nuclei is composed. In this study, charge particle induced nuclear reactions calculations of Boron target nuclei were investigated in the incident proton and alpha energy range of 5–50 MeV. The excitation functions for 10B target nuclei reactions have been calculated by using PCROSS Programming code. The semi-empirical calculations for (p,α reactions have been done by using cross section formula with new coefficient obtained by Tel et al. The calculated results were compared with the experimental data from the literature.

  18. Particle induced nuclear reaction calculations of Boron target nuclei

    Science.gov (United States)

    Tel, Eyyup; Sahan, Muhittin; Sarpün, Ismail Hakki; Kavun, Yusuf; Gök, Ali Armagan; Poyraz, Meltem

    2017-09-01

    Boron is usable element in many areas such as health, industry and energy. Especially, Boron neutron capture therapy (BNCT) is one of the medical applications. Boron target is irradiated with low energy thermal neutrons and at the end of reactions alpha particles occur. After this process recoiling lithium-7 nuclei is composed. In this study, charge particle induced nuclear reactions calculations of Boron target nuclei were investigated in the incident proton and alpha energy range of 5-50 MeV. The excitation functions for 10B target nuclei reactions have been calculated by using PCROSS Programming code. The semi-empirical calculations for (p,α) reactions have been done by using cross section formula with new coefficient obtained by Tel et al. The calculated results were compared with the experimental data from the literature.

  19. An abnormally glycosylated isoform of erythropoietin in hemangioblastoma is associated with polycythemia.

    Science.gov (United States)

    Delanghe, Sigurd E; Dierick, Jan; Maenhout, Thomas M; Zabeau, Lennart; Tavernier, Jan; Claes, Kathleen; Bleyen, Joris; Delanghe, Joris R

    2015-01-01

    Hemangioblastomas express erythropoietin and the patients often present with polycythemia. Serum erythropoietin was measured using a commercial immunoassay, a functional erythropoietin assay and iso-electric focusing. Despite the polycythemia, serum erythropoietin remained low, while a functional erythropoietin-assay showed a 4-5 higher activity in serum compared to the immunoassay. Iso-electric focusing of serum erythropoietin indicated overrepresentation of highly sialylated erythropoietin isoforms produced by the tumor. As a result, altered affinity of the monoclonal antibody used in the immunoassay for the hypersialylated isoforms was suggested. Analysis of erythropoietin isoforms may be helpful in distinguishing the ectopic erythropoietin isoforms from normally glycosylated erythropoietin. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. Prm3p is a pheromone-induced peripheral nuclear envelope protein required for yeast nuclear fusion.

    Science.gov (United States)

    Shen, Shu; Tobery, Cynthia E; Rose, Mark D

    2009-05-01

    Nuclear membrane fusion is the last step in the mating pathway of the yeast Saccharomyces cerevisiae. We adapted a bioinformatics approach to identify putative pheromone-induced membrane proteins potentially required for nuclear membrane fusion. One protein, Prm3p, was found to be required for nuclear membrane fusion; disruption of PRM3 caused a strong bilateral defect, in which nuclear congression was completed but fusion did not occur. Prm3p was localized to the nuclear envelope in pheromone-responding cells, with significant colocalization with the spindle pole body in zygotes. A previous report, using a truncated protein, claimed that Prm3p is localized to the inner nuclear envelope. Based on biochemistry, immunoelectron microscopy and live cell microscopy, we find that functional Prm3p is a peripheral membrane protein exposed on the cytoplasmic face of the outer nuclear envelope. In support of this, mutations in a putative nuclear localization sequence had no effect on full-length protein function or localization. In contrast, point mutations and deletions in the highly conserved hydrophobic carboxy-terminal domain disrupted both protein function and localization. Genetic analysis, colocalization, and biochemical experiments indicate that Prm3p interacts directly with Kar5p, suggesting that nuclear membrane fusion is mediated by a protein complex.

  1. Erythropoietin Pathway: A Potential Target for the Treatment of Depression

    Directory of Open Access Journals (Sweden)

    Chongyang Ma

    2016-05-01

    Full Text Available During the past decade, accumulating evidence from both clinical and experimental studies has indicated that erythropoietin may have antidepressant effects. In addition to the kidney and liver, many organs have been identified as secretory tissues for erythropoietin, including the brain. Its receptor is expressed in cerebral and spinal cord neurons, the hypothalamus, hippocampus, neocortex, dorsal root ganglia, nerve axons, and Schwann cells. These findings may highlight new functions for erythropoietin, which was originally considered to play a crucial role in the progress of erythroid differentiation. Erythropoietin and its receptor signaling through JAK2 activate multiple downstream signaling pathways including STAT5, PI3K/Akt, NF-κB, and MAPK. These factors may play an important role in inflammation and neuroprogression in the nervous system. This is particularly true for the hippocampus, which is possibly related to learning, memory, neurocognitive deficits and mood alterations. Thus, the influence of erythropoietin on the downstream pathways known to be involved in the treatment of depression makes the erythropoietin-related pathway an attractive target for the development of new therapeutic approaches. Focusing on erythropoietin may help us understand the pathogenic mechanisms of depression and the molecular basis of its treatment.

  2. Erythropoietin Pathway: A Potential Target for the Treatment of Depression.

    Science.gov (United States)

    Ma, Chongyang; Cheng, Fafeng; Wang, Xueqian; Zhai, Changming; Yue, Wenchao; Lian, Yajun; Wang, Qingguo

    2016-05-06

    During the past decade, accumulating evidence from both clinical and experimental studies has indicated that erythropoietin may have antidepressant effects. In addition to the kidney and liver, many organs have been identified as secretory tissues for erythropoietin, including the brain. Its receptor is expressed in cerebral and spinal cord neurons, the hypothalamus, hippocampus, neocortex, dorsal root ganglia, nerve axons, and Schwann cells. These findings may highlight new functions for erythropoietin, which was originally considered to play a crucial role in the progress of erythroid differentiation. Erythropoietin and its receptor signaling through JAK2 activate multiple downstream signaling pathways including STAT5, PI3K/Akt, NF-κB, and MAPK. These factors may play an important role in inflammation and neuroprogression in the nervous system. This is particularly true for the hippocampus, which is possibly related to learning, memory, neurocognitive deficits and mood alterations. Thus, the influence of erythropoietin on the downstream pathways known to be involved in the treatment of depression makes the erythropoietin-related pathway an attractive target for the development of new therapeutic approaches. Focusing on erythropoietin may help us understand the pathogenic mechanisms of depression and the molecular basis of its treatment.

  3. 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.

  4. Designing a small molecule erythropoietin mimetic.

    Science.gov (United States)

    Guarnieri, Frank

    2015-01-01

    Erythropoietin (EPO) is a protein made by the kidneys in response to low red blood cell count that is secreted into the bloodstream and binds to a receptor on hematopoietic stem cells in the bone marrow inducing them to become new red blood cells. EPO made with recombinant DNA technology was brought to market in the 1980s to treat anemia caused by kidney disease and cancer chemotherapy. Because EPO infusion was able to replace blood transfusions in many cases, it rapidly became a multibillion dollar per year drug and as the first biologic created with recombinant technology it launched the biotech industry. For many years intense research was focused on creating a small molecule orally available EPO mimetic. The Robert Wood Johnson (RWJ) group seemed to definitively establish that only large peptides with a minimum of 60 residues could replace EPO, as anything less was not a full agonist. An intense study of the published work led me to hypothesize that the size of the mimetic is not the real issue, but the symmetry making and breaking of the EPO receptor induced by the ligand is the key to activating the stem cells. This analysis meant that residues in the binding site of the receptor deemed absolutely essential for ligand binding and activation from mutagenesis experiments, were probably not really that important. My fundamental hypotheses were: (a) the symmetric state of the homodimeric receptor is the most stable state and thus must be the off-state, (b) a highly localized binding site exists at a pivot point where the two halves of the receptor meet, (c) small molecules can be created that have high potency for this site that will be competitive with EPO and thus can displace the protein-protein interaction, (d) small symmetric molecules will stabilize the symmetric off-state of the receptor, and (e) a key asymmetry in the small molecule will stabilize a mirror image asymmetry in the receptor resulting in the stabilization of the on-state and proliferation of

  5. Nuclear Fusion Effects Induced in Intense Laser-Generated Plasmas

    Directory of Open Access Journals (Sweden)

    Lorenzo Torrisi

    2013-01-01

    Full Text Available Deutered polyethylene (CD2n thin and thick targets were irradiated in high vacuum by infrared laser pulses at 1015W/cm2 intensity. The high laser energy transferred to the polymer generates plasma, expanding in vacuum at supersonic velocity, accelerating hydrogen and carbon ions. Deuterium ions at kinetic energies above 4 MeV have been measured by using ion collectors and SiC detectors in time-of-flight configuration. At these energies the deuterium–deuterium collisions may induce over threshold fusion effects, in agreement with the high D-D cross-section valuesaround 3 MeV energy. At the first instants of the plasma generation, during which high temperature, density and ionacceleration occur, the D-D fusions occur as confirmed by the detection of mono-energetic protonsand neutrons with a kinetic energy of 3.0 MeV and 2.5 MeV, respectively, produced by the nuclear reaction. The number of fusion events depends strongly on the experimental set-up, i.e. on the laser parameters (intensity, wavelength, focal spot dimension, target conditions (thickness, chemical composition, absorption coefficient, presence of secondary targets and used geometry (incidence angle, laser spot, secondary target positions.A number of D-D fusion events of the order of 106÷7 per laser shot has been measured.

  6. Nuclear EGFRvIII resists hypoxic microenvironment induced apoptosis via recruiting ERK1/2 nuclear translocation

    Energy Technology Data Exchange (ETDEWEB)

    Xie, Hui; Yang, Jinfeng; Xing, Wenjing; Dong, Yucui [Dept. of Immunology, Harbin Medical University, Harbin 150081 (China); Key Lab Infection & Immunity, Heilongjiang Province, Harbin 150081 (China); Ren, Huan, E-mail: renhuan@ems.hrbmu.edu.cn [Dept. of Immunology, Harbin Medical University, Harbin 150081 (China); Key Lab Infection & Immunity, Heilongjiang Province, Harbin 150081 (China)

    2016-02-05

    Glioblastoma (GBM) is the most aggressive type of primary brain tumor. Its interaction with the tumor microenvironment promotes tumor progression. Furthermore, GBM bearing expression of EGFRvIII displays more adaptation to tumor microenvironment related stress. But the mechanisms were poorly understood. Here, we presented evidence that in the human U87MG glioblastoma tumor model, EGFRvIII overexpression led aberrant kinase activation and nuclear translocation of EGFRvIII/ERK1/2 under hypoxia, which induced growth advantage by resisting apoptosis. Additionally, EGFRvIII defective in nuclear entry impaired this capacity in hypoxia adaptation, and partially interrupted ERK1/2 nuclear translocation. Pharmacology or genetic interference ERK1/2 decreased hypoxia resistance triggered by EGFRvIII expression, but not EGFRvIII nuclear translocation. In summary, this study identified a novel role for EGFRvIII in hypoxia tolerance, supporting an important link between hypoxia and subcellular localization alterations of the receptor. - Highlights: • Nuclear translocation of EGFRvIII contributes to GBM cell apoptotic resistance by hypoxia. • Nuclear ERK1/2 facilitates EGFRvIII in hypoxia resistance. • EGFRvIII nuclear translocation is not dependent on ERK1/2.

  7. Erythropoietine : enkele aspecten van de humorale regulatie van de erythropoiese

    NARCIS (Netherlands)

    G. Wagemaker (Gerard)

    1976-01-01

    textabstractDe regulatie van de erythropoiese verloopt in belangrijke mate via een humorale regulator. Deze wordt erythropoietine genoemd, en heeft een specifieke stimulerende werking op de erythropoiese, waarschiinliik in hoofdzaak door de inductie van erythroide differentiatie in een

  8. 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.

  9. Investigations of nuclear structure and nuclear reactions induced by complex projectiles

    Energy Technology Data Exchange (ETDEWEB)

    Sarantites, D.G.

    1990-01-01

    This report discusses research in the following areas: nuclear structure; fusion reactions near and below the barrier; incomplete fusion and fragmentation reactions; and instrumentation and analysis. (LSP).

  10. 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.

  11. Charged particle-induced nuclear fission reactions – Progress and ...

    Indian Academy of Sciences (India)

    many countries in the world. The nuclear fission phenomenon continues to be .... This way it has been possible to study the fission of many nuclei away from the line of stability at low excitation energies, around 11 ..... sion before interpretation of the data can be attempted. The nuclear structure and the. 864. Pramana – J.

  12. MYC-induced nuclear antigen (MINA) and preeclampsia.

    Science.gov (United States)

    Martinez-Fierro, Margarita L; Reyes-Oliva, Edwin A; Cabral-Pacheco, Griselda A; Garza-Veloz, Idalia; Aceves-Medina, Maria C; Luevano, Martha; Barbosa-Cisneros, Olga Y; Galvan-Valencia, Marisol; Yahuaca-Mendoza, Patricia; Delgado-Enciso, Ivan; Zamudio-Osuna, Michelle; Rodriguez-Sanchez, Iram P; Vazquez-Castro, Rosbel; Guerrero-Saucedo, Marycruz

    2016-05-01

    Inadequate trophoblast invasion and the subsequent inflammatory response have been implicated in preeclampsia (PE) pathogenesis. Because MYC-induced nuclear antigen (MINA) gene expression is involved in cell proliferation and differentiation, inflammatory response modulation, and the unpaired regulation of which is associated with human diseases, we sought to investigate the connection between MINA and PE. The aim of this study was to evaluate the possible relationship between the MINA rs4857304 variant and susceptibility to PE development as well as to estimate placental MINA gene expression and its association with PE. About 242 pregnant women (126 PE cases and 116 controls) were included. MINA genotyping and gene expression were evaluated by quantitative real-time polymerase chain reaction using TaqMan probes. The G/G genotype of the MINA rs4857304 variant was associated with severe PE (p = 0.027, OR = 1.8, 95% CI = 1.8-3.2). Carriers of one G allele of the MINA rs4857304 variant exhibited a 1.7-fold increased risk of severe PE (p = 0.029, 95% CI = 1.1-3.0). MINA was underexpressed in preeclamptic placentas and MINA expression differed between the mild and severe PE groups. Differences in the expression levels of MINA were found among women with the T/T genotype of the rs4857304 polymorphism and carriers of at least one G allele (p = 0.024). PE and its severity are associated with the underexpression of placental MINA, and the G/G genotype of the MINA rs4857304 variant may modify the risk of severe PE among the PE cases evaluated.

  13. Basic conditions for radioimmunoassay of erythropoietin, and plasma levels of erythropoietin in normal subjects and anemic patients

    Energy Technology Data Exchange (ETDEWEB)

    Mizoguchi, Hideaki; Ohta, Kazuo; Suzuki, Toshiaki; Murakami, Akihiko; Ueda, Masatsugu; Sasaki, Ryuzou; Chiba, Hideo

    1987-02-01

    We have developed a specific and sensitive radioimmunoassay for erythropoietin. The sensitivity of our assay is 0.5 mU or 5 mU/ml and is sufficient to detect normal plasma erythropoietin levels. The mean plasma erythropoietin titer of normal Japanese with our radioimmunoassay was found to be 21.9 +- 12.0 mU/ml (n = 199). The validity of the method was further confirmed by the observations that the plasma erythropoietin titers were inversely related to hemoglobin levels in patients with nonuremic anemias, lower in uremic patients than in patients with nonuremic anemias with similar hemoglobin levels, markedly elevated in patients with aplastic anemia and pure red cell aplasia, and in a low normal range in patients with polycythemia vera.

  14. Does Erythropoietin Regulate TRPC Channels in Red Blood Cells?

    Directory of Open Access Journals (Sweden)

    Jens Danielczok

    2017-03-01

    Full Text Available Background: Cation channels play an essential role in red blood cells (RBCs ion homeostasis. One set of ion channels are the transient receptor potential channels of canonical type (TRPC channels. The abundance of these channels in primary erythroblasts, erythroid cell lines and RBCs was associated with an increase in intracellular Ca2+ upon stimulation with Erythropoietin (Epo. In contrast two independent studies on Epo-treated patients revealed diminished basal Ca2+ concentration or reduced phosphatidylserine exposure to the outer membrane leaflet. Methods: To resolve the seemingly conflicting reports we challenged mature human and mouse RBCs of several genotypes with Epo and Prostaglandin E2 (PGE2 and recorded the intracellular Ca2+ content. Next Generation Sequencing was utilised to approach a molecular analysis of reticulocytes. Results/Conclusions: Our results allow concluding that Epo and PGE2 regulation of the Ca2+ homeostasis is distinctly different between murine and human RBCs and that changes in intracellular Ca2+ upon Epo treatment is a primary rather than a compensatory effect. In human RBCs, Epo itself has no effect on Ca2+ fluxes but inhibits the PGE2-induced Ca2+ entry. In murine mature RBCs functional evidence indicates TRPC4/C5 mediated Ca2+ entry activated by Epo whereas PGE2 leads to a TRPC independent Ca2+ entry.

  15. Activation Cross-sections of Deuteron-induced Nuclear Reactions on Natural Titanium

    Science.gov (United States)

    Khandaker, M. U.; Haba, H.; Kanaya, J.; Otuka, N.; Kassim, H. A.

    2014-05-01

    Activation cross-sections of deuteron-induced nuclear reactions on natural titanium were measured up to 24-MeV energy using a stacked-foil activation technique in combination with HPGe γ-ray spectrometry. Measured cross-sections show an overall good agreement with the earlier measurements, but only a partial agreement with predictions by the TALYS code extracted from the TENDL-2011 library. The new cross-sections of the investigated reaction products find importance in nuclear medicine, accelerator and nuclear technology, and testing of nuclear reaction theories.

  16. 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...... 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....

  17. Current perspectives on protective roles of erythropoietin in cardiovascular system: erythropoietin receptor as a novel therapeutic target.

    Science.gov (United States)

    Kagaya, Yutaka; Asaumi, Yasuhide; Wang, Wanting; Takeda, Morihiko; Nakano, Makoto; Satoh, Kimio; Fukumoto, Yoshihiro; Shimokawa, Hiroaki

    2012-06-01

    Erythropoietin (EPO) is a principal regulator that promotes proliferation and terminal differentiation of erythroid progenitor cells. EPO receptors are expressed not only in hematopoietic lineage cells but also in the cardiovascular system. We performed animal experiments using transgene-rescued EPO receptor null mutant mice (EpoR-/- rescued) that express the EPO receptor exclusively in the hematopoietic cells. The results of these experiments suggest that endogenous EPO/EPO receptor system in the heart exerts cardioprotective effects against myocardial injury induced by ischemia followed by reperfusion and pressure-overload induced left ventricular dysfunction. Many animal experiments have shown that the administration of recombinant human EPO also elicits cardioprotective effects against myocardial injury induced by ischemia and reperfusion. In contrast to the promising results of these animal experiments, recent clinical trials failed to demonstrate the reduction in infarct size or improvement of cardiac function by the administration of recombinant human EPO in patients with acute myocardial infarction who underwent primary percutaneous coronary intervention. It should be tested in future clinical studies whether a relatively low dose of recombinant human EPO or its derivatives that have no erythropoietic action reduces infarct size and ameliorates cardiac dysfunction in patients with acute myocardial infarction. In this article, we review implications of anemia associated with chronic heart failure, roles of the endogenous EPO/EPO receptor system, and the effects of the administration of erythropoiesis-stimulating agents in pathologic conditions of the heart by focusing on the EPO receptor as a potential candidate of novel therapeutic targets in cardiovascular diseases.

  18. Erythropoietin in Treatment of Methanol Optic Neuropathy.

    Science.gov (United States)

    Pakdel, Farzad; Sanjari, Mostafa S; Naderi, Asieh; Pirmarzdashti, Niloofar; Haghighi, Anousheh; Kashkouli, Mohsen B

    2018-01-03

    Methanol poisoning can cause an optic neuropathy that is usually severe and irreversible and often occurs after ingestion of illicit or homemade alcoholic beverages. In this study, we evaluated the potential neuroprotective effect of erythropoietin (EPO) on visual acuity (VA) in patients with methanol optic neuropathy. In a prospective, noncomparative interventional case series, consecutive patients with methanol optic neuropathy after alcoholic beverage ingestion were included. All patients initially received systemic therapy including metabolic stabilization and detoxification. Treatment with intravenous recombinant human EPO consisted of 20,000 units/day for 3 successive days. Depending on clinical response, some patients received a second course of EPO. VA, funduscopy, and spectral domain optical coherence tomography were assessed during the study. Main outcome measure was VA. Thirty-two eyes of 16 patients with methanol optic neuropathy were included. Mean age was 34.2 years (±13.3 years). The mean time interval between methanol ingestion and treatment with intravenous EPO was 9.1 days (±5.56 days). Mean follow-up after treatment was 7.5 months (±5.88 months). Median VA in the better eye of each patient before treatment was light perception (range: 3.90-0.60 logMAR). Median last acuity after treatment in the best eye was 1.00 logMAR (range: 3.90-0.00 logMAR). VA significantly increased in the last follow-up examination (P neuropathy and may represent a promising treatment for this disorder.

  19. 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.

  20. A primer for electroweak induced low-energy nuclear reactions

    Indian Academy of Sciences (India)

    Abstract. Under special circumstances, electromagnetic and weak interactions can in- duce low-energy nuclear reactions to occur with observable rates for a variety of processes. A common element in all these applications is that the electromagnetic energy stored in many relatively slow-moving electrons can – under ...

  1. Host nuclear abnormalities and depletion of nuclear antigens induced in Trichinella spiralis-infected muscle cells by the anthelmintic mebendazole.

    Science.gov (United States)

    Yao, C; Bohnet, S; Jasmer, D P

    1998-10-30

    Infection by the parasitic nematode Trichinella spiralis induces cell cycle repositioning (chronic suspension in apparent G2/M) and genetic reprogramming in differentiated mammalian skeletal muscle cells. These changes occur in association with dramatic enlargement of infected host cell nuclei (as large as 17 microm in diameter) and nucleoli. Nuclear antigens (NA) that colocalize with host chromatin have been detected by antibodies to T. spiralis antigens, but the functions of these NA are unresolved. Mebendazole (MBZ) preferentially binds parasite versus host beta-tubulins, is implicated in inhibiting secretion in nematodes and induces cytoplasmic changes in muscle cells infected with T. spiralis. These infected cell changes might be indirect via MBZ inhibition of parasite secretions. This effect would have implications for host/parasite interactions and was evaluated here. MBZ treatment of chronically infected mice caused: (1) a significant deformation of host nuclei and diminution of nucleoli by 4 and 6 days of treatment (dot), respectively; (2) a reduction of nuclear lamins A/C in infected cell nuclei that was concomitant with nuclear deformation; and (3) significant reductions in total RNA, general protein and acid phosphatase activity levels. These changes were associated with the depletion of NA from host nuclei detected by 4 dot. However, DNA content of infected cell nuclei was not detectably reduced and muscle gene expression was not reactivated. The cellular changes documented are likely to account for previously described cytoplasmic alterations induced by MBZ. Concomitant depletion of NA from infected cell nuclei suggests a role of these products in regulating nuclear functions of host cells.

  2. AIRE-induced apoptosis is associated with nuclear translocation of stress sensor protein GAPDH

    Energy Technology Data Exchange (ETDEWEB)

    Liiv, Ingrid, E-mail: ingrid.liiv@ut.ee [Molecular Pathology, Institute of General and Molecular Pathology, University of Tartu, Tartu (Estonia); Haljasorg, Uku; Kisand, Kai; Maslovskaja, Julia; Laan, Martti; Peterson, Paert [Molecular Pathology, Institute of General and Molecular Pathology, University of Tartu, Tartu (Estonia)

    2012-06-22

    Highlights: Black-Right-Pointing-Pointer AIRE induces apoptosis in epithelial cells. Black-Right-Pointing-Pointer CARD domain of AIRE is sufficient for apoptosis induction. Black-Right-Pointing-Pointer AIRE induced apoptosis involves GAPDH translocation to the nuclei. Black-Right-Pointing-Pointer Deprenyl inhibits AIRE induced apoptosis. -- Abstract: AIRE (Autoimmune Regulator) has a central role in the transcriptional regulation of self-antigens in medullary thymic epithelial cells, which is necessary for negative selection of autoreactive T cells. Recent data have shown that AIRE can also induce apoptosis, which may be linked to cross-presentation of these self-antigens. Here we studied AIRE-induced apoptosis using AIRE over-expression in a thymic epithelial cell line as well as doxycycline-inducible HEK293 cells. We show that the HSR/CARD domain in AIRE together with a nuclear localization signal is sufficient to induce apoptosis. In the nuclei of AIRE-positive cells, we also found an increased accumulation of a glycolytic enzyme, glyceraldehyde-3-phosphate (GAPDH) reflecting cellular stress and apoptosis. Additionally, AIRE-induced apoptosis was inhibited with an anti-apoptotic agent deprenyl that blocks GAPDH nitrosylation and nuclear translocation. We propose that the AIRE-induced apoptosis pathway is associated with GAPDH nuclear translocation and induction of NO-induced cellular stress in AIRE-expressing cells.

  3. 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).

  4. 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...

  5. Modeled Neutron Induced Nuclear Reaction Cross Sections for Radiochemistry in the region of Iriduim and Gold

    Energy Technology Data Exchange (ETDEWEB)

    Hoffman, R D; Dietrich, F S; Kelley, K; Escher, J; Bauer, R; Mustafa, M

    2008-02-26

    We have developed a set of modeled nuclear reaction cross sections for use in radiochemical diagnostics. Systematics for the input parameters required by the Hauser-Feshbach statistical model were developed and used to calculate neutron induced nuclear reaction cross sections for targets ranging from osmium (Z = 76) to gold (Z = 79). Of particular interest are the cross sections on Ir and Au including reactions on isomeric targets.

  6. AIRE-induced apoptosis is associated with nuclear translocation of stress sensor protein GAPDH.

    Science.gov (United States)

    Liiv, Ingrid; Haljasorg, Uku; Kisand, Kai; Maslovskaja, Julia; Laan, Martti; Peterson, Pärt

    2012-06-22

    AIRE (Autoimmune Regulator) has a central role in the transcriptional regulation of self-antigens in medullary thymic epithelial cells, which is necessary for negative selection of autoreactive T cells. Recent data have shown that AIRE can also induce apoptosis, which may be linked to cross-presentation of these self-antigens. Here we studied AIRE-induced apoptosis using AIRE over-expression in a thymic epithelial cell line as well as doxycycline-inducible HEK293 cells. We show that the HSR/CARD domain in AIRE together with a nuclear localization signal is sufficient to induce apoptosis. In the nuclei of AIRE-positive cells, we also found an increased accumulation of a glycolytic enzyme, glyceraldehyde-3-phosphate (GAPDH) reflecting cellular stress and apoptosis. Additionally, AIRE-induced apoptosis was inhibited with an anti-apoptotic agent deprenyl that blocks GAPDH nitrosylation and nuclear translocation. We propose that the AIRE-induced apoptosis pathway is associated with GAPDH nuclear translocation and induction of NO-induced cellular stress in AIRE-expressing cells. Copyright © 2012 Elsevier Inc. All rights reserved.

  7. Is the use of recombinant human erythropoietin in anaemia of ...

    African Journals Online (AJOL)

    In a double-blind placebo-eontrolled study we showed a 3-fold decrease in blood transfusions (BTFs) given to preterm infants with anaemia of prematurity who received recombinant erythropoietin. However, only 50% of placebo recipients required a BTF. Data from the placebo group indicated that either mean daily weight ...

  8. Erythropoietin protects the retinal pigment epithelial barrier against ...

    African Journals Online (AJOL)

    Erythropoietin (EPO) is not limited to hematopoiesis; it may act as a protective cytokine. In this study, the retinal pigment epithelial (RPE) cell viability, cell monolayer integrity, RPE barrier permeability, distribution of the junction proteins ZO-1, occludin and the levels of superoxide dismutase (SOD) and malondialdehyde ...

  9. Effect of recombinant human erythropoietin expressions of apoptosis ...

    African Journals Online (AJOL)

    Effect of recombinant human erythropoietin expressions of apoptosis genes in rats following traumatic brain injury. Xuesong Yuan1*, Xiaoxing Bian1, Wenfeng Wei1, Yin Tang2 and Qing Bao1. 1Department of Neurosurgery, 2Department of Pathology, The Affiliated Wujin Hospital of Jiangsu University, Changzhou. Jiangsu ...

  10. CORRECTION OF ANAEMIA WITH ERYTHROPOIETIN IN CKD/ESRD PATIENTS

    OpenAIRE

    Madhukar,; Shyamal; Rashmi; Anitha; Bhattacharjee; Anjaiah; Abdul; Kunal,

    2015-01-01

    Chronic kidney disease ( CKD) is characterized by gradual and permanent loss of kidney function. One of the most common complications of CKD is Anaemia . 1,3 Anaemia often appears earlier in course of CKD and worsens with disease progression. 1,2 Erythropoietin is a hormone synthesized in the kidney is deficient in the majority of ...

  11. 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

  12. Study the relationship of erythropoietin and chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    R.I. El-Korashy

    2012-07-01

    It also appeared that response to erythropoietin in COPD is probably blunted especially with increased severity of the condition. This might be considered as a contributing factor in the development of anemia in COPD which is considered as anemia of chronic disease.

  13. 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.

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

    African Journals Online (AJOL)

    Background: Renal ischemia–reperfusion (RIR) is an important etiopathological mechanism of acute renal failure (ARF). Erythropoietin (EPO) has been candidate as a nephroprotectant agent. However, its nephroprotective effect when it is accompanied with estrogen has not been studied in female. Methods: Fifty-six female ...

  15. 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 leve...

  16. Saw palmetto extract induces nuclear heterogeneity in mice.

    Science.gov (United States)

    Trinachartvanit, Wachareeporn; Francis, Bettina M; Rayburn, A Lane

    2009-01-01

    Saw palmetto (SW), a phytotherapeutic compound used in the treatment of prostate disease, was examined for potential nuclear effects. SW extract was incorporated into a complete casein-based semisynthetic rodent chow at 0%, 0.1% and 1% SW. SW was fed to mice for 6 weeks, after which the mice received a single i/p injection of either the known genotoxic agent methyl methanesulfonate (MMS) in saline or just saline. Forty-eight hours after injection, blood and bone marrow were collected for flow cytometric analysis. A significant effect of MMS was observed in both male and female mice with respect to: an increase in nuclear heterogeneity in bone marrow cells as measured by the coefficient of variation of the G1 peak in a flow histogram (6.32 versus 4.8 in male mice, 7.0 versus 4.9 in female mice) and an increase in the number of micronucleated blood cells (3.4% versus 0.56% male mice, 3.1% versus 0.6 in female mice) indicating a positive genotoxic response. SW also appears to increase the heterogeneity of bone marrow nuclei in a dose dependent manner (0-5.1%, 0.1-5.5% and 1-5.7% in male mice, 0-5.7%, 0.1-6.0% and 1-6.2% in female mice) without a concomitant increase in blood cell micronuclei. These results indicate that SW is not genotoxic with respect to physical DNA damage and that the changes observed in the bone marrow are due to chromatin conformation modifications in the nuclei of in vivo treated mouse cells. Copyright © 2008 Elsevier B.V. All rights reserved.

  17. Charged particle-induced nuclear fission reactions–Progress and ...

    Indian Academy of Sciences (India)

    The theoretical developments to describe the fission phenomenon have kept pace with the progress in the corresponding experimental measurements. As the fission process initiated by the neutrons has been well documented, the present article will be restricted to charged particle-induced fission reactions. The progress ...

  18. Nuclear-Spin-Induced Circular Dichroism in the Infrared Region for Liquids.

    Science.gov (United States)

    Chen, Fang; Yao, Guo-hua; Zhang, Zhen-lin; Liu, Fan-chen; Chen, Dong-ming

    2015-06-22

    Recently, the nuclear-spin-induced optical rotation (NSOR) and circular dichroism (NSCD) for liquids were discovered and extensively studied and developed. However, so far, nuclear-spin-induced magnetic circular dichroism in the IR region (IR-NSCD) has not been explored, even though all polyatomic molecules exhibit extensive IR spectra. Herein, IR-NSCD is proposed and discussed theoretically. The results indicate that in favorable conditions the IR-NSCD angle may be much larger than the NSOR angle in the UV/Vis region due to a vibrational resonance effect and can be measurable by using the NSOR experiment scheme. IR-NSCD can automatically combine and give NMR spectra and IRCD spectra of the nuclear spin prepolarized samples in liquids, which, in principle, could be developed to become a unique, novel analytical tool. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. Experimental studies of keV energy neutron-induced reactions relevant to astrophysics and nuclear physics

    Energy Technology Data Exchange (ETDEWEB)

    Shima, T.; Kii, T.; Kikuchi, T.; Okazaki, F.; Kobayashi, T.; Baba, T.; Nagai, Y. [Tokyo Inst. of Tech. (Japan). Faculty of Science; Igashira, M.

    1997-03-01

    Nuclear reactions induced by keV energy neutrons provide a plenty of informations for studies of both astrophysics and nuclear physics. In this paper we will show our experimental studies of neutron- induced reactions of light nuclei in the keV energy region by means of a pulsed keV neutron beam and high-sensitivity detectors. Also we will discuss astrophysical and nuclear-physical consequences by using the obtained results. (author)

  20. Coupling Nuclear Induced Phonon Propagation with Conversion Electron Moessbauer Spectroscopy

    Science.gov (United States)

    2015-06-18

    electric current would be oscillated to create pole flipping in the stainless steel 85 that would induce phonons. The frequency of the...Source 168.3 22 Pre-mix He-3%CH4 1200V 44 2” SS310 Rod 241 Am Source flipped – Figure 24 (b) (A) 218.1 (B) 383.4 (C) 459.9 (D...hours, respectively. But Run34 flipped the bar around from surface 1 to surface 2 to see if there was an inhomogeneity in the material from one

  1. Nuclear Fusion Effects Induced in Intense Laser-Generated Plasmas

    OpenAIRE

    Lorenzo Torrisi; Salvatore Cavallaro; Mariapompea Cutroneo; Josef Krasa

    2013-01-01

    Deutered polyethylene (CD2)n thin and thick targets were irradiated in high vacuum by infrared laser pulses at 1015W/cm2 intensity. The high laser energy transferred to the polymer generates plasma, expanding in vacuum at supersonic velocity, accelerating hydrogen and carbon ions. Deuterium ions at kinetic energies above 4 MeV have been measured by using ion collectors and SiC detectors in time-of-flight configuration. At these energies the deuterium–deuterium collisions may induce over thres...

  2. 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......Background: Erythropoietin receptors have been identified in human skeletal muscle tissue, but downstream signal transduction has not been investigated. We therefore studied in vivo effects of systemic erythropoietin exposure in human skeletal muscle. Methodology/Principal Findings: The protocols...... involved 1) acute effects of a single bolus injection of erythropoietin followed by consecutive muscle biopsies for 1-10 hours, and 2) a separate study with prolonged administration for 16 days with biopsies obtained before and after. The presence of erythropoietin receptors in muscle tissue as well...

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

    Science.gov (United States)

    Hung, Annie K; Guy, Jennifer; Behler, Caroline M; Lee, Eugene E

    2015-01-01

    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.

  4. 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.

  5. Nuclear-spin-induced cotton-mouton effect in a strong external magnetic field.

    Science.gov (United States)

    Fu, Li-Juan; Vaara, Juha

    2014-08-04

    Novel, high-sensitivity and high-resolution spectroscopic methods can provide site-specific nuclear information by exploiting nuclear magneto-optic properties. We present a first-principles electronic structure formulation of the recently proposed nuclear-spin-induced Cotton-Mouton effect in a strong external magnetic field (NSCM-B). In NSCM-B, ellipticity is induced in a linearly polarized light beam, which can be attributed to both the dependence of the symmetric dynamic polarizability on the external magnetic field and the nuclear magnetic moment, as well as the temperature-dependent partial alignment of the molecules due to the magnetic fields. Quantum-chemical calculations of NSCM-B were conducted for a series of molecular liquids. The overall order of magnitude of the induced ellipticities is predicted to be 10(-11) -10(-6) rad T(-1)  M(-1)  cm(-1) for fully spin-polarized nuclei. In particular, liquid-state heavy-atom systems should be promising for experiments in the Voigt setup. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Role of apoptosis-inducing factor (AIF in programmed nuclear death during conjugation in Tetrahymena thermophila

    Directory of Open Access Journals (Sweden)

    Endoh Hiroshi

    2010-02-01

    Full Text Available Abstract Background Programmed nuclear death (PND, which is also referred to as nuclear apoptosis, is a remarkable process that occurs in ciliates during sexual reproduction (conjugation. In Tetrahymena thermophila, when the new macronucleus differentiates, the parental macronucleus is selectively eliminated from the cytoplasm of the progeny, concomitant with apoptotic nuclear events. However, the molecular mechanisms underlying these events are not well understood. The parental macronucleus is engulfed by a large autophagosome, which contains numerous mitochondria that have lost their membrane potential. In animals, mitochondrial depolarization precedes apoptotic cell death, which involves DNA fragmentation and subsequent nuclear degradation. Results We focused on the role of mitochondrial apoptosis-inducing factor (AIF during PND in Tetrahymena. The disruption of AIF delays the normal progression of PND, specifically, nuclear condensation and kilobase-size DNA fragmentation. AIF is localized in Tetrahymena mitochondria and is released into the macronucleus prior to nuclear condensation. In addition, AIF associates and co-operates with the mitochondrial DNase to facilitate the degradation of kilobase-size DNA, which is followed by oligonucleosome-size DNA laddering. Conclusions Our results suggest that Tetrahymena AIF plays an important role in the degradation of DNA at an early stage of PND, which supports the notion that the mitochondrion-initiated apoptotic DNA degradation pathway is widely conserved among eukaryotes.

  7. Experimental investigation and theoretical calculation for 3He induced nuclear reactions on vanadium

    Science.gov (United States)

    Ali, B. M.; Al-Abyad, M.; Seddik, U.; El-Kameesy, S. U.; Ditrói, F.; Takács, S.; Tárkányi, F.

    2016-04-01

    Using stacked-foil activation technique and gamma-ray spectrometry, excitation functions for 3He induced nuclear reactions on natV were measured. Cross-sections for natV(3He, xn)52m,gMn and natV(3He, pxn)51Cr nuclear reactions were measured up to 27 MeV utilizing the MGC-20E cyclotron of ATOMKI. The measurements establish for the first time consistent excitation curves. Comparisons with results for values derived from different theoretical codes were included. Integral yield were calculated.

  8. Experimental investigation and theoretical calculation for {sup 3}He induced nuclear reactions on vanadium

    Energy Technology Data Exchange (ETDEWEB)

    Ali, B.M. [Physics Department (Cyclotron Facility), Nuclear Research Centre, Atomic Energy Authority, Cairo 13759 (Egypt); Al-Abyad, M., E-mail: alabyad_m@yahoo.com [Physics Department (Cyclotron Facility), Nuclear Research Centre, Atomic Energy Authority, Cairo 13759 (Egypt); Seddik, U. [Physics Department (Cyclotron Facility), Nuclear Research Centre, Atomic Energy Authority, Cairo 13759 (Egypt); El-Kameesy, S.U. [Physics Department, Faculty of Science, Ain Shams University, Cairo (Egypt); Ditrói, F.; Takács, S.; Tárkányi, F. [Institute for Nuclear Research (ATOMKI), Hungarian Academy of Sciences, Debrecen H4026 (Hungary)

    2016-04-15

    Using stacked-foil activation technique and gamma-ray spectrometry, excitation functions for {sup 3}He induced nuclear reactions on {sup nat}V were measured. Cross-sections for {sup nat}V({sup 3}He, xn){sup 52m,g}Mn and {sup nat}V({sup 3}He, pxn){sup 51}Cr nuclear reactions were measured up to 27 MeV utilizing the MGC-20E cyclotron of ATOMKI. The measurements establish for the first time consistent excitation curves. Comparisons with results for values derived from different theoretical codes were included. Integral yield were calculated.

  9. Phenylmethimazole Blocks dsRNA-Induced IRF3 Nuclear Translocation and Homodimerization

    Directory of Open Access Journals (Sweden)

    Maria C. Courreges

    2012-10-01

    Full Text Available Previous studies revealed that phenylmethimazole (C10 inhibits IRF3 signaling, preventing dsRNA-induction of type 1 interferon gene expression, production, and downstream signaling. In the present study, we investigated the molecular basis for C10 inhibition of dsRNA-stimulated IRF3 signaling. IRF-3 Trans-AM assays were used to measure C10 effects on dsRNA induction of IRF3 DNA binding. Green fluorescent protein-labeled IRF3 was used to measure C10 effects on dsRNA-induced IRF3 nuclear translocation. Native PAGE, SDS PAGE, and western blotting were used to identify effects of C10 on IRF3 homodimer formation and phosphorylation, respectively. There was a significant impairment of dsRNA-induced IRF3 DNA binding activity in human embryonic kidney and pancreatic cancer cells with C10 treatment. C10 also blocked dsRNA-induced IRF3 nuclear translocation and homodimer formation without blocking serine 396 phosphorylation of IRF3. Together, these results indicate that C10 interferes with IRF3 signaling by blocking dsRNA-induced IRF3 homodimer formation, a prerequisite for nuclear translocation and DNA binding activities.

  10. Application of Compton-suppressed self-induced XRF to spent nuclear fuel measurement

    Science.gov (United States)

    Park, Se-Hwan; Jo, Kwang Ho; Lee, Seung Kyu; Seo, Hee; Lee, Chaehun; Won, Byung-Hee; Ahn, Seong-Kyu; Ku, Jeong-Hoe

    2017-11-01

    Self-induced X-ray fluorescence (XRF) is a technique by which plutonium (Pu) content in spent nuclear fuel can be directly quantified. In the present work, this method successfully measured the plutonium/uranium (Pu/U) peak ratio of a pressurized water reactor (PWR)'s spent nuclear fuel at the Korea atomic energy research institute (KAERI)'s post irradiation examination facility (PIEF). In order to reduce the Compton background in the low-energy X-ray region, the Compton suppression system additionally was implemented. By use of this system, the spectrum's background level was reduced by a factor of approximately 2. This work shows that Compton-suppressed selfinduced XRF can be effectively applied to Pu accounting in spent nuclear fuel.

  11. Relation between molecular electronic structure and nuclear spin-induced circular dichroism

    DEFF Research Database (Denmark)

    Štěpánek, Petr; Coriani, Sonia; Sundholm, Dage

    2017-01-01

    The recently theoretically described nuclear spin-induced circular dichroism (NSCD) is a promising method for the optical detection of nuclear magnetization. NSCD involves both optical excitations of the molecule and hyperfine interactions and, thus, it offers a means to realize a spectroscopy...... with the spatial distribution of the excited states and couplings between them, reflecting changes in molecular structure and conformation. This constitutes a marked difference to the nuclear magnetic resonance (NMR) chemical shift, which only reflects the local molecular structure in the ground electronic state...... are discussed. The results underline NSCD spectroscopy as a plausible tool with a power for the identification of not only different molecules, but their specific structures as well....

  12. Erythropoietin and interleukin-2 activate distinct JAK kinase family members.

    OpenAIRE

    Barber, D L; D'Andrea, A D

    1994-01-01

    The erythropoietin (EPO) receptor and the interleukin-2 (IL-2) receptor beta-chain subunit are members of the cytokine receptor superfamily. They have conserved primary amino acid sequences in their cytoplasmic domains and activate phosphorylation of common substrates, suggesting common biochemical signaling mechanisms. We have generated a cell line, CTLL-EPO-R, that contains functional cell surface receptors for both EPO and IL-2. CTLL-EPO-R cells demonstrated similar growth kinetics in EPO ...

  13. Erythropoietin and hypothermia for hypoxic-ischemic encephalopathy.

    Science.gov (United States)

    Rogers, Elizabeth E; Bonifacio, Sonia L; Glass, Hannah C; Juul, Sandra E; Chang, Taeun; Mayock, Dennis E; Durand, David J; Song, Dongli; Barkovich, Anthony J; Ballard, Roberta A; Wu, Yvonne W

    2014-11-01

    Erythropoietin is neuroprotective in animal models of neonatal hypoxic-ischemic encephalopathy. We previously reported a phase I safety and pharmacokinetic study of erythropoietin in neonates. This article presents the neurodevelopmental follow-up of infants who were enrolled in the phase I clinical trial. We enrolled 24 newborns with hypoxic-ischemic encephalopathy in a dose-escalation study. Patients received up to six doses of erythropoietin in addition to hypothermia. All infants underwent neonatal brain magnetic resonance imaging (MRI) reviewed by a single neuroradiologist. Moderate-to-severe neurodevelopmental disability was defined as cerebral palsy with Gross Motor Function Classification System levels III-V or cognitive impairment based on Bayley Scales of Infant Development II mental developmental index or Bayley III cognitive composite score. Outcomes were available for 22 of 24 infants, at mean age 22 months (range, 8-34 months). There were no deaths. Eight (36%) had moderate-to-severe brain injury on neonatal MRI. Moderate-to-severe disability occurred in one child (4.5%), in the setting of moderate-to-severe basal ganglia and/or thalamic injury. Seven infants with moderate-to-severe watershed injury exhibited the following outcomes: normal (three), mild language delay (two), mild hemiplegic cerebral palsy (one), and epilepsy (one). All 11 patients with a normal brain MRI had a normal outcome. This study is the first to describe neurodevelopmental outcomes in infants who received high doses of erythropoietin and hypothermia during the neonatal period. The findings suggest that future studies are warranted to assess the efficacy of this new potential neuroprotective therapy. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. Does erythropoietin cause hemoglobin variability--is it 'normal'?

    Directory of Open Access Journals (Sweden)

    Ashwani K Gupta

    Full Text Available Hemoglobin variability (Hb-var in patients with chronic kidney disease has been stipulated to be a result of exogenous treatment with erythropoiesis stimulating agents (ESA and has been related to mortality in dialysis patients. We hypothesized the existence of Hb-var independent of ESA administration and compared it to that in healthy adults using data from the Scripps-Kaiser and NHANES III databases. We studied the Hb-var in 1571 peritoneal dialysis patients which included 116 patients not requiring treatment with erythropoietin. We systematically studied the differences between the groups that needed ESA therapy and those who did not. White race and male sex were significant predictors of need for erythropoietin therapy. We found peritoneal dialysis patients to exhibit significantly increased Hb-var independent of treatment with exogenous erythropoietin (0.99 gm/dL vs. 1.17 gm/dL, p-value60 years peritoneal dialysis patients was similar to that seen in healthy elders, suggesting similarity with anemia of aging. We conclude that exogenous ESA administration does not explain Hb-var entirely but may enhance it. Intrinsic factors affecting erythropoiesis including age may be the major determinants of Hb-var.

  15. Synaptic activity induces dramatic changes in the geometry of the cell nucleus: interplay between nuclear structure, histone H3 phosphorylation, and nuclear calcium signaling.

    Science.gov (United States)

    Wittmann, Malte; Queisser, Gillian; Eder, Anja; Wiegert, J Simon; Bengtson, C Peter; Hellwig, Andrea; Wittum, Gabriel; Bading, Hilmar

    2009-11-25

    Synaptic activity initiates many adaptive responses in neurons. Here we report a novel form of structural plasticity in dissociated hippocampal cultures and slice preparations. Using a recently developed algorithm for three-dimensional image reconstruction and quantitative measurements of cell organelles, we found that many nuclei from hippocampal neurons are highly infolded and form unequally sized nuclear compartments. Nuclear infoldings are dynamic structures, which can radically transform the geometry of the nucleus in response to neuronal activity. Action potential bursting causing synaptic NMDA receptor activation dramatically increases the number of infolded nuclei via a process that requires the ERK-MAP kinase pathway and new protein synthesis. In contrast, death-signaling pathways triggered by extrasynaptic NMDA receptors cause a rapid loss of nuclear infoldings. Compared with near-spherical nuclei, infolded nuclei have a larger surface and increased nuclear pore complex immunoreactivity. Nuclear calcium signals evoked by cytosolic calcium transients are larger in small nuclear compartments than in the large compartments of the same nucleus; moreover, small compartments are more efficient in temporally resolving calcium signals induced by trains of action potentials in the theta frequency range (5 Hz). Synaptic activity-induced phosphorylation of histone H3 on serine 10 was more robust in neurons with infolded nuclei compared with neurons with near-spherical nuclei, suggesting a functional link between nuclear geometry and transcriptional regulation. The translation of synaptic activity-induced signaling events into changes in nuclear geometry facilitates the relay of calcium signals to the nucleus, may lead to the formation of nuclear signaling microdomains, and could enhance signal-regulated transcription.

  16. Recombinant human erythropoietin increases survival and reduces neuronal apoptosis in a murine model of cerebral malaria

    DEFF Research Database (Denmark)

    Wiese, Lothar; Hempel, Casper; Penkowa, Milena

    2008-01-01

    BACKGROUND: Cerebral malaria (CM) is an acute encephalopathy with increased pro-inflammatory cytokines, sequestration of parasitized erythrocytes and localized ischaemia. In children CM induces cognitive impairment in about 10% of the survivors. Erythropoietin (Epo) has - besides of its well known...... with recombinant human Epo (rhEpo; 50-5000 U/kg/OD, i.p.) at different time points. The effect on survival was measured. Brain pathology was investigated by TUNEL (Terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP)-digoxigenin nick end labelling), as a marker of apoptosis. Gene...... expression in brain tissue was measured by real time PCR. RESULTS: Treatment with rhEpo increased survival in mice with CM in a dose- and time-dependent manner and reduced apoptotic cell death of neurons as well as the expression of pro-inflammatory cytokines in the brain. This neuroprotective effect...

  17. 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......-receptor interaction. Moreover, endurance training, but not Epo treatment, increases the SC content in type II myofibres, as well as the content of MyoD(+) SCs. Collectively, our results suggest that Epo treatment can regulate human SCs in vivo, supported by Epo receptor mRNA expression in human SCs. In effect, long......-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...

  18. Nuclear envelope breakdown induced by herpes simplex virus type 1 involves the activity of viral fusion proteins

    Energy Technology Data Exchange (ETDEWEB)

    Maric, Martina; Haugo, Alison C. [Department of Microbiology, University of Iowa, Iowa City, IA 52242 (United States); Dauer, William [Department of Neurology, University of Michigan, Ann Arbor, MI 48109 (United States); Johnson, David [Department of Microbiology and Immunology, Oregon Health Sciences University, Portland, OR 97201 (United States); Roller, Richard J., E-mail: richard-roller@uiowa.edu [Department of Microbiology, University of Iowa, Iowa City, IA 52242 (United States)

    2014-07-15

    Herpesvirus infection reorganizes components of the nuclear lamina usually without loss of integrity of the nuclear membranes. We report that wild-type HSV infection can cause dissolution of the nuclear envelope in transformed mouse embryonic fibroblasts that do not express torsinA. Nuclear envelope breakdown is accompanied by an eight-fold inhibition of virus replication. Breakdown of the membrane is much more limited during infection with viruses that lack the gB and gH genes, suggesting that breakdown involves factors that promote fusion at the nuclear membrane. Nuclear envelope breakdown is also inhibited during infection with virus that does not express UL34, but is enhanced when the US3 gene is deleted, suggesting that envelope breakdown may be enhanced by nuclear lamina disruption. Nuclear envelope breakdown cannot compensate for deletion of the UL34 gene suggesting that mixing of nuclear and cytoplasmic contents is insufficient to bypass loss of the normal nuclear egress pathway. - Highlights: • We show that wild-type HSV can induce breakdown of the nuclear envelope in a specific cell system. • The viral fusion proteins gB and gH are required for induction of nuclear envelope breakdown. • Nuclear envelope breakdown cannot compensate for deletion of the HSV UL34 gene.

  19. Acetylation dynamics of human nuclear proteins during the ionizing radiation-induced DNA damage response

    DEFF Research Database (Denmark)

    Bennetzen, Martin V; Larsen, Dorthe Helena; Dinant, Christoffel

    2013-01-01

    -dependent posttranslational modifications (PTMs). To complement our previous analysis of IR-induced temporal dynamics of nuclear phosphoproteome, we now identify a range of human nuclear proteins that are dynamically regulated by acetylation, and predominantly deacetylation, during IR-induced DDR by using mass spectrometry...... to genotoxic insults. Overall, these results present a resource of temporal profiles of a spectrum of protein acetylation sites during DDR and provide further insights into the highly dynamic nature of regulatory PTMs that help orchestrate the maintenance of genome integrity.......Genotoxic insults, such as ionizing radiation (IR), cause DNA damage that evokes a multifaceted cellular DNA damage response (DDR). DNA damage signaling events that control protein activity, subcellular localization, DNA binding, protein-protein interactions, etc. rely heavily on time...

  20. Retinoic acid induces nuclear accumulation of Raf1 during differentiation of HL-60 cells

    Energy Technology Data Exchange (ETDEWEB)

    Smith, James; Bunaciu, Rodica P.; Reiterer, Gudrun [Department of Biomedical Sciences, T4-008 VRT, Cornell University, Ithaca, NY 14853 (United States); Coder, David; George, Thaddeus [Amnis Corporation, Seattle, Washington (United States); Asaly, Michael [Department of Biomedical Sciences, T4-008 VRT, Cornell University, Ithaca, NY 14853 (United States); Yen, Andrew, E-mail: ay13@cornell.edu [Department of Biomedical Sciences, T4-008 VRT, Cornell University, Ithaca, NY 14853 (United States)

    2009-08-01

    All trans-retinoic acid (RA) is a standard therapeutic agent used in differentiation induction therapy treatment of acute promyelocytic leukemia (APL). RA and its metabolites use a diverse set of signal transduction pathways during the differentiation program. In addition to the direct transcriptional targets of the nuclear RAR and RXR receptors, signals derived from membrane receptors and the Raf-MEK-ERK pathway are required. Raf1 phosphorylation and the prolonged activation of Raf1 persisting during the entire differentiation process are required for RA-dependent differentiation of HL-60 cells. Here we identify a nuclear redistribution of Raf1 during the RA-induced differentiation of HL-60 cells. In addition, the nuclear accumulation of Raf1 correlates with an increase in Raf1 phosphorylated at serine 621. The serine 621 phosphorylated Raf1 is predominantly localized in the nucleus. The RA-dependent nuclear accumulation of Raf1 suggests a novel nuclear role for Raf1 during the differentiation process.

  1. Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging

    Science.gov (United States)

    Gomes, Ana P.; Price, Nathan L.; Ling, Alvin J.Y.; Moslehi, Javid J.; Montgomery, Magdalene K.; Rajman, Luis; White, James P.; Teodoro, João S.; Wrann, Christiane D.; Hubbard, Basil P.; Mercken, Evi M.; Palmeira, Carlos M.; de Cabo, Rafael; Rolo, Anabela P.; Turner, Nigel; Bell, Eric L.; Sinclair, David A.

    2014-01-01

    SUMMARY Ever since eukaryotes subsumed the bacterial ancestor of mitochondria, the nuclear and mitochondrial genomes have had to closely coordinate their activities, as each encode different subunits of the oxidative phosphorylation (OXPHOS) system. Mitochondrial dysfunction is a hallmark of aging, but its causes are debated. We show that, during aging, there is a specific loss of mitochondrial, but not nuclear, encoded OXPHOS subunits. We trace the cause to an alternate PGC-1α/β-independent pathway of nuclear-mitochondrial communication that is induced by a decline in nuclear NAD+ and the accumulation of HIF-1α under normoxic conditions, with parallels to Warburg reprogramming. Deleting SIRT1 accelerates this process, whereas raising NAD+ levels in old mice restores mitochondrial function to that of a young mouse in a SIRT1-dependent manner. Thus, a pseudohypoxic state that disrupts PGC-1α/β-independent nuclear-mitochondrial communication contributes to the decline in mitochondrial function with age, a process that is apparently reversible. PMID:24360282

  2. Uranium analysis by neutron induced fissionography method using solid state nuclear track detectors

    CERN Document Server

    Akyuez, T; Guezel, T; Akyuz, S

    1999-01-01

    In this study total twenty samples (eight reference materials and twelve sediment samples) were analysed for their uranium content which is in the range of 1-17 mu g/g, by neutron induced fissionography (NIF) method using solid state nuclear track detectors (SSNTDs) in comparison with the results of neutron activation analysis (NAA), delayed neutron counting (DNC) technique or fluorometric method. It is found that NIF method using SSNTDs is very sensitive for analysis of uranium.

  3. Retinoids induce integrin-independent lymphocyte adhesion through RAR-α nuclear receptor activity

    Energy Technology Data Exchange (ETDEWEB)

    Whelan, Jarrett T.; Wang, Lei; Chen, Jianming; Metts, Meagan E.; Nasser, Taj A.; McGoldrick, Liam J. [Department of Biochemistry and Molecular Biology, The Brody School of Medicine at East Carolina University, Greenville, NC 27834 (United States); Bridges, Lance C., E-mail: bridgesl@ecu.edu [Department of Biochemistry and Molecular Biology, The Brody School of Medicine at East Carolina University, Greenville, NC 27834 (United States); East Carolina Diabetes and Obesity Institute, The Brody School of Medicine at East Carolina University, Greenville, NC 27834 (United States)

    2014-11-28

    Highlights: • Transcription and translation are required for retinoid-induced lymphocyte adhesion. • RAR activation is sufficient to induced lymphocyte cell adhesion. • Vitamin D derivatives inhibit RAR-prompted lymphocyte adhesion. • Adhesion occurs through a novel binding site within ADAM disintegrin domains. • RARα is a key nuclear receptor for retinoid-dependent lymphocyte cell adhesion. - Abstract: Oxidative metabolites of vitamin A, in particular all-trans-retinoic acid (atRA), have emerged as key factors in immunity by specifying the localization of immune cells to the gut. Although it is appreciated that isomers of retinoic acid activate the retinoic acid receptor (RAR) and retinoid X receptor (RXR) family of nuclear receptors to elicit cellular changes, the molecular details of retinoic acid action remain poorly defined in immune processes. Here we employ a battery of agonists and antagonists to delineate the specific nuclear receptors utilized by retinoids to evoke lymphocyte cell adhesion to ADAM (adisintegrin and metalloprotease) protein family members. We report that RAR agonism is sufficient to promote immune cell adhesion in both immortal and primary immune cells. Interestingly, adhesion occurs independent of integrin function, and mutant studies demonstrate that atRA-induced adhesion to ADAM members required a distinct binding interface(s) as compared to integrin recognition. Anti-inflammatory corticosteroids as well as 1,25-(OH){sub 2}D{sub 3}, a vitamin D metabolite that prompts immune cell trafficking to the skin, potently inhibited the observed adhesion. Finally, our data establish that induced adhesion was specifically attributable to the RAR-α receptor isotype. The current study provides novel molecular resolution as to which nuclear receptors transduce retinoid exposure into immune cell adhesion.

  4. 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.

  5. Laminopathy-inducing lamin A mutants can induce redistribution of lamin binding proteins into nuclear aggregates.

    Science.gov (United States)

    Hübner, S; Eam, J E; Hübner, A; Jans, D A

    2006-01-15

    Lamins, members of the family of intermediate filaments, form a supportive nucleoskeletal structure underlying the nuclear envelope and can also form intranuclear structures. Mutations within the A-type lamin gene cause a variety of degenerative diseases which are collectively referred to as laminopathies. At the molecular level, laminopathies have been shown to be linked to a discontinuous localization pattern of A-type lamins, with some laminopathies containing nuclear lamin A aggregates. Since nuclear aggregate formation could lead to the mislocalization of proteins interacting with A-type lamins, we set out to examine the effects of FLAG-lamin A N195K and R386K protein aggregate formation on the subnuclear distribution of the retinoblastoma protein (pRb) and the sterol responsive element binding protein 1a (SREBP1a) after coexpression as GFP-fusion proteins in HeLa cells. We observed strong recruitment of both proteins into nuclear aggregates. Nuclear aggregate recruitment of the NPC component nucleoporin NUP153 was also observed and found to be dependent on the N-terminus. That these effects were specific was implied by the fact that a number of other coexpressed karyophilic GFP-fusion proteins, such as the nucleoporin NUP98 and kanadaptin, did not coaggregate with FLAG-lamin A N195K or R386K. Immunofluorescence analysis further indicated that the precursor form of lamin A, pre-lamin A, could be found in intranuclear aggregates. Our results imply that redistribution into lamin A-/pre-lamin A-containing aggregates of proteins such as pRb and SREBP1a could represent a key aspect underlying the molecular pathogenesis of certain laminopathies.

  6. 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.

  7. Attenuation of IL-32-induced caspase-1 and nuclear factor-κB activations by acteoside.

    Science.gov (United States)

    Nam, Sun-Young; Kim, Hyung-Min; Jeong, Hyun-Ja

    2015-12-01

    Acteoside has anti-inflammatory and antioxidant potentials. Nevertheless, little information is available about the pharmacological mechanism of acteoside. Here, we report the regulatory effects and underlying mechanisms of acteoside on interleukin (IL)-32-induced inflammatory reactions using human monocytes cells line, THP-1 cells. Acteoside suppressed IL-32-induced macrophage-like cells differentiation. Levels of thymic stromal lymphopoietin, tumor necrosis factor (TNF)-α, IL-1β, and IL-8 increased by IL-32 or LPS were significantly reduced by treatment with acteoside in THP-1 cells. Acteoside attenuated IL-32-induced caspase-1 and nuclear factor-κB activations in THP-1 cells. In IL-32-induced macrophages, acteoside significantly reduced LPS-induced TNF-α, IL-1β, IL-6, and IL-8 production. In addition, production of nitric oxide (NO) and expression of inducible NO synthase increased by LPS were significantly decreased by treatment with acteoside in IL-32-induced macrophages. Our data suggest that acteoside exhibits an anti-inflammatory activity by suppressing IL-32 signaling pathway. Collectively, the results indicate that acteoside may act as a regulator of the IL-32 induced immune responses. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. Insulin-induced translocation of IR to the nucleus in insulin responsive cells requires a nuclear translocation sequence.

    Science.gov (United States)

    Kesten, Dov; Horovitz-Fried, Miriam; Brutman-Barazani, Tamar; Sampson, Sanford R

    2018-04-01

    Insulin binding to its cell surface receptor (IR) activates a cascade of events leading to its biological effects. The Insulin-IR complex is rapidly internalized and then is either recycled back to the plasma membrane or sent to lysosomes for degradation. Although most of the receptor is recycled or degraded, a small amount may escape this pathway and migrate to the nucleus of the cell where it might be important in promulgation of receptor signals. In this study we explored the mechanism by which insulin induces IR translocation to the cell nucleus. Experiments were performed cultured L6 myoblasts, AML liver cells and 3T3-L1 adipocytes. Insulin treatment induced a rapid increase in nuclear IR protein levels within 2 to 5 min. Treatment with WGA, an inhibitor of nuclear import, reduced insulin-induced increases nuclear IR protein; IR was, however, translocated to a perinuclear location. Bioinformatics tools predicted a potential nuclear localization sequence (NLS) on IR. Immunofluorescence staining showed that a point mutation on the predicted NLS blocked insulin-induced IR nuclear translocation. In addition, blockade of nuclear IR activation in isolated nuclei by an IR blocking antibody abrogated insulin-induced increases in IR tyrosine phosphorylation and nuclear PKCδ levels. Furthermore, over expression of mutated IR reduced insulin-induced glucose uptake and PKB phosphorylation. When added to isolated nuclei, insulin induced IR phosphorylation but had no effect on nuclear IR protein levels. These results raise questions regarding the possible role of nuclear IR in IR signaling and insulin resistance. Copyright © 2018 Elsevier B.V. All rights reserved.

  9. 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...

  10. 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...

  11. 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,

  12. The overexpression of nuclear envelope protein Lap2β induces endoplasmic reticulum reorganisation via membrane stacking

    Directory of Open Access Journals (Sweden)

    Ekaterina G. Volkova

    2012-06-01

    Some nuclear envelope proteins are localised to both the nuclear envelope and the endoplasmic reticulum; therefore, it seems plausible that even small amounts of these proteins can influence the organisation of the endoplasmic reticulum. A simple method to study the possible effects of nuclear envelope proteins on endoplasmic reticulum organisation is to analyze nuclear envelope protein overexpression. Here, we demonstrate that Lap2β overexpression can induce the formation of cytoplasmic vesicular structures derived from endoplasmic reticulum membranes. Correlative light and electron microscopy demonstrated that these vesicular structures were composed of a series of closely apposed membranes that were frequently arranged in a circular fashion. Although stacked endoplasmic reticulum cisternae were highly ordered, Lap2β could readily diffuse into and out of these structures into the surrounding reticulum. It appears that low-affinity interactions between cytoplasmic domains of Lap2β can reorganise reticular endoplasmic reticulum into stacked cisternae. Although the effect of one protein may be insignificant at low concentrations, the cumulative effect of many non-specialised proteins may be significant.

  13. Outer nuclear membrane fusion of adjacent nuclei in varicella-zoster virus-induced syncytia.

    Science.gov (United States)

    Wang, Wei; Yang, Lianwei; Huang, Xiumin; Fu, Wenkun; Pan, Dequan; Cai, Linli; Ye, Jianghui; Liu, Jian; Xia, Ningshao; Cheng, Tong; Zhu, Hua

    2017-12-01

    Syncytia formation has been considered important for cell-to-cell spread and pathogenesis of many viruses. As a syncytium forms, individual nuclei often congregate together, allowing close contact of nuclear membranes and possibly fusion to occur. However, there is currently no reported evidence of nuclear membrane fusion between adjacent nuclei in wild-type virus-induced syncytia. Varicella-zoster virus (VZV) is one typical syncytia-inducing virus that causes chickenpox and shingles in humans. Here, we report, for the first time, an interesting observation of apparent fusion of the outer nuclear membranes from juxtaposed nuclei that comprise VZV syncytia both in ARPE-19 human epithelial cells in vitro and in human skin xenografts in the SCID-hu mouse model in vivo. This work reveals a novel aspect of VZV-related cytopathic effect in the context of multinucleated syncytia. Additionally, the information provided by this study could be helpful for future studies on interactions of viruses with host cell nuclei. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Transcriptional Profile of HIV-induced Nuclear Translocation of Amyloid β in Brain Endothelial Cells

    Science.gov (United States)

    András, Ibolya E.; Rampersaud, Evadnie; Eum, Sung Yong; Toborek, Michal

    2015-01-01

    Background and Aims Increased amyloid deposition in HIV-infected brains may contribute to the pathogenesis of neurocognitive dysfunction in infected patients. We have previously shown that exposure to HIV results in enhanced amyloid β (Aβ) levels in human brain microvascular endothelial cells, suggesting that brain endothelial cells contribute to accumulation of Aβ in HIV-infected brains. Importantly, Aβ not only accumulates in the cytoplasm of HIV-exposed cells but also enters the nuclei of brain endothelial cells. Methods cDNA microarray analysis was performed in order to examine changes in the transcriptional profile associated with Aβ nuclear entry in the presence of HIV-1. Results Gene network analysis indicated that inhibition of nuclear entry of Aβ resulted in enrichment in gene sets involved in apoptosis and survival, endoplasmic reticulum stress response, immune response, cell cycle, DNA damage, oxidative stress, cytoskeleton remodeling and transforming growth factor b (TGFβ) receptor signaling. Conclusions The obtained data indicate that HIV-inducednuclear uptake affects several cellular stress-related pathways relevant for HIV-induced Aβ pathology. PMID:25446617

  15. Metazoan Nuclear Pores Provide a Scaffold for Poised Genes and Mediate Induced Enhancer-Promoter Contacts.

    Science.gov (United States)

    Pascual-Garcia, Pau; Debo, Brian; Aleman, Jennifer R; Talamas, Jessica A; Lan, Yemin; Nguyen, Nha H; Won, Kyoung J; Capelson, Maya

    2017-04-06

    Nuclear pore complex components (Nups) have been implicated in transcriptional regulation, yet what regulatory steps are controlled by metazoan Nups remains unclear. We identified the presence of multiple Nups at promoters, enhancers, and insulators in the Drosophila genome. In line with this binding, we uncovered a functional role for Nup98 in mediating enhancer-promoter looping at ecdysone-inducible genes. These genes were found to be stably associated with nuclear pores before and after activation. Although changing levels of Nup98 disrupted enhancer-promoter contacts, it did not affect ongoing transcription but instead compromised subsequent transcriptional activation or transcriptional memory. In support of the enhancer-looping role, we found Nup98 to gain and retain physical interactions with architectural proteins upon stimulation with ecdysone. Together, our data identify Nups as a class of architectural proteins for enhancers and supports a model in which animal genomes use the nuclear pore as an organizing scaffold for inducible poised genes. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Nuclear quadrupole moment-induced Cotton-Mouton effect in molecules

    Energy Technology Data Exchange (ETDEWEB)

    Fu, Li-juan, E-mail: lijuan.fu@oulu.fi, E-mail: juha.vaara@iki.fi; Vaara, Juha, E-mail: lijuan.fu@oulu.fi, E-mail: juha.vaara@iki.fi [NMR Research Group, Department of Physics, University of Oulu, P.O. Box 3000, FIN-90014 Oulu (Finland)

    2014-01-14

    Nuclear magneto-optic effects could make important contributions to novel, high-sensitivity, and high-resolution spectroscopic and imaging methods that provide nuclear site-specific structural and dynamic information on molecular and materials systems. Here we present a first-principles electronic structure formulation of nuclear quadrupole moment-induced Cotton-Mouton effect in terms of response theory, as well as ab initio and density-functional theory calculations of this phenomenon for a series of molecular liquids: H{sub 2}O, CH{sub 3}NO{sub 2}, CH{sub 3}CH{sub 2}OH, C{sub 6}H{sub 6}, C{sub 6}H{sub 12} (cyclohexane), HI, XeF{sub 2}, WF{sub 5}Cl, and Pt(C{sub 2}dtp){sub 2}. The roles of basis-set convergence, electron correlation, and relativistic effects are discussed. The estimated order of magnitude of the overall ellipticities induced to linearly polarized light is 10{sup −3}–10{sup −7} rad/(M cm) for fully spin polarized nuclei. The cases with the largest presently obtained ellipticities should be detectable with modern instrumentation in the Voigt magneto-optic setup, particularly for the heavy nuclei.

  17. Nuclear quadrupole moment-induced Cotton-Mouton effect in molecules

    Science.gov (United States)

    Fu, Li-juan; Vaara, Juha

    2014-01-01

    Nuclear magneto-optic effects could make important contributions to novel, high-sensitivity, and high-resolution spectroscopic and imaging methods that provide nuclear site-specific structural and dynamic information on molecular and materials systems. Here we present a first-principles electronic structure formulation of nuclear quadrupole moment-induced Cotton-Mouton effect in terms of response theory, as well as ab initio and density-functional theory calculations of this phenomenon for a series of molecular liquids: H2O, CH3NO2, CH3CH2OH, C6H6, C6H12 (cyclohexane), HI, XeF2, WF5Cl, and Pt(C2dtp)2. The roles of basis-set convergence, electron correlation, and relativistic effects are discussed. The estimated order of magnitude of the overall ellipticities induced to linearly polarized light is 10-3-10-7 rad/(M cm) for fully spin polarized nuclei. The cases with the largest presently obtained ellipticities should be detectable with modern instrumentation in the Voigt magneto-optic setup, particularly for the heavy nuclei.

  18. Nonelastic nuclear reactions induced by light ions with the BRIEFF code

    CERN Document Server

    Duarte, H

    2010-01-01

    The intranuclear cascade (INC) code BRIC has been extended to compute nonelastic reactions induced by light ions on target nuclei. In our approach the nucleons of the incident light ion move freely inside the mean potential of the ion in its center-of-mass frame while the center-of-mass of the ion obeys to equations of motion dependant on the mean nuclear+Coulomb potential of the target nucleus. After transformation of the positions and momenta of the nucleons of the ion into the target nucleus frame, the collision term between the nucleons of the target and of the ion is computed taking into account the partial or total breakup of the ion. For reactions induced by low binding energy systems like deuteron, the Coulomb breakup of the ion at the surface of the target nucleus is an important feature. Preliminary results of nucleon production in light ion induced reactions are presented and discussed.

  19. Asymmetric Dimethylarginine Contributes to the Impaired Response to Erythropoietin in CKD-Anemia.

    Science.gov (United States)

    Yokoro, Miyuki; Nakayama, Yosuke; Yamagishi, Sho-Ichi; Ando, Ryotaro; Sugiyama, Miki; Ito, Sakuya; Yano, Junko; Taguchi, Kensei; Kaida, Yusuke; Saigusa, Daisuke; Kimoto, Masumi; Abe, Takaaki; Ueda, Seiji; Fukami, Kei

    2017-09-01

    Erythropoietin-resistant anemia is associated with adverse cardiovascular events in patients with ESRD, but the underlying mechanism remains unclear. Here, we evaluated the role of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA). In 54 patients with advanced CKD, erythrocyte but not plasma ADMA levels independently associated with low hemoglobin values, although levels of both types of ADMA were elevated compared with those in healthy volunteers. Furthermore, erythrocyte ADMA level associated with the erythropoietin resistance index in patients receiving a weekly injected dose of erythropoiesis-stimulating agents standardized for hemoglobin levels and body weight, whereas it correlated with the erythropoietin demand index (plasma erythropoietin units divided by the hemoglobin value) in patients not receiving erythropoiesis-stimulating agents. Compared with sham-operated controls, wild-type mice with 5/6 subtotal nephrectomy (Nx), a remnant kidney model with advanced CKD, had decreased hemoglobin, hematocrit, and mean corpuscular volume values but increased erythrocyte and plasma ADMA and plasma erythropoietin levels. In comparison, dimethylarginine dimethlaminohydrolase-1 transgenic (DDAH-1 Tg) mice, which efficiently metabolized ADMA, had significant improvements in all of the values except those for erythropoietin after 5/6 Nx. Additionally, wild-type Nx mice, but not DDAH-1 Tg Nx mice, had reduced splenic gene expression of erythropoietin receptor and erythroferrone, which regulates iron metabolism in response to erythropoietin. This study suggests that erythrocyte ADMA accumulation contributes to impaired response to erythropoietin in predialysis patients and advanced CKD mice via suppression of erythropoietin receptor expression. Copyright © 2017 by the American Society of Nephrology.

  20. 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

  1. Helicobacter pylori Infection Induces Genetic Instability of Nuclear and Mitochondrial DNA in Gastric Cells

    DEFF Research Database (Denmark)

    Machado, Ana Manuel; Figueiredo, Ceu; Touati, Eliette

    2009-01-01

    of genetic instabilities in the nuclear and mitochondrial DNA (mtDNA) were examined. Experimental Design: We observed the effects of H pylori infection on a gastric cell line (AGS), on C57BL/6 mice, and on individuals with chronic gastritis. In AGS cells, the effect of H pylori infection on base excision...... cells and chronic gastritis tissue were determined by PCR, single-stranded conformation polymorphism, and sequencing. H pylori vacA and cagA genotyping was determined by multiplex PCR and reverse hybridization. Results: Following H pylori infection, the activity and expression of base excision repair...... and MMR are down-regulated both in vitro and in vivo. Moreover, H. pylori induces genomic instability in nuclear CA repeats in mice and in mtDNA of AGS cells and chronic gastritis tissue, and this effect in mtDNA is associated with bacterial virulence. Conclusions: Our results suggest that H pylori...

  2. Nuclear dynamics of radiation-induced foci in euchromatin and heterochromatin

    Energy Technology Data Exchange (ETDEWEB)

    Chiolo, Irene; Tang, Jonathan; Georgescu, Walter; Costes, Sylvain V.

    2013-10-01

    Repair of double strand breaks (DSBs) is essential for cell survival and genome integrity. While much is known about the molecular mechanisms involved in DSB repair and checkpoint activation, the roles of nuclear dynamics of radiation-induced foci (RIF) in DNA repair are just beginning to emerge. Here, we summarize results from recent studies that point to distinct features of these dynamics in two different chromatin environments: heterochromatin and euchromatin. We also discuss how nuclear architecture and chromatin components might control these dynamics, and the need of novel quantification methods for a better description and interpretation of these phenomena. These studies are expected to provide new biomarkers for radiation risk and new strategies for cancer detection and treatment.

  3. Biological evaluation of recombinant human erythropoietin in pharmaceutical products

    Directory of Open Access Journals (Sweden)

    Ramos A.S.

    2003-01-01

    Full Text Available The potencies of mammalian cell-derived recombinant human erythropoietin pharmaceutical preparations, from a total of five manufacturers, were assessed by in vivo bioassay using standardized protocols. Eight-week-old normocythemic mice received a single subcutaneous injection followed by blood sampling 96 h later or multiple daily injections with blood sampling 24 h after the last injection. Reticulocyte counting by microscopic examination was employed as the end-point using the brilliant cresyl blue or selective hemolysis methods, together with automated flow cytometry. Different injection schedules were investigated and dose-response curves for the European Pharmacopoeia Biological Reference Preparation of erythropoietin were compared. Manual and automated methods of reticulocyte counting were correlated with respect to assay validity and precision. Using 8 mice per treatment group, intra-assay precision determined for all of the assays in the study showed coefficients of variation of 12.1-28.4% for the brilliant cresyl blue method, 14.1-30.8% for the selective hemolysis method and 8.5-19.7% for the flow cytometry method. Applying the single injection protocol, a combination of at least two independent assays was required to achieve the precision potency and confidence limits indicated by the manufacturers, while the multiple daily injection protocol yielded the same acceptable results within a single assay. Although the latter protocol using flow cytometry for reticulocyte counting gave more precise and reproducible results (intra-assay coefficients of variation: 5.9-14.2%, the well-characterized manual methods provide equally valid alternatives for the quality control of recombinant human erythropoietin therapeutic products.

  4. 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)

  5. Distinct cytoplasmic and nuclear functions of the stress induced protein DDIT3/CHOP/GADD153.

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    Alexandra Jauhiainen

    Full Text Available DDIT3, also known as GADD153 or CHOP, encodes a basic leucine zipper transcription factor of the dimer forming C/EBP family. DDIT3 is known as a key regulator of cellular stress response, but its target genes and functions are not well characterized. Here, we applied a genome wide microarray based expression analysis to identify DDIT3 target genes and functions. By analyzing cells carrying tamoxifen inducible DDIT3 expression constructs we show distinct gene expression profiles for cells with cytoplasmic and nuclear localized DDIT3. Of 175 target genes identified only 3 were regulated by DDIT3 in both cellular localizations. More than two thirds of the genes were downregulated, supporting a role for DDIT3 as a dominant negative factor that could act by either cytoplasmic or nuclear sequestration of dimer forming transcription factor partners. Functional annotation of target genes showed cell migration, proliferation and apoptosis/survival as the most affected categories. Cytoplasmic DDIT3 affected more migration associated genes, while nuclear DDIT3 regulated more cell cycle controlling genes. Cell culture experiments confirmed that cytoplasmic DDIT3 inhibited migration, while nuclear DDIT3 caused a G1 cell cycle arrest. Promoters of target genes showed no common sequence motifs, reflecting that DDIT3 forms heterodimers with several alternative transcription factors that bind to different motifs. We conclude that expression of cytoplasmic DDIT3 regulated 94 genes. Nuclear translocation of DDIT3 regulated 81 additional genes linked to functions already affected by cytoplasmic DDIT3. Characterization of DDIT3 regulated functions helps understanding its role in stress response and involvement in cancer and degenerative disorders.

  6. Lipopolysaccharide triggers nuclear import of Lpcat1 to regulate inducible gene expression in lung epithelia.

    Science.gov (United States)

    Ellis, Bryon; Kaercher, Leah; Snavely, Courtney; Zhao, Yutong; Zou, Chunbin

    2012-07-26

    To report that Lpcat1 plays an important role in regulating lipopolysaccharide (LPS) inducible gene transcription. Gene expression in Murine Lung Epithelial MLE-12 cells with LPS treatment or Haemophilus influenza and Escherichia coli infection was analyzed by employing quantitative Reverse Transcription Polymerase Chain Reaction techniques. Nucleofection was used to deliver Lenti-viral system to express or knock down Lpcat1 in MLE cells. Subcellular protein fractionation and Western blotting were utilized to study Lpcat1 nuclear relocation. Lpcat1 translocates into the nucleus from the cytoplasm in murine lung epithelia (MLE) after LPS treatment. Haemophilus influenza and Escherichia coli, two LPS-containing pathogens that cause pneumonia, triggered Lpcat1 nuclear translocation from the cytoplasm. The LPS inducible gene expression profile was determined by quantitative reverse transcription polymerase chain reaction after silencing Lpcat1 or overexpression of the enzyme in MLE cells. We detected that 17 out of a total 38 screened genes were upregulated, 14 genes were suppressed, and 7 genes remained unchanged in LPS treated cells in comparison to controls. Knockdown of Lpcat1 by shRNA dramatically changed the spectrum of the LPS inducible gene transcription, as 18 genes out of 38 genes were upregulated, of which 20 genes were suppressed or unchanged. Notably, in Lpcat1 overexpressed cells, 25 genes out of 38 genes were reduced in the setting of LPS treatment. These observations suggest that Lpcat1 relocates into the nucleus in response to bacterial infection to differentially regulate gene transcriptional repression.

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

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    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

  8. 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......, double-blind, placebo-controlled phase 2 trial, in which 52 patients with secondary or primary progressive MS were allocated to treatment with recombinant EPO (48,000 IU) or placebo, administered intravenously 17 times during 24 weeks. Patients had an Expanded Disability Status Score (EDSS) from 4 to 6...

  9. Three-Dimensional Reconstruction of Nuclear Envelope Architecture Using Dual-Color Metal-Induced Energy Transfer Imaging.

    Science.gov (United States)

    Chizhik, Anna M; Ruhlandt, Daja; Pfaff, Janine; Karedla, Narain; Chizhik, Alexey I; Gregor, Ingo; Kehlenbach, Ralph H; Enderlein, Jörg

    2017-12-26

    The nuclear envelope, comprising the inner and the outer nuclear membrane, separates the nucleus from the cytoplasm and plays a key role in cellular functions. Nuclear pore complexes (NPCs), which are embedded in the nuclear envelope, control transport of macromolecules between the two compartments. Here, using dual-color metal-induced energy transfer (MIET), we determine the axial distance between Lap2β and Nup358 as markers for the inner nuclear membrane and the cytoplasmic side of the NPC, respectively. Using MIET imaging, we reconstruct the 3D profile of the nuclear envelope over the whole basal area, with an axial resolution of a few nanometers. This result demonstrates that optical microscopy can achieve nanometer axial resolution in biological samples and without recourse to complex interferometric approaches.

  10. Deletion of von Hippel–Lindau Protein Converts Renin-Producing Cells into Erythropoietin-Producing Cells

    Science.gov (United States)

    Paliege, Alexander; Willam, Carsten; Schwarzensteiner, Ilona; Schucht, Kathrin; Neymeyer, Hanna; Sequeira-Lopez, Maria Luisa S.; Bachmann, Sebastian; Gomez, R. Ariel; Eckardt, Kai-Uwe; Kurtz, Armin

    2013-01-01

    States of low perfusion pressure of the kidney associate with hyperplasia or expansion of renin-producing cells, but it is unknown whether hypoxia-triggered genes contribute to these changes. Here, we stabilized hypoxia-inducible transcription factors (HIFs) in mice by conditionally deleting their negative regulator, Vhl, using the Cre/loxP system with renin-1d promoter-driven Cre expression. Vhl −/−REN mice were viable and had normal BP. Deletion of Vhl resulted in constitutive accumulation of HIF-2α in afferent arterioles and glomerular cells and HIF-1α in collecting duct cells of the adult kidney. The preglomerular vascular tree developed normally, but far fewer renin-expressing cells were present, with more than 70% of glomeruli not containing renin cells at the typical juxtaglomerular position. Moreover, these mice had an attenuated expansion of renin-producing cells in response to a low-salt diet combined with an ACE inhibitor. However, renin-producing cells of Vhl −/−REN mice expressed the erythropoietin gene, and they were markedly polycythemic. Taken together, these results suggest that hypoxia-inducible genes, regulated by VHL, are essential for normal development and physiologic adaptation of renin-producing cells. In addition, deletion of Vhl shifts the phenotype of juxtaglomerular cells from a renin- to erythropoietin-secreting cell type, presumably in response to HIF-2 accumulation. PMID:23393316

  11. Investigation of the {alpha}-particle induced nuclear reactions on natural molybdenum

    Energy Technology Data Exchange (ETDEWEB)

    Ditroi, F., E-mail: ditroi@atomki.hu [Institute of Nuclear Research of the Hungarian Academy of Sciences (ATOMKI), 4026 Debrecen (Hungary); Hermanne, A. [Cyclotron Laboratory, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels (Belgium); Tarkanyi, F.; Takacs, S. [Institute of Nuclear Research of the Hungarian Academy of Sciences (ATOMKI), 4026 Debrecen (Hungary); Ignatyuk, A.V. [Institute of Physics and Power Engineering (IPPE), Obninsk 249020 (Russian Federation)

    2012-08-15

    Highlights: Black-Right-Pointing-Pointer Excitation function measurement of {alpha}-particle induced reactions on natural molybdenum up to 40 MeV. Black-Right-Pointing-Pointer Model code calculations with EMPIRE-II, EMPIRE3.1, ALICE and TALYS. Black-Right-Pointing-Pointer Integral production yield calculation. Black-Right-Pointing-Pointer Comparison with deuteron and proton production. Black-Right-Pointing-Pointer Monitor reactions for {alpha}-irradiations. - Abstract: Cross-sections of alpha particle induced nuclear reactions on natural molybdenum have been studied in the frame of a systematic investigation of charged particle induced nuclear reactions on metals for different applications. The excitation functions of {sup 93m}Tc, {sup 93g}Tc{sup (m+)}, {sup 94m}Tc, {sup 94g}Tc, {sup 95m}Tc, {sup 95g}Tc, {sup 96g}Tc{sup (m+)}, {sup 99m}Tc, {sup 93m}Mo, {sup 99}Mo{sup (cum)}, {sup 90}Nb{sup (m+)}, {sup 94}Ru, {sup 95}Ru,{sup 97}Ru, {sup 103}Ru and {sup 88}Zr were measured up to 40 MeV alpha energy by using a stacked foil technique and activation method. The main goals of this work were to get experimental data for accelerator technology, for monitoring of alpha beam, for thin layer activation technique and for testing nuclear reaction theories. The experimental data were compared with critically analyzed published data and with the results of model calculations, obtained by using the ALICE-IPPE, EMPIRE and TALYS codes (TENDL-2011).

  12. The identification of experimentally induced appendicitis using in vitro nuclear magnetic resonance.

    Science.gov (United States)

    Jacobs, D O; Clarke, J R; Settle, R G; Sachdeva, A K; Wheeler, J E; Trerotola, S O; Wolf, G L; Rombeau, J L

    1985-07-01

    Appendicitis was induced in six New Zealand white rabbits. The appendices from these animals had significantly higher spin-lattice relaxation times, T1, as determined in vitro by nuclear magnetic resonance (NMR) (10 controls vs 6 experimentals, 413 +/- 23 vs 455 +/- 41, X +/- SD, P less than (0.02). T1 correlated significantly with the water content of the appendiceal tissue (P less than 0.001). These findings suggest that in vivo NMR imaging techniques weighted on T1 might be able to identify human appendicitis noninvasively by detecting localized edema.

  13. Nuclear factor-kappa B is not involved in titanium dioxide-induced inflammation.

    Science.gov (United States)

    Wilson, Donald; Zaqout, Mazen; Heo, Jeong-Hoon; Park, Eun-Kee; Oak, Chul-Ho; Ueno, Susumu

    2012-06-01

    Research over recent years have shown that titanium dioxide (TiO2) nanoparticles (NPs) induce inflammation in various lung, kidney, liver and brain cells. Although the mechanism of inflammation is unclear, existing literature suggests the underlying role of oxidative stress. On the other hand, it has also been shown that nuclear factor-kappa B (NF-kappaB) is activated in response to pro-inflammatory cytokines. In this study we investigated the involvement of NF-kappaB in TiO2-induced inflammation in human lung adenocarcinomic epithelial cells (A549 cells). After 24h of treatment, IL-8 protein release from A549 cells, induced by 10, 50 and 250 microg/ml of P25 TiO2 NPs, were statistically significantly raised, compared to that of the control. This finding corroborates existing literature in that TiO2 NPs induce a dose-dependent increase in the release of IL-8 protein when exposed to A549 cells. However, the binding of NF-kappaB DNA was not affected after 6 h of incubation with P25. Therefore, NF-kappaB DNA binding is not the likely transcription pathway that leads to TiO2-induced inflammation.

  14. Nuclear Spiral Shocks and Induced Gas Inflows in Weak Oval Potentials

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Woong-Tae [Department of Physics and Astronomy, Seoul National University, Seoul 151-742 (Korea, Republic of); Elmegreen, Bruce G., E-mail: wkim@astro.snu.ac.kr, E-mail: bge@us.ibm.com [IBM T. J. Watson Research Center, 1101 Kitchawan Road, Yorktown Heights, NY 10598 (United States)

    2017-05-20

    Nuclear spirals are ubiquitous in galaxy centers. They exist not only in strong barred galaxies but also in galaxies without noticeable bars. We use high-resolution hydrodynamic simulations to study the properties of nuclear gas spirals driven by weak bar-like and oval potentials. The amplitude of the spirals increases toward the center by a geometric effect, readily developing into shocks at small radii even for very weak potentials. The shape of the spirals and shocks depends rather sensitively on the background shear. When shear is low, the nuclear spirals are loosely wound and the shocks are almost straight, resulting in large mass inflows toward the center. When shear is high, on the other hand, the spirals are tightly wound and the shocks are oblique, forming a circumnuclear disk through which gas flows inward at a relatively lower rate. The induced mass inflow rates are enough to power black hole accretion in various types of Seyfert galaxies as well as to drive supersonic turbulence at small radii.

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

    Directory of Open Access Journals (Sweden)

    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.

  16. Experimental determination of activation cross section of alpha-induced nuclear reactions on natPt

    Science.gov (United States)

    Hermanne, A.; Tárkányi, F.; Takács, S.; Shubin, Yu. N.; Kovalev, S.

    2006-10-01

    Alpha-particle induced nuclear reactions that result in the generation of several Hg (mass numbers 192, 193m, 193g, 195m, 195g, 197m, 197g, 199m) and Au (mass numbers 194, 195m, 195g, 196n, 196g, 198m, 198g, 199, 200m) radionuclides were investigated. The stacked-foil activation technique on natural platinum targets was used. Excitation functions are reported for Eα from threshold up to 37 MeV. Cross sections are reported for the first time for reactions of the type natPt(α, xn) ∗Hg ( x = 1-5) and natPd(α,p xn) ∗Au ( x = 1-5). The experimental results are compared with literature values and with model calculations performed with the ALICE-IPPE code. Use of the data for possible applications in comparison with our earlier results for proton and deuteron induced reactions is discussed.

  17. 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

  18. Gastrin Induces Nuclear Export and Proteasome Degradation of Menin in Enteric Glial Cells.

    Science.gov (United States)

    Sundaresan, Sinju; Meininger, Cameron A; Kang, Anthony J; Photenhauer, Amanda L; Hayes, Michael M; Sahoo, Nirakar; Grembecka, Jolanta; Cierpicki, Tomasz; Ding, Lin; Giordano, Thomas J; Else, Tobias; Madrigal, David J; Low, Malcolm J; Campbell, Fiona; Baker, Ann-Marie; Xu, Haoxing; Wright, Nicholas A; Merchant, Juanita L

    2017-12-01

    The multiple endocrine neoplasia, type 1 (MEN1) locus encodes the nuclear protein and tumor suppressor menin. MEN1 mutations frequently cause neuroendocrine tumors such as gastrinomas, characterized by their predominant duodenal location and local metastasis at time of diagnosis. Diffuse gastrin cell hyperplasia precedes the appearance of MEN1 gastrinomas, which develop within submucosal Brunner's glands. We investigated how menin regulates expression of the gastrin gene and induces generation of submucosal gastrin-expressing cell hyperplasia. Primary enteric glial cultures were generated from the VillinCre:Men1FL/FL:Sst-/- mice or C57BL/6 mice (controls), with or without inhibition of gastric acid by omeprazole. Primary enteric glial cells from C57BL/6 mice were incubated with gastrin and separated into nuclear and cytoplasmic fractions. Cells were incubated with forskolin and H89 to activate or inhibit protein kinase A (a family of enzymes whose activity depends on cellular levels of cyclic AMP). Gastrin was measured in blood, tissue, and cell cultures using an ELISA. Immunoprecipitation with menin or ubiquitin was used to demonstrate post-translational modification of menin. Primary glial cells were incubated with leptomycin b and MG132 to block nuclear export and proteasome activity, respectively. We obtained human duodenal, lymph node, and pancreatic gastrinoma samples, collected from patients who underwent surgery from 1996 through 2007 in the United States or the United Kingdom. Enteric glial cells that stained positive for glial fibrillary acidic protein (GFAP+) expressed gastrin de novo through a mechanism that required PKA. Gastrin-induced nuclear export of menin via cholecystokinin B receptor (CCKBR)-mediated activation of PKA. Once exported from the nucleus, menin was ubiquitinated and degraded by the proteasome. GFAP and other markers of enteric glial cells (eg, p75 and S100B), colocalized with gastrin in human duodenal gastrinomas. MEN1-associated

  19. Erythropoietin inhibits osteoblast function in myelodysplastic syndromes via the canonical Wnt pathway.

    Science.gov (United States)

    Balaian, Ekaterina; Wobus, Manja; Weidner, Heike; Baschant, Ulrike; Stiehler, Maik; Ehninger, Gerhard; Bornhäuser, Martin; Hofbauer, Lorenz C; Rauner, Martina; Platzbecker, Uwe

    2018-01-01

    The effects of erythropoietin on osteoblasts and bone formation are controversial. Since patients with myelodysplastic syndromes often display excessively high erythropoietin levels, we aimed to analyze the effect of erythropoietin on osteoblast function in myelodysplastic syndromes and define the role of Wnt signaling in this process. Expression of osteoblast-specific genes and subsequent osteoblast mineralization was increased in mesenchymal stromal cells from healthy young donors by in vitro erythropoietin treatment. However, erythropoietin failed to increase osteoblast mineralization in old healthy donors and in patients with myelodysplasia, whereas the basal differentiation potential of the latter was already significantly reduced compared to that of age-matched controls ( P <0.01). This was accompanied by a significantly reduced expression of genes of the canonical Wnt pathway. Treatment of these cells with erythropoietin further inhibited the canonical Wnt pathway. Exposure of murine cells (C2C12) to erythropoietin also produced a dose-dependent inhibition of TCF/LEF promoter activity (maximum at 500 IU/mL, -2.8-fold; P <0.01). The decreased differentiation capacity of erythropoietin-pretreated mesenchymal stromal cells from patients with myelodysplasia could be restored by activating the Wnt pathway using lithium chloride or parathyroid hormone. Its hematopoiesis-supporting capacity was reduced, while reactivation of the canonical Wnt pathway in mesenchymal stromal cells could reverse this effect. Thus, these data demonstrate that erythropoietin modulates components of the osteo-hematopoietic niche in a context-dependent manner being anabolic in young, but catabolic in mature bone cells. Targeting the Wnt pathway in patients with myelodysplastic syndromes may be an appealing strategy to promote the functional capacity of the osteo-hematopoietic niche. Copyright© 2018 Ferrata Storti Foundation.

  20. MicroRNA-375 Is Induced in Cisplatin Nephrotoxicity to Repress Hepatocyte Nuclear Factor 1-β.

    Science.gov (United States)

    Hao, Jielu; Lou, Qiang; Wei, Qingqing; Mei, Shuqin; Li, Lin; Wu, Guangyu; Mi, Qing-Sheng; Mei, Changlin; Dong, Zheng

    2017-03-17

    Nephrotoxicity is a major adverse effect of cisplatin-mediated chemotherapy in cancer patients. The pathogenesis of cisplatin-induced nephrotoxicity remains largely unclear, making it difficult to design effective renoprotective approaches. Here, we have examined the role of microRNAs (miRNAs) in cisplatin-induced nephrotoxicity. We show that cisplatin nephrotoxicity was not affected by overall depletion of both beneficial and detrimental miRNAs from kidney proximal tubular cells in mice in which the miRNA-generating enzyme Dicer had been conditionally knocked out. To identify miRNAs involved in cisplatin nephrotoxicity, we used microarray analysis to profile miRNA expression and identified 47 up-regulated microRNAs and 20 down-regulated microRNAs in kidney cortical tissues. One up-regulated miRNA was miR-375, whose expression was also induced in cisplatin-treated renal tubular cells. Interestingly, inhibition of miR-375 decreased cisplatin-induced apoptosis, suggesting that miR-375 is a cell-damaging or pro-apoptotic agent. Blockade of P53 or NF-κB attenuated cisplatin-induced miR-375 expression, supporting a role of P53 and NF-κB in miR-375 induction. We also identified hepatocyte nuclear factor 1 homeobox B (HNF-1β) as a key downstream target of miR-375. Of note, we further demonstrated that HNF-1β protected renal cells against cisplatin-induced apoptosis. Together, these results suggest that upon cisplatin exposure, P53 and NF-κB collaboratively induce miR-375 expression, which, in turn, represses HNF-1β activity, resulting in renal tubular cell apoptosis and nephrotoxicity. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  1. Activation cross sections of proton induced nuclear reactions on natural hafnium

    Energy Technology Data Exchange (ETDEWEB)

    Takacs, S., E-mail: s.takacs@atomki.hu [Institute of Nuclear Research of the Hungarian Academy of Sciences (ATOMKI), 4026 Debrecen (Hungary); Tarkanyi, F. [Institute of Nuclear Research of the Hungarian Academy of Sciences (ATOMKI), 4026 Debrecen (Hungary); Hermanne, A.; Adam Rebeles, R. [Cyclotron Laboratory, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels (Belgium)

    2011-12-01

    Highlights: {yields} Cross sections of proton induced reactions on natural hafnium. {yields} Production of Ta, Hf and Lu isotopes. {yields} Comparison of experimental cross sections with results of TENDL-2010 calculations. {yields} Thick target yields. {yields} Production of {sup 177g}Lu for medical use is not feasible. - Abstract: In a systematic study of light charged particle induced nuclear reactions we investigated the excitation functions of proton induced reactions on natural hafnium targets. Experimental excitation functions of proton induced reactions up to 36 MeV on high purity natural hafnium were determined using the stacked foil activation technique. High resolution off-line gamma-ray spectrometry was applied to assess the activity of each foil. From the measured activity independent and/or cumulative elemental or isotopic cross section data for production of Ta, Hf and Lu radioisotopes were determined. The experimental data were compared to the data published earlier by other authors and to results of TALYS theoretical code taken from TENDL-2010 database. Thick target yields of the investigated radionuclides were calculated from the excitation function that was deduced as an analytical fit to our experimental cross section data points.

  2. Erythropoietin Slows Photoreceptor Cell Death in a Mouse Model of Autosomal Dominant Retinitis Pigmentosa.

    Science.gov (United States)

    Rex, Tonia S; Kasmala, Lorraine; Bond, Wesley S; de Lucas Cerrillo, Ana M; Wynn, Kristi; Lewin, Alfred S

    2016-01-01

    To test the efficacy of systemic gene delivery of a mutant form of erythropoietin (EPO-R76E) that has attenuated erythropoietic activity, in a mouse model of autosomal dominant retinitis pigmentosa. Ten-day old mice carrying one copy of human rhodopsin with the P23H mutation and both copies of wild-type mouse rhodopsin (hP23H RHO+/-,mRHO+/+) were injected into the quadriceps with recombinant adeno-associated virus (rAAV) carrying either enhanced green fluorescent protein (eGFP) or EpoR76E. Visual function (electroretinogram) and retina structure (optical coherence tomography, histology, and immunohistochemistry) were assessed at 7 and 12 months of age. The outer nuclear layer thickness decreased over time at a slower rate in rAAV.EpoR76E treated as compared to the rAAV.eGFP injected mice. There was a statistically significant preservation of the electroretinogram at 7, but not 12 months of age. Systemic EPO-R76E slows death of the photoreceptors and vision loss in hP23H RHO+/-,mRHO+/+ mice. Treatment with EPO-R76E may widen the therapeutic window for retinal degeneration patients by increasing the number of viable cells. Future studies might investigate if co-treatment with EPO-R76E and gene replacement therapy is more effective than gene replacement therapy alone.

  3. 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.

  4. Comparison and characterization of α-amylase inducers in Aspergillus nidulans based on nuclear localization of AmyR

    OpenAIRE

    Murakoshi, Yuriko; Makita, Tomohiro; Kato, Masashi; Kobayashi, Tetsuo

    2012-01-01

    AmyR, a fungal transcriptional activator responsible for induction of amylolytic genes in Aspergillus nidulans, localizes to the nucleus in response to the physiological inducer isomaltose. Maltose, kojibiose, and d-glucose were also found to trigger the nuclear localization of GFP-AmyR. Isomaltose- and kojibiose-triggered nuclear localization was not inhibited by the glucosidase inhibitor, castanospermine, while maltose-triggered localization was inhibited. Thus, maltose itself does not appe...

  5. The role of nuclear β-catenin accumulation in the Twist2-induced ovarian cancer EMT.

    Science.gov (United States)

    Mao, Yubin; Xu, Jinfei; Li, Zhihan; Zhang, Nini; Yin, Hao; Liu, Zuguo

    2013-01-01

    Twist2 has been shown to promote human tumor invasion as in breast cancer and cervical cancer. However, whether Twist2 promotes human ovarian cancer progression remains to be elucidated. Here, we investigate the role of Twist2 in ovarian cancer invasion and metastasis as well as the underlying molecular mechanisms. Twist2 expression was detected by Immunohistochemistry (IHC) on tissue microarray of human ovarian cancers with scoring procedure according to the staining intensity and pattern. Twist2 gene was stably introduced into SKOV-3 ovarian cancer cells to examine the changes of cellular morphology, motility, invasiveness, and EMT molecular markers. Twist2 expression is significantly increased in ovarian cancers along with the FIGO disease stage, indicating that Twist2 may be associated with ovarian cancer metastasis. Overexpression of Twist2 induced the EMT phenotype including downregulation of E-cadherin, and upregulation of N-cadherin and β-catenin in human ovarian cancer cells, suggesting that Twist2 might promote β-catenin release from the E-cadherin/β-catenin complex through inhibition of E-cadherin. Thus, β-catenin degradation was inhibited due to inhibition of APC, and the Wnt/β-catenin pathway was then activated by nuclear β-catenin accumulation, which may activate transcription of downstream target genes to promote tumor invasion and metastasis. Collectively, these data indicated that β-catenin is involved in Twist2-induced EMT in ovarian cancer. Our data indicates that upregulation of Twist2 is correlated with the FIGO stage in human ovarian cancers. In this report, we demonstrated that nuclear β-catenin is accumulated in Twist2-induced EMT cells to facilitates ovarian cancer invasion and metastasis.

  6. The role of nuclear β-catenin accumulation in the Twist2-induced ovarian cancer EMT.

    Directory of Open Access Journals (Sweden)

    Yubin Mao

    Full Text Available BACKGROUND: Twist2 has been shown to promote human tumor invasion as in breast cancer and cervical cancer. However, whether Twist2 promotes human ovarian cancer progression remains to be elucidated. Here, we investigate the role of Twist2 in ovarian cancer invasion and metastasis as well as the underlying molecular mechanisms. METHODS: Twist2 expression was detected by Immunohistochemistry (IHC on tissue microarray of human ovarian cancers with scoring procedure according to the staining intensity and pattern. Twist2 gene was stably introduced into SKOV-3 ovarian cancer cells to examine the changes of cellular morphology, motility, invasiveness, and EMT molecular markers. RESULTS: Twist2 expression is significantly increased in ovarian cancers along with the FIGO disease stage, indicating that Twist2 may be associated with ovarian cancer metastasis. Overexpression of Twist2 induced the EMT phenotype including downregulation of E-cadherin, and upregulation of N-cadherin and β-catenin in human ovarian cancer cells, suggesting that Twist2 might promote β-catenin release from the E-cadherin/β-catenin complex through inhibition of E-cadherin. Thus, β-catenin degradation was inhibited due to inhibition of APC, and the Wnt/β-catenin pathway was then activated by nuclear β-catenin accumulation, which may activate transcription of downstream target genes to promote tumor invasion and metastasis. Collectively, these data indicated that β-catenin is involved in Twist2-induced EMT in ovarian cancer. CONCLUSION: Our data indicates that upregulation of Twist2 is correlated with the FIGO stage in human ovarian cancers. In this report, we demonstrated that nuclear β-catenin is accumulated in Twist2-induced EMT cells to facilitates ovarian cancer invasion and metastasis.

  7. An analytical study on excitation of nuclear-coupled thermal-hydraulic instability due to seismically induced resonance in BWR

    Energy Technology Data Exchange (ETDEWEB)

    Hirano, Masashi [Japan Atomic Energy Research Institute, Ibaraki-ken (Japan)

    1997-07-01

    This paper describes the results of a scoping study on seismically induced resonance of nuclear-coupled thermal-hydraulic instability in BWRs, which was conducted by using TRAC-BF1 within a framework of a point kinetics model. As a result of the analysis, it is shown that a reactivity insertion could occur accompanied by in-surge of coolant into the core resulted from the excitation of the nuclear-coupled instability by the external acceleration. In order to analyze this phenomenon more in detail, it is necessary to couple a thermal-hydraulic code with a three-dimensional nuclear kinetics code.

  8. Nuclear physics of cosmic ray interaction with semiconductor materials: Particle induced soft errors from a physicist`s perspective

    Energy Technology Data Exchange (ETDEWEB)

    Tang, H.H.K.

    1996-01-01

    The key issues of cosmic-ray-induced soft-error rates, SER (also referred to as single-event upset, SEU, rates) in microelectronic devices are discussed from the viewpoint of fundamental atomic and nuclear interactions between high-energy particles and semiconductors. From sea level to moderate altitudes, the cosmic ray spectrum is dominated by three particle species: nucleons (protons and neutrons), pions, and muons. The characteristic features of high-energy nuclear reactions of these particles with light elements are reviewed. A major cause of soft errors is identified to be the ionization electron-hole pairs induced by the secondary nuclear fragments produced in certain processes. These processes are the inelastic collisions between the cosmic ray particles and nuclei in the host material. A state-of-the-art nuclear spallation reaction model, NUSPA, is developed to simulate these reactions. This model is tested and validated by a large set of nuclear experiments. It is used to generate the crucial database for the soft-error simulators which are currently used throughout IBM for device and circuit analysis. The relative effectiveness of nucleons, pions, and muons as soft-error-inducing agents is evaluated on the basis of nuclear reaction rate calculations and energy-deposition analysis.

  9. Smad Nuclear Interacting Protein 1 Acts as a Protective Regulator of Pressure Overload-Induced Pathological Cardiac Hypertrophy.

    Science.gov (United States)

    Lu, Yu-Yan; Xu, Da-Chun; Zhao, Yi-Fan; Zhu, Guo-Fu; Zhu, Meng-Yun; Liu, Wei-Jing; Yu, Xue-Jing; Chen, Wei; Liu, Zheng; Xu, Ya-Wei

    2016-10-26

    Smad nuclear interacting protein 1 (SNIP1) plays a critical role in cell proliferation, transformation of embryonic fibroblasts, and immune regulation. However, the role of SNIP1 in cardiac hypertrophy remains unclear. Here we examined the role of SNIP1 in pressure overload-induced cardiac hypertrophy and its mechanisms. Our results demonstrated that SNIP1 expression was downregulated in human dilated cardiomyopathic hearts, aortic banding-induced mice hearts, and angiotensin II-treated cardiomyocytes. Accordingly, SNIP1 deficiency significantly exacerbated aortic banding-induced cardiac hypertrophy, fibrosis, and contractile dysfunction, whereas cardiac-specific overexpression of SNIP1 markedly recovered pressure overload-induced cardiac hypertrophy and fibrosis. Besides that, SNIP1 protected neonatal rat cardiomyocytes against angiotensin II-induced hypertrophy in vitro. Moreover, we identified that SNIP1 suppressed nuclear factor-κB signaling during pathological cardiac hypertrophy, and inhibition of nuclear factor-κB signaling by a cardiac-specific conditional inhibitor of κB S 32A/S36A transgene blocked these adverse effects of SNIP1 deficiency on hearts. Together, our findings demonstrated that SNIP1 had protective effects in pressure overload-induced pathological cardiac hypertrophy via inhibition of nuclear factor-κB signaling. Thus, SNIP1 may be a novel approach for the treatment of heart failure. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

  10. 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

  11. Plasmodium berghei ANKA: erythropoietin activates neural stem cells in an experimental cerebral malaria model

    DEFF Research Database (Denmark)

    Core, Andrew; Hempel, Casper; Kurtzhals, Jørgen A L

    2011-01-01

    Cerebral malaria (CM) causes substantial mortality and neurological sequelae in survivors, and no neuroprotective regimens are currently available for this condition. Erythropoietin (EPO) reduces neuropathology and improves survival in murine CM. Using the Plasmodium berghei model of CM, we...

  12. 6-gingerol ameliorated doxorubicin-induced cardiotoxicity: role of nuclear factor kappa B and protein glycation.

    Science.gov (United States)

    El-Bakly, Wesam M; Louka, Manal L; El-Halawany, Ali M; Schaalan, Mona F

    2012-12-01

    Doxorubicin is a widely used antitumour drug. Cardiotoxicity is considered a major limitation for its clinical use. The present study was designed to assess the possible antioxidant and antiapoptotic effects of 6-gingerol in attenuating doxorubicin-induced cardiac damage. Male albino rats were treated with either intraperitoneal doxorubicin (18 mg/kg divided into six equal doses for 2 weeks) and/or oral 6-gingerol (10 mg/kg starting 5 days before and continued till the end of the experiment). 6-gingerol significantly ameliorated the doxorubicin-induced elevation in the cardiac enzymes. The stimulation of oxidative stress by doxorubicin was evidenced by the significant decrease in the serum soluble receptor for advanced glycation endproduct allowing unopposed serum advanced glycation endproduct availability. Moreover, doxorubicin activated nuclear factor kappa B (NF-κB) which was indicated by an increase in its immunohistochemical staining in the nucleus. In addition, doxorubicin-induced cardiotoxicity was accompanied by elevation of cardiac caspase-3. Notably, pretreatment with 6-gingerol significantly ameliorated the changes in sRAGE, NF-κB and cardiac caspase-3. Cardiac enzymes showed significant positive correlation with NF-κB and caspase-3 but negative with serum sRAGE, suggesting their role in doxorubicin-induced cardiac injury. These findings were confirmed by cardiac tissue histopathology. 6-gingerol, a known single compound from ginger with anticancer activity, was shown to have a promising role in cardioprotection against doxorubicin-induced cardiotoxicity. This study suggested a novel mechanism for 6-gingerol cardioprotection, which might be mediated through its antioxidative effect and modulation of NF-κB as well as apoptosis.

  13. Up-regulation of erythropoietin receptor by nitric oxide mediates hypoxia preconditioning.

    Science.gov (United States)

    Chen, Zhi-Yong; Wang, Li; Asavaritkrai, Pundit; Noguchi, Constance Tom

    2010-11-01

    Erythropoietin (Epo), known to stimulate erythroid progenitor cell survival, proliferation, and differentiation, has been shown to be neuroprotective against brain ischemia in animal models. Both Epo and Epo receptor (EpoR) are expressed in the brain and are up-regulated by hypoxia. Brain Epo signaling can stimulate neural cell survival and prevent neuron apoptosis. Neurons from EpoR null mice exhibit marked increased sensitivity to hypoxia. In endothelial cells, Epo has been shown to stimulate nitric oxide (NO) production, particularly at low pO(2). We found here that the EpoR expression on neural cells and Epo's neuroprotective effect were regulated by NO. Hypoxia increased NO production as well as EpoR expression, and inhibition of NOS activity reduced the proportion of EpoR-expressing neurons induced at low pO(2). Conversely, addition of NO donor to cultures grown under normoxia induced EpoR. Similarly, NO donor increased EpoR promoter activity in a reporter gene assay, suggesting that NO regulates EpoR at the transcription level. Preincubation of neurons with NO results in induction of EpoR, which gives rise to protection against hypoxia even in the absence of exogenous Epo, although at high concentration NO is toxic. These data provide evidence of a role for NO in Epo activity in brain and suggest links between NO production, EpoR expression, and Epo signaling in neuroprotection.

  14. Analysis of factors related to man-induced hazard for nuclear facilities

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Young Soon; Jung, Jea Hee; Lee, Keun O; Son, Ki Sang; Wang, Sang Chul; Lee, Chang Jin; Ku, Min Ho; Park, Nam Young [Seoul National Univ. of Technology, Seoul (Korea, Republic of)

    2003-03-15

    This study is to show a guide for installing hazardous facilities adjoined atomic power plant after finding out how much these facilities could impact to the atomic plant. Nuclear power plant is an important facility which is closely connected with public life, industrial activity, and the conduct of public business, so it should not be damaged. Therefore, if there are hazardous and harmful facilities near the plant, then they must be evaluated by the size, the type, and the shape. First of all, any factors that could cause man induced accident must be investigated. And they must be exactly evaluated from how much it will damage the plant facilities. The purpose of this study is to set a technical standard for the installation of these facilities by evaluating the man induced accident. Also, it is to make out the evaluation methods by investigating the hazardous facilities which are placed near the plant. Our country is now using CFR standard : reg. guide and IAEA safety series. However, not only the standard of technology which is related to man induced accident but also the evaluation methods for facilities are not yet layed down. As It was mentioned above, we should evaluate these facilities adequately, and these methods must be made out.

  15. Exploring laser-induced breakdown spectroscopy for nuclear materials analysis and in-situ applications

    Energy Technology Data Exchange (ETDEWEB)

    Martin, Madhavi Z., E-mail: martinm1@ornl.gov [Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831 (United States); Allman, Steve [Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831 (United States); Brice, Deanne J. [Environmental Sciences Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831 (United States); Martin, Rodger C. [Fuel Cycle and Isotopes Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831 (United States); Andre, Nicolas O. [Center for Renewable Carbon, University of Tennessee, Knoxville, TN 37996 (United States)

    2012-08-15

    Laser-induced breakdown spectroscopy (LIBS) has been used to determine the limits of detection of strontium (Sr) and cesium (Cs), common nuclear fission products. Additionally, detection limits were determined for cerium (Ce), often used as a surrogate for radioactive plutonium in laboratory studies. Results were obtained using a laboratory instrument with a Nd:YAG laser at fundamental wavelength of 1064 nm, frequency doubled to 532 nm with energy of 50 mJ/pulse. The data was compared for different concentrations of Sr and Ce dispersed in a CaCO{sub 3} (white) and carbon (black) matrix. We have addressed the sampling errors, limits of detection, reproducibility, and accuracy of measurements as they relate to multivariate analysis in pellets that were doped with the different elements at various concentrations. These results demonstrate that LIBS technique is inherently well suited for in situ analysis of nuclear materials in hot cells. Three key advantages are evident: (1) small samples (mg) can be evaluated; (2) nuclear materials can be analyzed with minimal sample preparation; and (3) samples can be remotely analyzed very rapidly (ms-seconds). Our studies also show that the methods can be made quantitative. Very robust multivariate models have been used to provide quantitative measurement and statistical evaluation of complex materials derived from our previous research on wood and soil samples. - Highlights: Black-Right-Pointing-Pointer Did the detection of strontium, cerium, and cesium in CaCO{sub 3} and graphite matrices. Black-Right-Pointing-Pointer The detection of these elements was performed in a systematic manner. Black-Right-Pointing-Pointer Univariate calibration curves were used to determine strontium detection. Black-Right-Pointing-Pointer Univariate and multivariate statistical analysis built improved statistical models. Black-Right-Pointing-Pointer Limits of detection are comparable or better in case of cerium and cesium.

  16. 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.

  17. Nuclear translocation of the cytoplasmic domain of HB-EGF induces gastric cancer invasion

    Science.gov (United States)

    2012-01-01

    and a novel signal for HB-EGF-C nuclear translocation induce gastric cancer growth, whereas HB-EGF-C nuclear translocation independently plays a critical role in gastric cancer invasion. The present study demonstrated that HB-EGF-C nuclear translocation might be crucial in gastric cancer invasion. HB-EGF-C nuclear translocation may offer a prognostic marker and a new molecular target for gastric cancer therapy. PMID:22646534

  18. The effect of erythropoietin on cognition in affective disorders

    DEFF Research Database (Denmark)

    Ott, Caroline Vintergaard; Vinberg, Maj; Kessing, Lars V

    2016-01-01

    This is a secondary data analysis from our erythropoietin (EPO) trials. We examine (I) whether EPO improves speed of complex cognitive processing across bipolar and unipolar disorder, (II) if objective and subjective baseline cognitive impairment increases patients׳ chances of treatment......-efficacy and (III) if cognitive improvement correlates with better subjective cognitive function, quality of life and socio-occupational capacity. Patients with unipolar or bipolar disorder were randomized to eight weekly EPO (N=40) or saline (N=39) infusions. Cognition, mood, quality of life and socio......-occupational capacity were assessed at baseline (week 1), after treatment completion (week 9) and at follow-up (week 14). We used repeated measures analysis of covariance to investigate the effect of EPO on speed of complex cognitive processing. With logistic regression, we examined whether baseline cognitive...

  19. Neuroprotective effects of erythropoietin in patients with carbon monoxide poisoning.

    Science.gov (United States)

    Pang, Li; Bian, Miao; Zang, Xiu-Xian; Wu, Yang; Xu, Da-Hai; Dong, Ning; Wang, Zhi-Hao; Yan, Bai-Ling; Wang, Da-Wei; Zhao, Hui-Jie; Zhang, Nan

    2013-05-01

    The purpose of this study was to evaluate the efficacy of erythropoietin (EPO) for treating patients with carbon monoxide (CO) poisoning. We conducted a randomized, prospective study of 103 patients with CO poisoning in two groups: an EPO group (n = 54; patients received EPO) and a placebo group (n = 49; patients received normal saline). The study endpoints were the functional outcome at day 30 (the Barthel index and neurologic sequelae), National Institutes of Health Stroke Scale (NIHSS) score, and the levels of S-100β. At 18 days, the NIHSS score improved significantly and S-100β levels significantly decreased in patients in the EPO group. At 30 days, patients in the EPO group had a superior Barthel index and fewer patients had delayed neurologic sequelae (DNS). This study demonstrated that early administration of EPO to patients with CO poisoning improved neurological outcomes and reduced the incidence of DNS. © 2013 Wiley Periodicals, Inc.

  20. 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.

  1. 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.

  2. Erythropoietin enhances hippocampal response during memory retrieval in humans

    DEFF Research Database (Denmark)

    Miskowiak, Kamilla; O'Sullivan, Ursula; Harmer, Catherine J

    2007-01-01

    Although erythropoietin (Epo) is best known for its effects on erythropoiesis, recent evidence suggests that it also has neurotrophic and neuroprotective properties in animal models of hippocampal function. Such an action in humans would make it an intriguing novel compound for the treatment......) or saline in a between-subjects, double-blind, randomized design. Neural response during picture encoding and retrieval was tested 1 week later. Epo increased hippocampus response during picture retrieval (n = 11) compared with placebo (n = 12; p = 0.04) independent of changes in hematocrit....... This is consistent with upregulation of hippocampal BDNF and neurotrophic actions found in animals and highlights Epo as a promising candidate for treatment of psychiatric disorders....

  3. Nuclear and hadron matter equation of state within the induced surface tension approach

    Science.gov (United States)

    Sagun, V. V.; Bugaev, K. A.; Ivanytskyi, A. I.; Oliinychenko, D. R.; Mishustin, I. N.

    2017-12-01

    We present a novel equation of state which is based on the virial expansion for the multicomponent mixtures with hard core repulsion. The suggested equation of state explicitly contains the surface tension which is induced by particle interaction. At high densities such a surface tension vanishes and in this way it switches the excluded volume treatment of hard core repulsion to its eigen volume treatment. The great advantage of the developed model is that the number of equations to be solved is two and it does not depend on the number of independent hard-core radii. Using the suggested equation of state we obtained a high quality fit of the hadron multiplicities measured at AGS, SPS, RHIC and ALICE energies and studied the properties of the nuclear matter phase diagram. It is shown the developed equation of state is softer than the gas of hard spheres and remains causal up to the several normal nuclear densities. Therefore, it could be applied to the neutron star interior modeling.

  4. Magnon-induced nuclear relaxation in the quantum critical region of a Heisenberg linear chain

    Science.gov (United States)

    Hoch, M. J. R.

    2017-07-01

    The low-temperature properties of spin-1/2 one-dimensional (1D) Heisenberg antiferromagnetic (HAF) chains which have relatively small exchange couplings between the spins can be tuned using laboratory-scale magnetic fields. Magnetization measurements, made as a function of temperature, provide phase diagrams for these systems and establish the quantum critical point (QCP). The evolution of the spin dynamics behavior with temperature and applied field in the quantum critical (QC) region, near the QCP, is of particular interest and has been experimentally investigated in a number of 1D HAFs using neutron scattering and nuclear magnetic resonance as the preferred techniques. In the QC phase both quantum and thermal spin fluctuations are present. As a result of extended spin correlations in the chains, magnon excitations are important at finite temperatures. An expression for the NMR spin-lattice relaxation rate 1 /T1 of probe nuclei in the QC phase of 1D HAFs is obtained by considering Raman scattering processes which induce nuclear spin flips. The relaxation rate expression, which involves the temperature and the chemical potential, predicts scaling behavior of 1 /T1 consistent with recent experimental findings for quasi-1D HAF systems. A simple relationship between 1 /T1 and the deviation of the magnetization from saturation (MS-M ) is predicted for the QC region.

  5. Degradation of nuclear Ubc9 induced by listeriolysin O is dependent on K(+) efflux.

    Science.gov (United States)

    Li, Jiexin; Lam, Wendy Wai-Ling; Lai, Tsz-Wah; Au, Shannon Wing-Ngor

    2017-11-18

    Listeriolysin O (LLO) is a pore-forming toxin produced by L. monocytogenes, and is belonged to a protein family of cholesterol-dependent cytolysins (CDCs). Previous studies have demonstrated that LLO triggers Ubc9 degradation and disrupts host SUMOylation to facilitate bacterial infection. However, the underlying mechanism of Ubc9 degradation is unclear. Here we show that LLO-induced down-regulation of Ubc9 is independent of Ubc9-SUMO interaction, however, it may involve phosphorylation signaling. Additionally, LLO exerts its effects primarily on nuclear Ubc9 and this process is mediated by K(+) efflux. Interestingly, for intracellular CDCs such as pneumolysin and suilysin, blockage of K(+) efflux enhances degradation of nuclear Ubc9, suggesting that extracellular and intracellular pathogens may exploit different mechanisms to modulate host SUMOylation system. Furthermore, up-regulation of SUMOylation by stable expression of SUMO-1 or SUMO-2 shows a delay in membrane perforation by LLO, indicating that SUMO modification of host proteins may act at the frontline for the defense response against LLO. Taken together, our study provides insights to the understanding of host-pathogen interactions. Copyright © 2017. Published by Elsevier Inc.

  6. Laser-Induced Fluorescence Measurements for Optical Single Atom Detection for Nuclear Astrophysics

    Science.gov (United States)

    Parzuchowski, Kristen; Singh, Jaideep; Wenzl, Jennifer; Frisbie, Dustin; Johnson, Maegan

    2016-09-01

    We propose a new highly selective detector to measure rare nuclear reactions relevant for nuclear astrophysics. Our primary interest is the 22Ne(α , n) 25Mg reaction, which is a primary source of neutrons for the s-process. Our proposed detector, in conjunction with a recoil separator, captures the recoil products resulting from the reaction in a cryogenically frozen thin film of solid neon. The fluorescence spectra of the captured atoms is shifted from the absorption spectra by hundreds of nanometers. This allows for the optical detection of individual fluorescence photons against a background of intense excitation light. We will describe our initial studies of laser-induced fluorescence of Yb and Mg in solid Ne. Neon is an attractive medium because it is optically transparent and provides efficient, pure, stable, & chemically inert confinement for a wide variety of atomic and molecular species. Yb is used as a test atom because of its similar atomic structure to Mg and much brighter fluorescence signal. This work is supported by funds from Michigan State University.

  7. The effects of solar-geomagnetically induced currents on electrical systems in nuclear power stations

    Energy Technology Data Exchange (ETDEWEB)

    Subudhi, M. [Brookhaven National Lab., Upton, NY (United States); Carroll, D.P. [Florida Univ., Gainesville, FL (United States); Kasturi, S. [MOS, Inc., Melville, NY (United States)

    1994-01-01

    This report presents the results of a study to evaluate the potential effects of geomagnetically induced currents (GICs) caused by the solar disturbances on the in-plant electrical distribution system and equipment in nuclear power stations. The plant-specific electrical distribution system for a typical nuclear plant is modeled using the ElectroMagnetic Transient Program (EMTP). The computer model simulates online equipment and loads from the station transformer in the switchyard of the power station to the safety-buses at 120 volts to which all electronic devices are connected for plant monitoring. The analytical model of the plant`s electrical distribution system is studied to identify the transient effects caused by the half-cycle saturation of the station transformers due to GIC. This study provides results of the voltage harmonics levels that have been noted at various electrical buses inside the plant. The emergency circuits appear to be more susceptible to high harmonics due to the normally light load conditions. In addition to steady-state analysis, this model was further analyzed simulating various plant transient conditions (e.g., loss of load or large motor start-up) occurring during GIC events. Detail models of the plant`s protective relaying system employed in bus transfer application were included in this model to study the effects of the harmonic distortion of the voltage input. Potential harmonic effects on the uniterruptable power system (UPS) are qualitatively discussed as well.

  8. Transfer-induced fission in inverse kinematics: Impact on experimental and evaluated nuclear data bases

    Energy Technology Data Exchange (ETDEWEB)

    Farget, F.; Schmidt, K.H.; Clement, E.; Delaune, O.; Derkx, X.; Dijon, A.; Golabek, C.; Lemasson, A.; Roger, T.; Schmitt, C. [CEA/DSM-CNRS/IN2P3, GANIL, Caen (France); Caamano, M.; Ramos, D.; Benlliure, J.; Cortina, D.; Fernandez-Dominguez, B.; Paradela, C. [Universidade de Santiago de Compostela, Santiago de Compostela (Spain); Rodriguez-Tajes, C. [CEA/DSM-CNRS/IN2P3, GANIL, Caen (France); Universidade de Santiago de Compostela, Santiago de Compostela (Spain); Audouin, L. [Universite Paris-Sud 11, CNRS/IN2P3, Institut de Physique Nucleaire, Orsay (France); Casarejos, E. [Universidade de Vigo, Vigo (Spain); Dore, D.; Salsac, M.D. [Centre de Saclay, CEA, Irfu, Gif-sur-Yvette (France); Gaudefroy, L. [CEA DAM Ile-de-France, BP 12, Bruyeres-le-Chatel (France); Heinz, A. [Chalmers Tekniska Hoegskola, Fundamental Fysik, Goeteborg (Sweden); Jurado, B. [Universite Bordeaux, CENBG, UMR 5797 CNRS/IN2P3, Gradignan (France)

    2015-12-15

    Inverse kinematics is a new tool to study nuclear fission. Its main advantage is the possibility to measure with an unmatched resolution the atomic number of fission fragments, leading to new observables in the properties of fission-fragment distributions. In addition to the resolution improvement, the study of fission based on nuclear collisions in inverse kinematics beneficiates from a larger view with respect to the neutron-induced fission, as in a single experiment the number of fissioning systems and the excitation energy range are widden. With the use of spectrometers, mass and kinetic-energy distributions may now be investigated as a function of the proton and neutron number sharing. The production of fissioning nuclei in transfer reactions allows studying the isotopic yields of fission fragments as a function of the excitation energy. The higher excitation energy resulting in the fusion reaction leading to the compound nucleus {sup 250}Cf at an excitation energy of 45MeV is also presented. With the use of inverse kinematics, the charge polarisation of fragments at scission is now revealed with high precision, and it is shown that it cannot be neglected, even at higher excitation energies. In addition, the kinematical properties of the fragments inform on the deformation configuration at scission. (orig.)

  9. Investigation of activation cross-sections of alpha-induced nuclear reactions on natural cadmium

    Energy Technology Data Exchange (ETDEWEB)

    Khandaker, Mayeen Uddin [Department of Physics, Kyungpook National University, Daegu 702-701 (Korea, Republic of); Department of Physics, University of Malaya, 50603 Kuala Lumpur (Malaysia); Kim, Kwangsoo [Department of Physics, Kyungpook National University, Daegu 702-701 (Korea, Republic of); Lee, Manwoo [Department of Physics, Kyungpook National University, Daegu 702-701 (Korea, Republic of); Research Center, Dongnam Institute of Radiological and Medical Science, Busan 619-953 (Korea, Republic of); Kim, Guinyun, E-mail: gnkim@knu.ac.kr [Department of Physics, Kyungpook National University, Daegu 702-701 (Korea, Republic of)

    2014-08-15

    We measured production cross-sections of Sn, In, and Cd radionuclides from alpha-induced reactions on {sup nat}Cd from their respective threshold to 45 MeV by using a stacked-foil activation technique at the MC-50 cyclotron of the Korea Institute of Radiological and Medical Sciences. The results were compared with the earlier measurements as well as with the theoretical values obtained from the TENDL-2012 library based on the TALYS 1.4 code. Our measurements for the {sup 110,113g,117m}Sn, {sup 108m,108g,109g,110m,110g,111g,113m,114m,115m,116m,117m,117g}In, and {sup 111m,115g}Cd radionuclides in the energy region from the threshold energy to 45 MeV are in general good agreement with the other experimental data and calculated results. The integral yields for thick target were also deduced using the measured cross-sections and the stopping power of natural cadmium target and found in agreement with the directly measured yields available in the literature. The measured cross-sections find importance in various practical applications including nuclear medicine and improvement of nuclear model calculations.

  10. Investigation of activation cross-sections of alpha-induced nuclear reactions on natural cadmium

    Science.gov (United States)

    Khandaker, Mayeen Uddin; Kim, Kwangsoo; Lee, Manwoo; Kim, Guinyun

    2014-08-01

    We measured production cross-sections of Sn, In, and Cd radionuclides from alpha-induced reactions on natCd from their respective threshold to 45 MeV by using a stacked-foil activation technique at the MC-50 cyclotron of the Korea Institute of Radiological and Medical Sciences. The results were compared with the earlier measurements as well as with the theoretical values obtained from the TENDL-2012 library based on the TALYS 1.4 code. Our measurements for the 110,113g,117mSn, 108m,108g,109g,110m,110g,111g,113m,114m,115m,116m,117m,117gIn, and 111m,115gCd radionuclides in the energy region from the threshold energy to 45 MeV are in general good agreement with the other experimental data and calculated results. The integral yields for thick target were also deduced using the measured cross-sections and the stopping power of natural cadmium target and found in agreement with the directly measured yields available in the literature. The measured cross-sections find importance in various practical applications including nuclear medicine and improvement of nuclear model calculations.

  11. Application of laser induced fluorescence analysis to nuclear fuel reprocessing plant

    Energy Technology Data Exchange (ETDEWEB)

    Hayashibara, Hirofumi; Miyake, Takafumi; Izumi, Jyun [Mitsubishi Heavy Industries Ltd., Takasago, Hyogo (Japan). Takasago Research and Development Center; Taguchi, Syouzou; Watanabe, Ryuuichi

    1996-09-01

    In nuclear fuel reprocessing plants, to maintain the system integrity, many kinds of chemical analysis must be done. However, with chemical analysis performed under a high radiation field, to reduce the occupational radiation exposure, a new type of trace analysis technique is desirable, concerning the technique of trace analysis, a laser ray method enables us to achieve higher sensitivity and selectivity than the conventional methods, due to its higher energy and narrow spectral width. Then, we developed a laser induced fluorescence (LIF) method and performed an application study for fuel reprocessing plants by using the simulated samples. Main investigated analyzed elements are an impurities of uranium in nitric acid solution. As a result of this investigation, a pretreatment procedure of analysis was found to be simple compared with the conventional analysis method. (author)

  12. Search for Perturbations of Nuclear Decay Rates Induced by Reactor Electron Antineutrinos

    CERN Document Server

    Barnes, V E; Bryan, C D; Cinko, N; Deichert, G G; Gruenwald, J T; Heim, J M; Kaplan, H B; LaZur, R; Neff, D; Nistor, J M; Sahelijo, N; Fischbach, E

    2016-01-01

    We report the results of an experiment conducted near the High Flux Isotope Reactor of Oak Ridge National Laboratory, designed to address the question of whether a flux of reactor-generated electron antineutrinos can alter the rates of weak nuclear interaction-induced decays for Mn-54, Na-22, and Co-60. This experiment, while quite sensitive, cannot exclude perturbations less than one or two parts in $10^4$ in $\\beta$ decay (or electron capture) processes, in the presence of an antineutrino flux of $3\\times 10^{12}$ cm$^{-2}$ s$^{-1}$. The present experimental methods are applicable to a wide range of isotopes. Improved sensitivity in future experiments may be possible if we can understand and reduce the dominant systematic uncertainties.

  13. Analysis of simulated high burnup nuclear fuel by laser induced breakdown spectroscopy

    Science.gov (United States)

    Singh, Manjeet; Sarkar, Arnab; Banerjee, Joydipta; Bhagat, R. K.

    2017-06-01

    Advanced Heavy Water Reactor (AHWR) grade (Th-U)O2 fuel sample and Simulated High Burn-Up Nuclear Fuels (SIMFUEL) samples mimicking the 28 and 43 GWd/Te irradiated burn-up fuel were studied using laser-induced breakdown spectroscopy (LIBS) setup in a simulated hot-cell environment from a distance of > 1.5 m. Resolution of 60 emission lines of fission products was identified. Among them only a few emission lines were found to generate calibration curves. The study demonstrates the possibility to investigate impurities at concentrations around hundreds of ppm, rapidly at atmospheric pressure without any sample preparation. The results of Ba and Mo showed the advantage of LIBS analysis over traditional methods involving sample dissolution, which introduces possible elemental loss. Limits of detections (LOD) under Ar atmosphere shows significant improvement, which is shown to be due to the formation of stable plasma.

  14. Comparison and characterization of α-amylase inducers in Aspergillus nidulans based on nuclear localization of AmyR.

    Science.gov (United States)

    Murakoshi, Yuriko; Makita, Tomohiro; Kato, Masashi; Kobayashi, Tetsuo

    2012-06-01

    AmyR, a fungal transcriptional activator responsible for induction of amylolytic genes in Aspergillus nidulans, localizes to the nucleus in response to the physiological inducer isomaltose. Maltose, kojibiose, and D: -glucose were also found to trigger the nuclear localization of GFP-AmyR. Isomaltose- and kojibiose-triggered nuclear localization was not inhibited by the glucosidase inhibitor, castanospermine, while maltose-triggered localization was inhibited. Thus, maltose itself does not appear to be an direct inducer, but its degraded or transglycosylated product does. Non-metabolizable D: -glucose analogues were also able to trigger the nuclear localization, implying that these sugars, except maltose, directly function as the inducers of AmyR nuclear entry. The inducing activity of D: -glucose was 4 orders-of-magnitude weaker compared with isomaltose. Although D: -glucose has the ability to induce α-amylase production, this activity would generally be masked by CreA-dependent carbon catabolite repression. Significant induction of α-amylase by D: -glucose was observed in creA-defective A. nidulans.

  15. Recombinant erythropoietin and analogues: a challenge for doping control.

    Science.gov (United States)

    Pascual, J A; Belalcazar, V; de Bolos, C; Gutiérrez, R; Llop, E; Segura, J

    2004-04-01

    Erythropoietin (EPO) increases the number of circulating erythrocytes and thus muscle oxygenation. The availability of the recombinant protein (rEPO) has increased the risk of its illegal use in sports, its detection being a difficult challenge. Five different hematopoietic parameters were initially chosen as indirect markers of rEPO abuse: concentration of serum EPO, concentration of serum-soluble transferrin receptors (sTFr), hematocrit, percentage of reticulocytes, and percentage of macrocytes. New models considering only hemoglobin, serum EPO concentration, and percentage of reticulocytes are simpler and seem to be more sensitive when low doses of rEPO are used. A more direct method of urine analysis (isoelectrofocusing, double blotting, and chemiluminescent detection) based on the charge differences between rEPO and endogenous EPO, related to their carbohydrate composition, provides proof of rEPO use. Furthermore, this approach permits the detection of darbepoetin, a direct analogue of EPO also known as NESP ("new erythropoiesis stimulating protein"). Recently a protein conjugate, "synthetic erythropoiesis protein" (SEP), containing precision-length, monodisperse, negatively charged polymers instead of oligosaccharides has been synthesized. Finally, EPO-mimetics are molecules capable of acting as EPO in dimerizing the EPO receptor. Two kinds of EPO-mimetics have been described: peptides and nonpeptides. The enhancement of oxygen availability to muscles by rEPO, analogues, and mimetics constitutes one of the main challenges to doping control. Major steps have already been developed for detection ofrEPO and some analogues. In the near future, the transfection to an athlete's body of genes that code for erythropoietin might be an emerging doping issue, and sports authorities have incorporated "gene doping" among the prohibited practices.

  16. Hepcidin clearance is associated with erythropoietin requirement in stable hemodialysis patients
.

    Science.gov (United States)

    Ashby, Damien; Busbridge, Mark; Hildebrand, Sarah; Clarke, Candice; Aldous, Georgina; Palan, Mitul; Murphy, Kevin; Duncan, Neill; Choi, Peter

    2017-05-01

    The discovery of hepcidin, the hormone regulating iron absorption and transport, has improved the understanding of anemia and erythropoietin treatment. Excessive hepcidin signaling causes anemia in chronic inflammatory conditions by restricting iron delivery to the bone marrow. Hepcidin is normally eliminated in the urine, and the high levels seen in renal failure are thought to contribute to renal anemia and resistance to erythropoietin. Clearance of hepcidin by hemodialysis was investigated in this study by measurement of plasma hepcidin before and after a single dialysis session in 204 patients. Results: Dialysis significantly reduced circulating hepcidin (p < 0.001) with median (IQR) clearance 47.7 (34.2 - 61.0)%. Dialytic hepcidin clearance was correlated with spKt/V (R = 0.202, p = 0.006), but not related to session length or membrane flux. There was also a strong correlation between hepcidin clearance and erythropoietin dose (R = -0.193, p = 0.007), sufficient to displace more traditional markers of erythropoietin resistance in a linear regression model, suggesting that increased dialytic removal of hepcidin could improve erythropoietin sensitivity. Hemodialysis reduces circulating hepcidin. Greater hepcidin clearance, which is related to spKt/V, is strongly associated with reduced erythropoietin requirement. This further implicates hepcidin in the pathogenesis of renal anemia and suggests that hepcidin could be a useful therapeutic target for dialysis patients.
.

  17. Heterogeneous nuclear ribonucleoprotein K inhibits heat shock-induced transcriptional activity of heat shock factor 1.

    Science.gov (United States)

    Kim, Hee-Jung; Lee, Jae-Jin; Cho, Jin-Hwan; Jeong, Jaeho; Park, A Young; Kang, Wonmo; Lee, Kong-Joo

    2017-08-04

    When cells are exposed to heat shock and various other stresses, heat shock factor 1 (HSF1) is activated, and the heat shock response (HSR) is elicited. To better understand the molecular regulation of the HSR, we used 2D-PAGE-based proteome analysis to screen for heat shock-induced post-translationally modified cellular proteins. Our analysis revealed that two protein spots typically present on 2D-PAGE gels and containing heterogeneous nuclear ribonucleoprotein K (hnRNP K) with trioxidized Cys132 disappeared after the heat shock treatment and reappeared during recovery, but the total amount of hnRNP K protein remained unchanged. We next tested whether hnRNP K plays a role in HSR by regulating HSF1 and found that hnRNP K inhibits HSF1 activity, resulting in reduced expression of hsp70 and hsp27 mRNAs. hnRNP K also reduced binding affinity of HSF1 to the heat shock element by directly interacting with HSF1 but did not affect HSF1 phosphorylation-dependent activation or nuclear localization. hnRNP K lost its ability to induce these effects when its Cys132 was substituted with Ser, Asp, or Glu. These findings suggest that hnRNP K inhibits transcriptional activity of HSF1 by inhibiting its binding to heat shock element and that the oxidation status of Cys132 in hnRNP K is critical for this inhibition. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  18. Nuclear magnetic resonance-based metabolomics for prediction of gastric damage induced by indomethacin in rats

    Energy Technology Data Exchange (ETDEWEB)

    Um, So Young [Department of Pharmacology, National Institute of Toxicological Research, Korea Food and Drug Administration, 643 Yeonje-ri, Gangoe-myeon, Cheongwon-gun, Chungbuk (Korea, Republic of); Division of Life and Pharmaceutical Science and College of Pharmacy, Ewha Womans University, 52 Ewahyeodae-gil, Seodaemun-gu, Seoul (Korea, Republic of); Park, Jung Hyun [Division of Life and Pharmaceutical Science and College of Pharmacy, Ewha Womans University, 52 Ewahyeodae-gil, Seodaemun-gu, Seoul (Korea, Republic of); Chung, Myeon Woo [Department of Pharmacology, National Institute of Toxicological Research, Korea Food and Drug Administration, 643 Yeonje-ri, Gangoe-myeon, Cheongwon-gun, Chungbuk (Korea, Republic of); Kim, Kyu-Bong [College of Pharmacy, Dankook University, Dandae-ro, Cheonan, Chungnam (Korea, Republic of); Kim, Seon Hwa [Department of Pharmacology, National Institute of Toxicological Research, Korea Food and Drug Administration, 643 Yeonje-ri, Gangoe-myeon, Cheongwon-gun, Chungbuk (Korea, Republic of); Division of Life and Pharmaceutical Science and College of Pharmacy, Ewha Womans University, 52 Ewahyeodae-gil, Seodaemun-gu, Seoul (Korea, Republic of); College of Pharmacy, Dankook University, Dandae-ro, Cheonan, Chungnam (Korea, Republic of); Choi, Ki Hwan, E-mail: hyokwa11@korea.kr [Department of Pharmacology, National Institute of Toxicological Research, Korea Food and Drug Administration, 643 Yeonje-ri, Gangoe-myeon, Cheongwon-gun, Chungbuk (Korea, Republic of); Lee, Hwa Jeong, E-mail: hwalee@ewha.ac.kr [Division of Life and Pharmaceutical Science and College of Pharmacy, Ewha Womans University, 52 Ewahyeodae-gil, Seodaemun-gu, Seoul (Korea, Republic of)

    2012-04-13

    Highlights: Black-Right-Pointing-Pointer NMR based metabolomics - gastric damage by indomethacin. Black-Right-Pointing-Pointer Pattern recognition analysis was performed to biomarkers of gastric damage. Black-Right-Pointing-Pointer 2-Oxoglutarate, acetate, taurine and hippurate were selected as putative biomarkers. Black-Right-Pointing-Pointer The gastric damage induced by NSAIDs can be screened in the preclinical step of drug. - Abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) have side effects including gastric erosions, ulceration and bleeding. In this study, pattern recognition analysis of the {sup 1}H-nuclear magnetic resonance (NMR) spectra of urine was performed to develop surrogate biomarkers related to the gastrointestinal (GI) damage induced by indomethacin in rats. Urine was collected for 5 h after oral administration of indomethacin (25 mg kg{sup -1}) or co-administration with cimetidine (100 mg kg{sup -1}), which protects against GI damage. The {sup 1}H-NMR urine spectra were divided into spectral bins (0.04 ppm) for global profiling, and 36 endogenous metabolites were assigned for targeted profiling. The level of gastric damage in each animal was also determined. Indomethacin caused severe gastric damage; however, indomethacin administered with cimetidine did not. Simultaneously, the patterns of changes in their endogenous metabolites were different. Multivariate data analyses were carried out to recognize the spectral pattern of endogenous metabolites related to indomethacin using partial least square-discrimination analysis. In targeted profiling, a few endogenous metabolites, 2-oxoglutarate, acetate, taurine and hippurate, were selected as putative biomarkers for the gastric damage induced by indomethacin. These metabolites changed depending on the degree of GI damage, although the same dose of indomethacin (10 mg kg{sup -1}) was administered to rats. The results of global and targeted profiling suggest that the gastric damage induced by

  19. Physician Education: The Erythropoietin Receptor and Signal Transduction.

    Science.gov (United States)

    Yoshimura; Arai

    1996-01-01

    ERYTHROPOIETIN (EPO): Erythropoietin (EPO) is a hormone that promotes the proliferation and differentiation of erythroid progenitor cells and regulates the number of erythrocytes in peripheral blood. EPO is produced mainly by the kidneys, and transcription of the EPO gene is promoted by a reduction in the oxygen concentration in the blood. The existence of EPO was suggested near the end of the 19th century by the discovery that hypoxia increases the production of red blood cells. EPO was identified as a serum factor in the 1950s, and in 1970 Miyake and coworkers succeeded in purifying it by using the urine of patients with aplastic anemia as a starting material. The human EPO gene was cloned in 1985 using a partial amino acid sequence from this purified EPO, and it is well known that recombinant EPO is currently used as a drug to treat anemia associated with chronic renal failure and other illnesses. ACTION OF EPO: When human bone marrow cells are cultured in a semisolid medium containing EPO, they form small erythroblast colonies in five to seven days, and by day 10 large erythroblast colonies appear that resemble fireworks ("burst" colonies). The original cells in the former colonies are called colony forming units-erythroid (CFU-E) or late-stage erythroblast progenitor cells and in the latter colonies they are called burst forming units-erythroid (BFU-E) or early-stage erythroblast progenitor cells. As shown in Figure 1, red blood cells are produced through differentiation from stem cells to BFU-E, CFU-E, and erythroblasts. Although EPO acts on both BFU-E and CFU-E cells, CFU-E cells show greater sensitivity to EPO, and other factors such as stem cell factor (SCF), interleukin (IL)-3, IL-4, and granulocyte macrophage colony-stimulating factor (GM-CSF) must be present together with EPO for BFU-E cell proliferation. In erythroblasts beyond the CFU-E stage, sensitivity to EPO decreases as the cells mature. THE EPO RECEPTOR AND THE CYTOKINE RECEPTOR FAMILY: The EPO

  20. Engineering light-inducible nuclear localization signals for precise spatiotemporal control of protein dynamics in living cells.

    Science.gov (United States)

    Niopek, Dominik; Benzinger, Dirk; Roensch, Julia; Draebing, Thomas; Wehler, Pierre; Eils, Roland; Di Ventura, Barbara

    2014-07-14

    The function of many eukaryotic proteins is regulated by highly dynamic changes in their nucleocytoplasmic distribution. The ability to precisely and reversibly control nuclear translocation would, therefore, allow dissecting and engineering cellular networks. Here we develop a genetically encoded, light-inducible nuclear localization signal (LINuS) based on the LOV2 domain of Avena sativa phototropin 1. LINuS is a small, versatile tag, customizable for different proteins and cell types. LINuS-mediated nuclear import is fast and reversible, and can be tuned at different levels, for instance, by introducing mutations that alter AsLOV2 domain photo-caging properties or by selecting nuclear localization signals (NLSs) of various strengths. We demonstrate the utility of LINuS in mammalian cells by controlling gene expression and entry into mitosis with blue light.

  1. Recombinant human erythropoietin alpha improves the efficacy of radiotherapy of a human tumor xenograft, affecting tumor cells and microvessels

    Energy Technology Data Exchange (ETDEWEB)

    Loevey, J. [Dept. of Radiotherapy, National Inst. of Oncology, Budapest (Hungary); Bereczky, B.; Gilly, R.; Kenessey, I.; Raso, E.; Simon, E.; Timar, J. [Dept. of Tumor Progression, National Inst. of Oncology, Budapest (Hungary); Dobos, J. [Dept. of Tumor Progression, National Inst. of Oncology, Budapest (Hungary); National Koranyi Inst. of TBC and Pulmonology, Budapest (Hungary); Vago, A. [Central Lab., National Inst. of Oncology, Budapest (Hungary); Kasler, M. [Head and Neck Surgery, National Inst. of Oncology, Budapest (Hungary); Doeme, B. [National Koranyi Inst. of TBC and Pulmonology, Budapest (Hungary); Tovari, J. [National Koranyi Inst. of TBC and Pulmonology, Budapest (Hungary); 1. Inst. of Pathology and Experimental Cancer Research, Semmelweis Univ., Budapest (Hungary)

    2008-01-15

    Background and purpose: tumor-induced anemia often occurs in cancer patients, and is corrected by recombinant human erythropoietins (rHuEPOs). Recent studies indicated that, besides erythroid progenitor cells, tumor and endothelial cells express erythropoietin receptor (EPOR) as well; therefore, rHuEPO may affect their functions. Here, the effect of rHuEPO{alpha} on irradiation in EPOR-positive human squamous cell carcinoma xenograft was tested. Material and methods: A431 tumor-bearing SCID mice were treated from the tumor implantation with rHuEPO{alpha} at human-equivalent dose. Xenografts were irradiated (5 Gy) on day 14, and the final tumor mass was measured on day 22. The systemic effects of rHuEPO{alpha} on the hemoglobin level, on tumor-associated blood vessels and on hypoxia-inducible factor-(HIF-)1{alpha} expression of the tumor xenografts were monitored. The proliferation, apoptosis and clonogenic capacity of A431 cancer cells treated with rHuEPO{alpha} and irradiation were also tested in vitro. Results: in vitro, rHuEPO{alpha} treatment alone did not modify the proliferation of EPOR-positive A431 tumor cells but enhanced the effect of irradiation on proliferation, apoptosis and clonogenic capacity. In vivo, rHuEPO{alpha} administration compensated the tumor-induced anemia in SCID mice and decreased tumoral HIF-1{alpha} expression but had no effect on tumor growth. At the same time rHuEPO{alpha} treatment significantly increased the efficacy of radiotherapy in vivo (tumor weight of 23.9 {+-} 4.7 mg and 34.9 {+-} 4.6 mg, respectively), mediated by increased tumoral blood vessel destruction. Conclusion: rHuEPO{alpha} treatment may modulate the efficacy of cancer radiotherapy not only by reducing systemic hypoxia and tumoral HIF-1{alpha} expression, but also by destroying tumoral vessels. (orig.)

  2. Dissociation of heterochromatin protein 1 from lamin B receptor induced by human polyomavirus agnoprotein: role in nuclear egress of viral particles.

    Science.gov (United States)

    Okada, Yuki; Suzuki, Tadaki; Sunden, Yuji; Orba, Yasuko; Kose, Shingo; Imamoto, Naoko; Takahashi, Hidehiro; Tanaka, Shinya; Hall, William W; Nagashima, Kazuo; Sawa, Hirofumi

    2005-05-01

    The nuclear envelope is one of the chief obstacles to the translocation of macromolecules that are larger than the diameter of nuclear pores. Heterochromatin protein 1 (HP1) bound to the lamin B receptor (LBR) is thought to contribute to reassembly of the nuclear envelope after cell division. Human polyomavirus agnoprotein (Agno) has been shown to bind to HP1alpha and to induce its dissociation from LBR, resulting in destabilization of the nuclear envelope. Fluorescence recovery after photobleaching showed that Agno increased the lateral mobility of LBR in the inner nuclear membrane. Biochemical and immunofluorescence analyses showed that Agno is targeted to the nuclear envelope and facilitates the nuclear egress of polyomavirus-like particles. These results indicate that dissociation of HP1alpha from LBR and consequent perturbation of the nuclear envelope induced by polyomavirus Agno promote the translocation of virions out of the nucleus.

  3. Nitric oxide and hypoxia stimulate erythropoietin receptor via MAPK kinase in endothelial cells.

    Science.gov (United States)

    Cokic, Bojana B Beleslin; Cokic, Vladan P; Suresh, Sukanya; Wirt, Stacey; Noguchi, Constance Tom

    2014-03-01

    Erythropoietin receptor (EPOR) expression level determines the extent of erythropoietin (EPO) response. Previously we showed that EPOR expression in endothelial cells is increased at low oxygen tension and that EPO stimulation of endothelial cells during hypoxia can increase endothelial nitric oxide (NO) synthase (eNOS) expression and activation as well as NO production. We now observe that while EPO can stimulate NO production, NO in turn can regulate EPOR expression. Human umbilical vein endothelial cells (HUVEC) treated with 10-50 μM of NO donor diethylenetriamine NONOate (DETANO) for 24h showed significant induction of EPOR gene expression at 5% and 2% of oxygen. Also human bone marrow microvascular endothelial cell line (TrHBMEC) cultured at 21 and 2% oxygen with 50 μM DETANO demonstrated a time and oxygen dependent induction of EPOR mRNA expression after 24 and 48 h, particularly at low oxygen tension. EPOR protein was also induced by DETANO at 2% oxygen in TrHBMEC and HUVEC. The activation of signaling pathways by NO donor stimulation appeared to be distinct from EPO stimulation. In reporter gene assays, DETANO treatment of HeLa cells at 2% oxygen increased EPOR promoter activity indicated by a 48% increase in luciferase activity with a 2 kb EPOR promoter fragment and a 71% increase in activity with a minimal EPOR promoter fragment containing 0.2 kb 5'. We found that DETANO activated MAPK kinase in TrHBMEC both in normoxia and hypoxia, while MAPK kinase inhibition showed significant reduction of EPOR mRNA gene expression at low oxygen tension, suggesting MAPK involvement in NO mediated induction of EPOR. Furthermore, DETANO stimulated Akt anti-apoptotic activity after 30 min in normoxia, whereas it inhibited Akt phosphorylation in hypoxia. In contrast, EPO did not significantly increase MAPK activity while EPO stimulated Akt phosphorylation in TrHBMEC in normoxia and hypoxia. These observations provide a new effect of NO on EPOR expression to enhance EPO

  4. Nuclear export signal within CALM is necessary for CALM-AF10-induced leukemia.

    Science.gov (United States)

    Suzuki, Mai; Yamagata, Kazutsune; Shino, Mika; Aikawa, Yukiko; Akashi, Koichi; Watanabe, Toshio; Kitabayashi, Issay

    2014-03-01

    The CALM-AF10 fusion gene, which results from a t(10;11) translocation, is found in a variety of hematopoietic malignancies. Certain HOXA cluster genes and MEIS1 genes are upregulated in patients and mouse models that express CALM-AF10. Wild-type clathrin assembly lymphoid myeloid leukemia protein (CALM) primarily localizes in a diffuse pattern within the cytoplasm, whereas AF10 localizes in the nucleus; however, it is not clear where CALM-AF10 acts to induce leukemia. To investigate the influence of localization on leukemogenesis involving CALM-AF10, we determined the nuclear export signal (NES) within CALM that is necessary and sufficient for cytoplasmic localization of CALM-AF10. Mutations in the NES eliminated the capacity of CALM-AF10 to immortalize murine bone-marrow cells in vitro and to promote development of acute myeloid leukemia in mouse models. Furthermore, a fusion of AF10 with the minimal NES can immortalize bone-marrow cells and induce leukemia in mice. These results suggest that during leukemogenesis, CALM-AF10 plays its critical roles in the cytoplasm. © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

  5. Targeting proliferating cell nuclear antigen and its protein interactions induces apoptosis in multiple myeloma cells.

    Directory of Open Access Journals (Sweden)

    Rebekka Müller

    Full Text Available Multiple myeloma is a hematological cancer that is considered incurable despite advances in treatment strategy during the last decade. Therapies targeting single pathways are unlikely to succeed due to the heterogeneous nature of the malignancy. Proliferating cell nuclear antigen (PCNA is a multifunctional protein essential for DNA replication and repair that is often overexpressed in cancer cells. Many proteins involved in the cellular stress response interact with PCNA through the five amino acid sequence AlkB homologue 2 PCNA-interacting motif (APIM. Thus inhibiting PCNA's protein interactions may be a good strategy to target multiple pathways simultaneously. We initially found that overexpression of peptides containing the APIM sequence increases the sensitivity of cancer cells to contemporary therapeutics. Here we have designed a cell-penetrating APIM-containing peptide, ATX-101, that targets PCNA and show that it has anti-myeloma activity. We found that ATX-101 induced apoptosis in multiple myeloma cell lines and primary cancer cells, while bone marrow stromal cells and primary healthy lymphocytes were much less sensitive. ATX-101-induced apoptosis was caspase-dependent and cell cycle phase-independent. ATX-101 also increased multiple myeloma cells' sensitivity against melphalan, a DNA damaging agent commonly used for treatment of multiple myeloma. In a xenograft mouse model, ATX-101 was well tolerated and increased the anti-tumor activity of melphalan. Therefore, targeting PCNA by ATX-101 may be a novel strategy in multiple myeloma treatment.

  6. First measurement of proton-induced low-momentum dielectron radiation off cold nuclear matter

    Science.gov (United States)

    HADES Collaboration; Agakishiev, G.; Balanda, A.; Belver, D.; Belyaev, A.; Berger-Chen, J. C.; Blanco, A.; Böhmer, M.; Boyard, J. L.; Cabanelas, P.; Chernenko, S.; Dybczak, A.; Epple, E.; Fabbietti, L.; Fateev, O.; Finocchiaro, P.; Fonte, P.; Friese, J.; Fröhlich, I.; Galatyuk, T.; Garzón, J. A.; Gernhäuser, R.; Göbel, K.; Golubeva, M.; González-Díaz, D.; Guber, F.; Gumberidze, M.; Heinz, T.; Hennino, T.; Holzmann, R.; Ierusalimov, A.; Iori, I.; Ivashkin, A.; Jurkovic, M.; Kämpfer, B.; Karavicheva, T.; Koenig, I.; Koenig, W.; Kolb, B. W.; Kornakov, G.; Kotte, R.; Krása, A.; Krizek, F.; Krücken, R.; Kuc, H.; Kühn, W.; Kugler, A.; Kurepin, A.; Ladygin, V.; Lalik, R.; Lang, S.; Lapidus, K.; Lebedev, A.; Liu, T.; Lopes, L.; Lorenz, M.; Maier, L.; Mangiarotti, A.; Markert, J.; Metag, V.; Michalska, B.; Michel, J.; Mishra, D.; Müntz, C.; Naumann, L.; Pachmayer, Y. C.; Palka, M.; Parpottas, Y.; Pechenov, V.; Pechenova, O.; Pietraszko, J.; Przygoda, W.; Ramstein, B.; Reshetin, A.; Rustamov, A.; Sadovsky, A.; Salabura, P.; Schmah, A.; Schwab, E.; Siebenson, J.; Sobolev, Yu. G.; Spataro, S.; Spruck, B.; Ströbele, H.; Stroth, J.; Sturm, C.; Tarantola, A.; Teilab, K.; Tlusty, P.; Traxler, M.; Trebacz, R.; Tsertos, H.; Vasiliev, T.; Wagner, V.; Weber, M.; Wendisch, C.; Wüstenfeld, J.; Yurevich, S.; Zanevsky, Y.

    2012-09-01

    We present data on dielectron emission in proton induced reactions on a Nb target at 3.5 GeV kinetic beam energy measured with HADES installed at GSI. The data represent the first high statistics measurement of proton-induced dielectron radiation from cold nuclear matter in a kinematic regime, where strong medium effects are expected. Combined with the good mass resolution of 2%, it is the first measurement sensitive to changes of the spectral functions of vector mesons, as predicted by models for hadrons at rest or small relative momenta. Comparing the e+e- invariant mass spectra to elementary p + p data, we observe for e+e- momenta Pee<0.8 GeV/c a strong modification of the shape of the spectrum, which we attribute to an additional ρ-like contribution and a decrease of ω yield. These opposite trends are tentatively interpreted as a strong coupling of the ρ meson to baryonic resonances and an absorption of the ω meson, which are two aspects of in-medium modification of vector mesons.

  7. Different experimental approaches in modelling cataractogenesis: An overview of selenite-induced nuclear cataract in rats.

    Science.gov (United States)

    Kyselova, Zuzana

    2010-03-01

    Cataract, the opacification of eye lens, is the leading cause of blindness worldwide. At present, the only remedy is surgical removal of the cataractous lens and substitution with a lens made of synthetic polymers. However, besides significant costs of operation and possible complications, an artificial lens just does not have the overall optical qualities of a normal one. Hence it remains a significant public health problem, and biochemical solutions or pharmacological interventions that will maintain the transparency of the lens are highly required. Naturally, there is a persistent demand for suitable biological models. The ocular lens would appear to be an ideal organ for maintaining culture conditions because of lacking blood vessels and nerves. The lens in vivo obtains its nutrients and eliminates waste products via diffusion with the surrounding fluids. Lens opacification observed in vivo can be mimicked in vitro by addition of the cataractogenic agent sodium selenite (Na(2)SeO(3)) to the culture medium. Moreover, since an overdose of sodium selenite induces also cataract in young rats, it became an extremely rapid and convenient model of nuclear cataract in vivo. The main focus of this review will be on selenium (Se) and its salt sodium selenite, their toxicological characteristics and safety data in relevance of modelling cataractogenesis, either under in vivo or in vitro conditions. The studies revealing the mechanisms of lens opacification induced by selenite are highlighted, the representatives from screening for potential anti-cataract agents are listed.

  8. Effect of erythropoietin administration on proteins participating in iron homeostasis in Tmprss6-mutated mask mice.

    Science.gov (United States)

    Frýdlová, Jana; Rychtarčíková, Zuzana; Gurieva, Iuliia; Vokurka, Martin; Truksa, Jaroslav; Krijt, Jan

    2017-01-01

    Tmprss6-mutated mask mice display iron deficiency anemia and high expression of hepcidin. The aim of the study was to determine the effect of erythropoietin administration on proteins participating in the control of iron homeostasis in the liver and spleen in C57BL/6 and mask mice. Administration of erythropoietin for four days at 50 IU/mouse/day increased hemoglobin and hematocrit in C57BL/6 mice, no such increase was seen in mask mice. Erythropoietin administration decreased hepcidin expression in C57BL/6 mice, but not in mask mice. Erythropoietin treatment significantly increased the spleen size in both C57BL/6 and mask mice. Furthermore, erythropoietin administration increased splenic Fam132b, Fam132a and Tfr2 mRNA content. At the protein level, erythropoietin increased the amount of splenic erythroferrone and transferrin receptor 2 both in C57BL/6 and mask mice. Splenic ferroportin content was decreased in erythropoietin-treated mask mice in comparison with erythropoietin-treated C57BL/6 mice. In mask mice, the amount of liver hemojuvelin was decreased in comparison with C57BL/6 mice. The pattern of hemojuvelin cleavage was different between C57BL/6 and mask mice: In both groups, a main hemojuvelin band was detected at approximately 52 kDa; in C57BL/6 mice, a minor cleaved band was seen at 47 kDa. In mask mice, the 47 kDa band was absent, but additional minor bands were detected at approximately 45 kDa and 48 kDa. The results provide support for the interaction between TMPRSS6 and hemojuvelin in vivo; they also suggest that hemojuvelin could be cleaved by another as yet unknown protease in the absence of functional TMPRSS6. The lack of effect of erythropoietin on hepcidin expression in mask mice can not be explained by changes in erythroferrone synthesis, as splenic erythroferrone content increased after erythropoietin administration in both C57BL/6 and mask mice.

  9. 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

  10. Effect of erythropoietin administration on proteins participating in iron homeostasis in Tmprss6-mutated mask mice.

    Directory of Open Access Journals (Sweden)

    Jana Frýdlová

    Full Text Available Tmprss6-mutated mask mice display iron deficiency anemia and high expression of hepcidin. The aim of the study was to determine the effect of erythropoietin administration on proteins participating in the control of iron homeostasis in the liver and spleen in C57BL/6 and mask mice. Administration of erythropoietin for four days at 50 IU/mouse/day increased hemoglobin and hematocrit in C57BL/6 mice, no such increase was seen in mask mice. Erythropoietin administration decreased hepcidin expression in C57BL/6 mice, but not in mask mice. Erythropoietin treatment significantly increased the spleen size in both C57BL/6 and mask mice. Furthermore, erythropoietin administration increased splenic Fam132b, Fam132a and Tfr2 mRNA content. At the protein level, erythropoietin increased the amount of splenic erythroferrone and transferrin receptor 2 both in C57BL/6 and mask mice. Splenic ferroportin content was decreased in erythropoietin-treated mask mice in comparison with erythropoietin-treated C57BL/6 mice. In mask mice, the amount of liver hemojuvelin was decreased in comparison with C57BL/6 mice. The pattern of hemojuvelin cleavage was different between C57BL/6 and mask mice: In both groups, a main hemojuvelin band was detected at approximately 52 kDa; in C57BL/6 mice, a minor cleaved band was seen at 47 kDa. In mask mice, the 47 kDa band was absent, but additional minor bands were detected at approximately 45 kDa and 48 kDa. The results provide support for the interaction between TMPRSS6 and hemojuvelin in vivo; they also suggest that hemojuvelin could be cleaved by another as yet unknown protease in the absence of functional TMPRSS6. The lack of effect of erythropoietin on hepcidin expression in mask mice can not be explained by changes in erythroferrone synthesis, as splenic erythroferrone content increased after erythropoietin administration in both C57BL/6 and mask mice.

  11. Effect of erythropoietin administration on proteins participating in iron homeostasis in Tmprss6-mutated mask mice

    Science.gov (United States)

    Frýdlová, Jana; Rychtarčíková, Zuzana; Gurieva, Iuliia; Vokurka, Martin; Truksa, Jaroslav

    2017-01-01

    Tmprss6-mutated mask mice display iron deficiency anemia and high expression of hepcidin. The aim of the study was to determine the effect of erythropoietin administration on proteins participating in the control of iron homeostasis in the liver and spleen in C57BL/6 and mask mice. Administration of erythropoietin for four days at 50 IU/mouse/day increased hemoglobin and hematocrit in C57BL/6 mice, no such increase was seen in mask mice. Erythropoietin administration decreased hepcidin expression in C57BL/6 mice, but not in mask mice. Erythropoietin treatment significantly increased the spleen size in both C57BL/6 and mask mice. Furthermore, erythropoietin administration increased splenic Fam132b, Fam132a and Tfr2 mRNA content. At the protein level, erythropoietin increased the amount of splenic erythroferrone and transferrin receptor 2 both in C57BL/6 and mask mice. Splenic ferroportin content was decreased in erythropoietin-treated mask mice in comparison with erythropoietin-treated C57BL/6 mice. In mask mice, the amount of liver hemojuvelin was decreased in comparison with C57BL/6 mice. The pattern of hemojuvelin cleavage was different between C57BL/6 and mask mice: In both groups, a main hemojuvelin band was detected at approximately 52 kDa; in C57BL/6 mice, a minor cleaved band was seen at 47 kDa. In mask mice, the 47 kDa band was absent, but additional minor bands were detected at approximately 45 kDa and 48 kDa. The results provide support for the interaction between TMPRSS6 and hemojuvelin in vivo; they also suggest that hemojuvelin could be cleaved by another as yet unknown protease in the absence of functional TMPRSS6. The lack of effect of erythropoietin on hepcidin expression in mask mice can not be explained by changes in erythroferrone synthesis, as splenic erythroferrone content increased after erythropoietin administration in both C57BL/6 and mask mice. PMID:29073189

  12. 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

  13. BET bromodomain inhibition rescues erythropoietin differentiation of human erythroleukemia cell line UT7

    Energy Technology Data Exchange (ETDEWEB)

    Goupille, Olivier [CEA, Institute of Emerging Diseases and Innovative Therapies, Fontenay-aux-Roses (France); UMR INSERM U.962, University Paris XI, CEA, Fontenay-aux-Roses (France); Penglong, Tipparat [CEA, Institute of Emerging Diseases and Innovative Therapies, Fontenay-aux-Roses (France); UMR INSERM U.962, University Paris XI, CEA, Fontenay-aux-Roses (France); Thalassemia Research Center and Department of Clinical Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University (Thailand); Lefevre, Carine; Granger, Marine; Kadri, Zahra [CEA, Institute of Emerging Diseases and Innovative Therapies, Fontenay-aux-Roses (France); UMR INSERM U.962, University Paris XI, CEA, Fontenay-aux-Roses (France); Fucharoen, Suthat [Thalassemia Research Center and Department of Clinical Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University (Thailand); Maouche-Chretien, Leila [CEA, Institute of Emerging Diseases and Innovative Therapies, Fontenay-aux-Roses (France); UMR INSERM U.962, University Paris XI, CEA, Fontenay-aux-Roses (France); Leboulch, Philippe [CEA, Institute of Emerging Diseases and Innovative Therapies, Fontenay-aux-Roses (France); UMR INSERM U.962, University Paris XI, CEA, Fontenay-aux-Roses (France); Genetics Division, Department of Medicine, Brigham and Women' s Hospital and Harvard Medical School, Boston, MA (United States); Chretien, Stany, E-mail: stany.chretien@cea.fr [CEA, Institute of Emerging Diseases and Innovative Therapies, Fontenay-aux-Roses (France); UMR INSERM U.962, University Paris XI, CEA, Fontenay-aux-Roses (France)

    2012-12-07

    Highlights: Black-Right-Pointing-Pointer UT7 erythroleukemia cells are known to be refractory to differentiate. Black-Right-Pointing-Pointer Brief JQ1 treatment initiates the first steps of erythroid differentiation program. Black-Right-Pointing-Pointer Engaged UT7 cells then maturate in the presence of erythropoietin. Black-Right-Pointing-Pointer Sustained JQ1 treatment inhibits both proliferation and erythroid differentiation. -- Abstract: Malignant transformation is a multistep process requiring oncogenic activation, promoting cellular proliferation, frequently coupled to inhibition of terminal differentiation. Consequently, forcing the reengagement of terminal differentiation of transformed cells coupled or not with an inhibition of their proliferation is a putative therapeutic approach to counteracting tumorigenicity. UT7 is a human leukemic cell line able to grow in the presence of IL3, GM-CSF and Epo. This cell line has been widely used to study Epo-R/Epo signaling pathways but is a poor model for erythroid differentiation. We used the BET bromodomain inhibition drug JQ1 to target gene expression, including that of c-Myc. We have shown that only 2 days of JQ1 treatment was required to transitory inhibit Epo-induced UT7 proliferation and to restore terminal erythroid differentiation. This study highlights the importance of a cellular erythroid cycle break mediated by c-Myc inhibition before initiation of the erythropoiesis program and describes a new model for BET bromodomain inhibitor drug application.

  14. Genistein attenuates hypoxic pulmonary hypertension via enhanced nitric oxide signaling and the erythropoietin system.

    Science.gov (United States)

    Kuriyama, Sachiko; Morio, Yoshiteru; Toba, Michie; Nagaoka, Tetsutaro; Takahashi, Fumiyuki; Iwakami, Shin-Ichiro; Seyama, Kuniaki; Takahashi, Kazuhisa

    2014-06-01

    Upregulation of the erythropoietin (EPO)/EPO receptor (EPOR) system plays a protective role against chronic hypoxia-induced pulmonary hypertension (hypoxic PH) through enhancement of endothelial nitric oxide (NO)-mediated signaling. Genistein (Gen), a phytoestrogen, is considered to ameliorate NO-mediated signaling. We hypothesized that Gen attenuates and prevents hypoxic PH. In vivo, Sprague-Dawley rats raised in a hypobaric chamber were treated with Gen (60 mkg/kg) for 21 days. Pulmonary hemodynamics and vascular remodeling were ameliorated in Gen-treated hypoxic PH rats. Gen also restored cGMP levels and phosphorylated endothelial NO synthase (p-eNOS) at Ser(1177) and p-Akt at Ser(473) expression in the lungs. Additionally, Gen potentiated plasma EPO concentration and EPOR-positive endothelial cell counts. In experiments with hypoxic PH rats' isolated perfused lungs, Gen caused NO- and phosphatidylinositol 3-kinase (PI3K)/Akt-dependent vasodilation that reversed abnormal vasoconstriction. In vitro, a combination of EPO and Gen increased the p-eNOS and the EPOR expression in human umbilical vein endothelial cells under a hypoxic environment. Moreover, Gen potentiated the hypoxic increase in EPO production from human hepatoma cells. We conclude that Gen may be effective for the prevention of hypoxic PH through the improvement of PI3K/Akt-dependent, NO-mediated signaling in association with enhancement of the EPO/EPOR system. Copyright © 2014 the American Physiological Society.

  15. Epidermal growth factor and erythropoietin infusion accelerate functional recovery in combination with rehabilitation.

    Science.gov (United States)

    Jeffers, Matthew S; Hoyles, Amy; Morshead, Cindi; Corbett, Dale

    2014-06-01

    Rehabilitation is the only treatment option for chronic stroke deficits, but unfortunately, it often provides incomplete recovery. In this study, a novel combination of growth factor administration and rehabilitation therapy was used to facilitate functional recovery in a rat model of cortical stroke. Ischemia was induced via injection of endothelin-1 into the sensorimotor cortex. This was followed by either a 2-week infusion of epidermal growth factor and erythropoietin or artificial cerebrospinal fluid into the ipsilateral lateral ventricle. Two weeks after ischemia, animals began an 8-week enriched rehabilitation program. Functional recovery was assessed after ischemia using the Montoya staircase-reaching task, beam-traversing, and cylinder test of forelimb asymmetry. The combination of growth factor infusion and rehabilitation led to a significant acceleration in recovery in the staircase task. When compared with controls, animals receiving the combination treatment attained significant recovery of function at 4 weeks after stroke, whereas those receiving rehabilitation alone did not recover until 10 weeks. Significant recovery was also observed on the beam-traversing and cylinder tasks. Combining behavioral rehabilitation with growth factor infusion accelerates motor recovery. These data suggest a promising new avenue of combination therapies that may have the potential to reduce the rehabilitation time necessary to recover from sensorimotor deficits arising from stroke. © 2014 American Heart Association, Inc.

  16. 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.

  17. Erythropoietin Exacerbates Inflammation and Increases the Mortality of Histoplasma capsulatum-Infected Mice

    Directory of Open Access Journals (Sweden)

    Gisele Aparecida Locachevic

    2015-01-01

    Full Text Available Erythropoietin (EPO is a key hormone involved in red blood cell formation, but its effects on nonerythroid cells, such as macrophages, have not been described. Macrophages are key cells in controlling histoplasmosis, a fungal infection caused by Histoplasma capsulatum (Hc. Considering that little is known about EPO’s role during fungal infections and its capacity to activate macrophages, in this study we investigated the impact of EPO pretreatment on the alveolar immune response during Hc infection. The consequence of EPO pretreatment on fungal infection was determined by evaluating animal survival, fungal burden, activation of bronchoalveolar macrophages, inflammatory mediator release, and lung inflammation. Pretreatment with EPO diminished mononuclear cell numbers, increased the recruitment of F4/80+/CD80+ and F4/80+/CD86+ cells to the bronchoalveolar space, induced higher production of IFN-γ, IL-6, MIP-1α, MCP-1, and LTB4, reduced PGE2 concentration, and did not affect fungal burden. As a consequence, we observed an increase in lung inflammation with extensive tissue damage that might account for augmented mouse mortality after infection. Our results demonstrate for the first time that EPO treatment has a deleterious impact on lung immune responses during fungal infection.

  18. DNA methylation is necessary for erythropoietin to improve spatial learning and memory in SAMP8 mice.

    Science.gov (United States)

    Yu, Nengwei; Liu, Jie; Yi, Gang; Ye, Fang; Xiao, Jun; Guo, Fuqiang

    2015-09-01

    To reveal the role of Dnmts in the improvement of spatial learning and memory induced by erythropoietin (EPO) in SAMP8 mice. The Morris water maze (MWM) was used to assess spatial learning and memory. Mice were administered by intraperitoneal (i.p.) injection of recombinant human EPO and hippocamppi infusion (IH) of 5-aza-2'-deoxycytidine (5-AZA). The expression of genes Dnmt1, Dnmt3a and Dnmt3b in the hippocampus was detected by real-time qPCR. The level of proteins DNMT1, DNMT3A and DNMT3B was measured by Western blotting. Spatial learning and memory in SAMP8 were promoted after i.p. injection of EPO (5000IU/kg/day) and expression of Dnmt3b mRNA and DNMT3B proteins in the hippocampus increased. The improved memory by EPO was blocked after IH 5-AZA. DNA methylation is necessary for EPO to enhance spatial learning and memory in SAMP8 mice. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Erythropoietin Promotes Neural Plasticity and Spatial Memory Recovery in Fimbria-Fornix-Lesioned Rats.

    Science.gov (United States)

    Almaguer-Melian, William; Mercerón-Martínez, Daymara; Pavón-Fuentes, Nancy; Alberti-Amador, Esteban; Leon-Martinez, Rilda; Ledón, Nuris; Delgado Ocaña, Susana; Bergado Rosado, Jorge A

    2015-01-01

    Erythropoietin (EPO) upregulates the mitogen activated protein kinase (MAPK) cascade, a central signaling pathway in cellular plastic mechanisms, and is critical for normal brain development. We hypothesized that EPO could modulate the plasticity mechanisms supporting spatial memory recovery in fimbria-fornix-transected animals. Fimbria-fornix was transected in 3 groups of rats. Seven days later, EPO was injected daily for 4 consecutive days within 10 minutes after training on a water maze task. Our results show that EPO injections 10 minutes after training produced a substantial spatial memory recovery in fimbria-fornix-lesioned animals. In contrast, an EPO injection shortly after fimbria-fornix lesion surgery does not promote spatial-memory recovery. Neither does daily EPO injection 5 hours after the water maze performance. EPO, on the other hand, induced the expression of plasticity-related genes like arc and bdnf, but this effect was independent of training or lesion. This finding supports our working hypothesis that EPO can modulate transient neuroplastic mechanisms triggered by training in lesioned animals. Consequently, we propose that EPO administration can be a useful trophic factor to promote neural restoration when given in combination with training. © The Author(s) 2015.

  20. Erythropoietin-Derived Peptide Protects Against Acute Lung Injury After Rat Traumatic Brain Injury

    Directory of Open Access Journals (Sweden)

    Yuan Liu

    2017-04-01

    Full Text Available Background: Traumatic brain injury (TBI can be complicated by TBI-triggered acute lung injury (ALI, in which inflammation plays a central role. It has been reported that an Erythropoietin-derived peptide (pHBSP was able to ameliorate TBI; however, its function in TBI-caused ALI has not been reported yet. Methods: In this study, we studied the effect of pHBSP on TBI-caused ALI by using a weight-drop induced TBI model. At 8 h and 24 h post-TBI, pulmonary edema (PE and bronchoalveolar lavage fluid (BALF proteins were measured, and haematoxylin and eosin (H&E staining of lung sections was carried out. At 24 h following TBI, the lungs were harvested for immunofluorescence staining and qRT-PCR analysis. Results: At 8 h and 24 h post-TBI, pHBSP treatment significantly decreased wet/dry ratios, decreased total BALF protein, and attenuated the histological signs of pulmonary injury. At 24 h post-TBI, pHBSP treatment decreased the accumulation of CD68+ macrophages in the lung and reduced the mRNA levels of TNF-α, IL-6, IL-1β and iNOS in the lung. Conclusions: We identified the protective role that pHBSP played in TBI-caused ALI, suggesting that pHBSP is a potent candidate for systemic therapy in TBI patients.

  1. Erythropoietin ameliorates the motor and cognitive function impairments in a rat model of hepatic cirrhosis.

    Science.gov (United States)

    Aghaei, Iraj; Nazeri, Masoud; Shabani, Mohammad; Mossavinasab, Marziehsadat; Mirhosseini, Fatemeh Khaleghi; Nayebpour, Mohsen; Dalili, Afshin

    2015-02-01

    Hepatic encephalopathy (HE) is a serious consequence of hepatic cirrhosis (HC). Previous studies have demonstrated cognitive impairments in both clinical and animal experiments of HC. Some potential therapeutic agents have been used to alleviate the cognitive symptoms in the animal models of HC. In the current study, the possible effect of erythropoietin (ERY) as a potent neuroprotective agent on motor and cognitive impairments induced by HC has been studied. Male Wistar rats (180-200 g) underwent bile duct ligation (BDL) or sham surgery. Administration of ERY (5,000 IU/kg, i.p., daily for three days) was initiated 2 weeks after surgery and lasted for the next 28 days. Open field, rotarod, Morris water maze and passive avoidance learning was used to evaluate the motor and cognitive function of the animals. ANOVA and repeated measures ANOVA were used to analyze the data. p balance function by BDL was reversed by ERY. Spatial and passive avoidance learning impairments observed in BDL rats were also reversed by chronic administration of ERY. ERY can be offered as a potential neuroprotective agent in the treatment of patients with HC that manifest mental dysfunctions. Though further studies are needed to clarify the exact mechanisms, the neuroprotective properties of ERY against BDL impairments were demonstrated in the current study.

  2. Dexamethasone mimics aspects of physiological acclimatization to 8 hours of hypoxia but suppresses plasma erythropoietin

    Science.gov (United States)

    Liu, Chun; Croft, Quentin P. P.; Kalidhar, Swati; Brooks, Jerome T.; Herigstad, Mari; Smith, Thomas G.; Dorrington, Keith L.

    2013-01-01

    Dexamethasone ameliorates the severity of acute mountain sickness (AMS) but it is unknown whether it obtunds normal physiological responses to hypoxia. We studied whether dexamethasone enhanced or inhibited the ventilatory, cardiovascular, and pulmonary vascular responses to sustained (8 h) hypoxia. Eight healthy volunteers were studied, each on four separate occasions, permitting four different protocols. These were: dexamethasone (20 mg orally) beginning 2 h before a control period of 8 h of air breathing; dexamethasone with 8 h of isocapnic hypoxia (end-tidal Po2 = 50 Torr); placebo with 8 h of air breathing; and placebo with 8 h of isocapnic hypoxia. Before and after each protocol, the following were determined under both euoxic and hypoxic conditions: ventilation; pulmonary artery pressure (estimated using echocardiography to assess maximum tricuspid pressure difference); heart rate; and cardiac output. Plasma concentrations of erythropoietin (EPO) were also determined. Dexamethasone had no early (2-h) effect on any variable. Both dexamethasone and 8 h of hypoxia increased euoxic values of ventilation, pulmonary artery pressure, and heart rate, together with the ventilatory sensitivity to acute hypoxia. These effects were independent and additive. Eight hours of hypoxia, but not dexamethasone, increased the sensitivity of pulmonary artery pressure to acute hypoxia. Dexamethasone, but not 8 h of hypoxia, increased both cardiac output and systemic arterial pressure. Dexamethasone abolished the rise in EPO induced by 8 h of hypoxia. In summary, dexamethasone enhances ventilatory acclimatization to hypoxia. Thus, dexamethasone in AMS may improve oxygenation and thereby indirectly lower pulmonary artery pressure. PMID:23393065

  3. Laser-induced breakdown spectroscopy of light water reactor simulated used nuclear fuel: Main oxide phase

    Science.gov (United States)

    Campbell, Keri R.; Judge, Elizabeth J.; Barefield, James E.; Colgan, James P.; Kilcrease, David P.; Czerwinski, Ken R.; Clegg, Samuel M.

    2017-07-01

    The analysis of light water reactor simulated used nuclear fuel using laser-induced breakdown spectroscopy (LIBS) is explored using a simplified version of the main oxide phase. The main oxide phase consists of the actinides, lanthanides, and zirconium. The purpose of this study is to develop a rapid, quantitative technique for measuring zirconium in a uranium dioxide matrix without the need to dissolve the material. A second set of materials including cerium oxide is also analyzed to determine precision and limit of detection (LOD) using LIBS in a complex matrix. Two types of samples are used in this study: binary and ternary oxide pellets. The ternary oxide, (U,Zr,Ce)O2 pellets used in this study are a simplified version the main oxide phase of used nuclear fuel. The binary oxides, (U,Ce)O2 and (U,Zr)O2 are also examined to determine spectral emission lines for Ce and Zr, potential spectral interferences with uranium and baseline LOD values for Ce and Zr in a UO2 matrix. In the spectral range of 200 to 800 nm, 33 cerium lines and 25 zirconium lines were identified and shown to have linear correlation values (R2) > 0.97 for both the binary and ternary oxides. The cerium LOD in the (U,Ce)O2 matrix ranged from 0.34 to 1.08 wt% and 0.94 to 1.22 wt% in (U,Ce,Zr)O2 for 33 of Ce emission lines. The zirconium limit of detection in the (U,Zr)O2 matrix ranged from 0.84 to 1.15 wt% and 0.99 to 1.10 wt% in (U,Ce,Zr)O2 for 25 Zr lines. The effect of multiple elements in the plasma and the impact on the LOD is discussed.

  4. Stress-induced nuclear RNA degradation pathways regulate yeast bromodomain factor 2 to promote cell survival.

    Directory of Open Access Journals (Sweden)

    Kevin Roy

    2014-09-01

    Full Text Available Bromodomain proteins are key regulators of gene expression. How the levels of these factors are regulated in specific environmental conditions is unknown. Previous work has established that expression of yeast Bromodomain factor 2 (BDF2 is limited by spliceosome-mediated decay (SMD. Here we show that BDF2 is subject to an additional layer of post-transcriptional control through RNase III-mediated decay (RMD. We found that the yeast RNase III Rnt1p cleaves a stem-loop structure within the BDF2 mRNA to down-regulate its expression. However, these two nuclear RNA degradation pathways play distinct roles in the regulation of BDF2 expression, as we show that the RMD and SMD pathways of the BDF2 mRNA are differentially activated or repressed in specific environmental conditions. RMD is hyper-activated by salt stress and repressed by hydroxyurea-induced DNA damage while SMD is inactivated by salt stress and predominates during DNA damage. Mutations of cis-acting signals that control SMD and RMD rescue numerous growth defects of cells lacking Bdf1p, and show that SMD plays an important role in the DNA damage response. These results demonstrate that specific environmental conditions modulate nuclear RNA degradation pathways to control BDF2 expression and Bdf2p-mediated gene regulation. Moreover, these results show that precise dosage of Bromodomain factors is essential for cell survival in specific environmental conditions, emphasizing their importance for controlling chromatin structure and gene expression in response to environmental stress.

  5. Stress-Induced Nuclear RNA Degradation Pathways Regulate Yeast Bromodomain Factor 2 to Promote Cell Survival

    Science.gov (United States)

    Roy, Kevin; Chanfreau, Guillaume

    2014-01-01

    Bromodomain proteins are key regulators of gene expression. How the levels of these factors are regulated in specific environmental conditions is unknown. Previous work has established that expression of yeast Bromodomain factor 2 (BDF2) is limited by spliceosome-mediated decay (SMD). Here we show that BDF2 is subject to an additional layer of post-transcriptional control through RNase III-mediated decay (RMD). We found that the yeast RNase III Rnt1p cleaves a stem-loop structure within the BDF2 mRNA to down-regulate its expression. However, these two nuclear RNA degradation pathways play distinct roles in the regulation of BDF2 expression, as we show that the RMD and SMD pathways of the BDF2 mRNA are differentially activated or repressed in specific environmental conditions. RMD is hyper-activated by salt stress and repressed by hydroxyurea-induced DNA damage while SMD is inactivated by salt stress and predominates during DNA damage. Mutations of cis-acting signals that control SMD and RMD rescue numerous growth defects of cells lacking Bdf1p, and show that SMD plays an important role in the DNA damage response. These results demonstrate that specific environmental conditions modulate nuclear RNA degradation pathways to control BDF2 expression and Bdf2p-mediated gene regulation. Moreover, these results show that precise dosage of Bromodomain factors is essential for cell survival in specific environmental conditions, emphasizing their importance for controlling chromatin structure and gene expression in response to environmental stress. PMID:25232960

  6. Overexpression of nuclear receptor SHP in adipose tissues affects diet-induced obesity and adaptive thermogenesis

    National Research Council Canada - National Science Library

    Imene Tabbi-Anneni; Robert Cooksey; Viswanath Gunda; Shiguo Liu; Aubrey Mueller; Guisheng Song; Donald A. McClain; Li Wang

    2010-01-01

    The orphan nuclear receptor small heterodimer partner (SHP) regulates metabolic pathways involved in hepatic bile acid production and both lipid and glucose homeostasis via the transcriptional repression of other nuclear receptors...

  7. Erythropoietin to Reduce Mortality in Traumatic Brain Injury: A Post-hoc Dose-effect Analysis.

    Science.gov (United States)

    Gantner, Dashiell C; Bailey, Michael; Presneill, Jeffrey; French, Craig J; Nichol, Alistair; Little, Lorraine; Bellomo, Rinaldo

    2017-02-01

    We aimed to assess whether the dosing regimen of erythropoietin shows a relationship to mortality in critically ill patients with traumatic brain injury (TBI). Erythropoietin may decrease mortality in patients with TBI; however, the optimal dosing regimen remains uncertain. We conducted a post-hoc analysis of a multicenter, randomized trial of weekly erythropoietin versus placebo in patients with moderate and severe TBI admitted to intensive care. We assessed whether the cumulative dosage of erythropoietin was differentially associated with all-cause patient mortality evaluated at 6 months after injury. There was a nonlinear relationship between dose and mortality (P = 0.008) that remained after adjustment for site and severity of illness (P = 0.01). Six-month mortality was lower in randomized patients who received 1 [adjusted hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.33-1.01; P = 0.06] or 2 doses of erythropoietin (HR 0.31, 95% CI 0.12-0.80; P = 0.02) compared with those who received no doses. No benefit was seen with 3 doses (HR 1.55, 95% CI 0.66-3.62; P = 0.33). There was no differential effect of dose on functional neurological outcomes. Results across subgroups and secondary intention to treat analyses were consistent with primary findings. This post-hoc, hypothesis-generating analysis found potential reductions in mortality following 1 or 2 weekly doses of 40,000 IU of erythropoietin in intensive care unit patients with moderate or severe TBI, but not with 3 doses. These findings will inform the design of future trials of erythropoietin in critically ill patients with TBI and trauma.

  8. Non-hematopoietic effects of endogenous erythropoietin on lean mass and body weight regulation.

    Science.gov (United States)

    Reinhardt, Martin; Dey, Soumyadeep; Tom Noguchi, Constance; Zhang, Yuanyuan; Krakoff, Jonathan; Thearle, Marie S

    2016-07-01

    To investigate the concurrent relationships between human plasma erythropoietin concentrations and energy expenditure (EE), body composition, plasma leptin concentrations, and associations with weight change. Plasma to measure erythropoietin and leptin; data for body composition; 24-h EE measured in a whole-room calorimeter; and 75 g oral glucose tolerance testing were available from 109 full-heritage Pima Indians (55% male) from a larger study designed to understand the causes of obesity. Seventy-nine subjects had data for weight at a later visit (mean follow-up = 4.3 ± 1.9 years) to calculate percent weight change per year. Erythropoietin, adjusted for covariates, correlated with 24-h EE (r = 0.26, P = 0.007), sleeping EE (r = 0.29, P = 0.003), fat-free mass (r = 0.19, P = 0.05), and fat mass (r = 0.27, P = 0.005), but not insulin or glucose measures. The association of erythropoietin with 24-h EE was fully mediated by fat-free mass. Erythropoietin associated with leptin in women (ρ = 0.36, P = 0.01), but not in men (P = 0.9), independently from fat mass. The association of erythropoietin with percent weight change per year was in opposing directions (interaction: P = 0.002) in males (r = -0.35, P = 0.02) versus females (r = 0.37, P = 0.02). Non-hematopoietic endogenous erythropoietin action may be involved in body weight regulation in opposing directions in men and women, i.e., weight loss in men and weight gain in women. © 2016 The Obesity Society.

  9. Detection of Special Nuclear Material from Delayed Neutron Emission Induced by a Dual-Particle Monoenergetic Source

    Energy Technology Data Exchange (ETDEWEB)

    Mayer, Michael F.; Nattress, J.; Jovanovic, I

    2016-06-30

    Detection of unique signatures of special nuclear materials is critical for their interdiction in a variety of nuclear security and nonproliferation scenarios. We report on the observation of delayed neutrons from fission of uranium induced in dual-particle active interrogation based on the 11B(d,n gamma)12C nuclear reaction. Majority of the fissions are attributed to fast fission induced by the incident quasi-monoenergetic neutrons. A Li-doped glass–polymer composite scintillation neutron detector, which displays excellent neutron/γ discrimination at low energies, was used in the measurements, along with a recoil-based liquid scintillation detector. Time- dependent buildup and decay of delayed neutron emission from 238U were measured between the interrogating beam pulses and after the interrogating beam was turned off, respectively. Characteristic buildup and decay time profiles were compared to the common parametrization into six delayed neutron groups, finding a good agreement between the measurement and nuclear data. This method is promising for detecting fissile and fissionable materials in cargo scanning applications and can be readily integrated with transmission radiography using low-energy nuclear reaction sources.

  10. Detection of special nuclear material from delayed neutron emission induced by a dual-particle monoenergetic source

    Energy Technology Data Exchange (ETDEWEB)

    Mayer, M. [Department of Mechanical and Nuclear Engineering, The Pennsylvania State University, University Park, Pennsylvania 16802 (United States); Nattress, J.; Jovanovic, I., E-mail: ijov@umich.edu [Department of Nuclear Engineering and Radiological Sciences, University of Michigan, Ann Arbor, Michigan 48109 (United States)

    2016-06-27

    Detection of unique signatures of special nuclear materials is critical for their interdiction in a variety of nuclear security and nonproliferation scenarios. We report on the observation of delayed neutrons from fission of uranium induced in dual-particle active interrogation based on the {sup 11}B(d,n γ){sup 12}C nuclear reaction. Majority of the fissions are attributed to fast fission induced by the incident quasi-monoenergetic neutrons. A Li-doped glass–polymer composite scintillation neutron detector, which displays excellent neutron/γ discrimination at low energies, was used in the measurements, along with a recoil-based liquid scintillation detector. Time-dependent buildup and decay of delayed neutron emission from {sup 238}U were measured between the interrogating beam pulses and after the interrogating beam was turned off, respectively. Characteristic buildup and decay time profiles were compared to the common parametrization into six delayed neutron groups, finding a good agreement between the measurement and nuclear data. This method is promising for detecting fissile and fissionable materials in cargo scanning applications and can be readily integrated with transmission radiography using low-energy nuclear reaction sources.

  11. Erythropoietin enhances mitochondrial biogenesis in cardiomyocytes exposed to chronic hypoxia through Akt/eNOS signalling pathway.

    Science.gov (United States)

    Qin, Chuan; Zhou, Shengkai; Xiao, Yingbin; Chen, Lin

    2014-03-01

    Adaptation of cardiomyocytes to chronic hypoxia in cyanotic patients remains unclear. Mitochondrial biogenesis is enhanced in myocardium from cyanotic patients, which is possibly an adaptive response. Erythropoietin (EPO) in blood and its receptor (EPOR) on cardiomyocytes are upregulated by chronic hypoxia, suggesting that EPO-EPOR interaction is increased, which is inferred to positively regulate mitochondrial biogenesis through protein kinase B (Akt)/endothelial nitric oxide synthase (eNOS) signalling pathway. H9c2 cardiomyocytes were exposed to hypoxia (1% O(2)) for 1 week and treated with different doses of recombinant human erythropoietin (rhEPO). Mitochondrial number, mitochondrial DNA (mtDNA) copy number and peroxisome proliferator activated receptor gamma coactivator alpha (PGC-1α) mRNA expression increased in a dose-dependent manner induced by rhEPO. Akt and eNOS were significantly phosphorylated by rhEPO. Both blocking Akt with Wortmannin and silencing eNOS expression with shRNA plasmid decreased the mtDNA copy number and PGC-1α mRNA expression induced by rhEPO. Blocking Akt was associated with the decreased phosphorylation of Akt and eNOS. RNA interference led to a reduction in the total and phosphorylated proteins of eNOS. Thus EPO enhances mitochondrial biogenesis in cardiomyocytes exposed to chronic hypoxia, at least partly through Akt/eNOS signalling, which might be an adaptive mechanism of cardiomyocytes associated with the increased EPO-EPOR interaction in patients with cyanotic congenital heart disease (CCHD). © 2013 International Federation for Cell Biology.

  12. 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

  13. Virus-Induced Chaperone-Enriched (VICE domains function as nuclear protein quality control centers during HSV-1 infection.

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    Christine M Livingston

    2009-10-01

    Full Text Available Virus-Induced Chaperone-Enriched (VICE domains form adjacent to nuclear viral replication compartments (RC during the early stages of HSV-1 infection. Between 2 and 3 hours post infection at a MOI of 10, host protein quality control machinery such as molecular chaperones (e.g. Hsc70, the 20S proteasome and ubiquitin are reorganized from a diffuse nuclear distribution pattern to sequestration in VICE domains. The observation that VICE domains contain putative misfolded proteins suggests that they may be similar to nuclear inclusion bodies that form under conditions in which the protein quality control machinery is overwhelmed by the presence of misfolded proteins. The detection of Hsc70 in VICE domains, but not in nuclear inclusion bodies, indicates that Hsc70 is specifically reorganized by HSV-1 infection. We hypothesize that HSV-1 infection induces the formation of nuclear protein quality control centers to remodel or degrade aberrant nuclear proteins that would otherwise interfere with productive infection. Detection of proteolytic activity in VICE domains suggests that substrates may be degraded by the 20S proteasome in VICE domains. FRAP analysis reveals that GFP-Hsc70 is dynamically associated with VICE domains, suggesting a role for Hsc70 in scanning the infected nucleus for misfolded proteins. During 42 degrees C heat shock, Hsc70 is redistributed from VICE domains into RC perhaps to remodel viral replication and regulatory proteins that have become insoluble in these compartments. The experiments presented in this paper suggest that VICE domains are nuclear protein quality control centers that are modified by HSV-1 to promote productive infection.

  14. Tau-Induced Ca2+/Calmodulin-Dependent Protein Kinase-IV Activation Aggravates Nuclear Tau Hyperphosphorylation.

    Science.gov (United States)

    Wei, Yu-Ping; Ye, Jin-Wang; Wang, Xiong; Zhu, Li-Ping; Hu, Qing-Hua; Wang, Qun; Ke, Dan; Tian, Qing; Wang, Jian-Zhi

    2017-06-23

    Hyperphosphorylated tau is the major protein component of neurofibrillary tangles in the brains of patients with Alzheimer's disease (AD). However, the mechanism underlying tau hyperphosphorylation is not fully understood. Here, we demonstrated that exogenously expressed wild-type human tau40 was detectable in the phosphorylated form at multiple AD-associated sites in cytoplasmic and nuclear fractions from HEK293 cells. Among these sites, tau phosphorylated at Thr205 and Ser214 was almost exclusively found in the nuclear fraction at the conditions used in the present study. With the intracellular tau accumulation, the Ca 2+ concentration was significantly increased in both cytoplasmic and nuclear fractions. Further studies using site-specific mutagenesis and pharmacological treatment demonstrated that phosphorylation of tau at Thr205 increased nuclear Ca 2+ concentration with a simultaneous increase in the phosphorylation of Ca 2+ /calmodulin-dependent protein kinase IV (CaMKIV) at Ser196. On the other hand, phosphorylation of tau at Ser214 did not significantly change the nuclear Ca 2+ /CaMKIV signaling. Finally, expressing calmodulin-binding protein-4 that disrupts formation of the Ca 2+ /calmodulin complex abolished the okadaic acid-induced tau hyperphosphorylation in the nuclear fraction. We conclude that the intracellular accumulation of phosphorylated tau, as detected in the brains of AD patients, can trigger nuclear Ca 2+ /CaMKIV signaling, which in turn aggravates tau hyperphosphorylation. Our findings provide new insights for tauopathies: hyperphosphorylation of intracellular tau and an increased Ca 2+ concentration may induce a self-perpetuating harmful loop to promote neurodegeneration.

  15. Integrated Geophysical Measurements for Bioremediation Monitoring: Combining Spectral Induced Polarization, Nuclear Magnetic Resonance and Magnetic Methods

    Energy Technology Data Exchange (ETDEWEB)

    Keating, Kristina [Rutgers Univ., Newark, NJ (United States). Dept. of Earth and Environmental Sciences; Slater, Lee [Rutgers Univ., Newark, NJ (United States). Dept. of Earth and Environmental Sciences; Ntarlagiannis, Dimitris [Rutgers Univ., Newark, NJ (United States). Dept. of Earth and Environmental Sciences; Williams, Kenneth H. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Earth Sciences Division

    2015-02-24

    This documents contains the final report for the project "Integrated Geophysical Measurements for Bioremediation Monitoring: Combining Spectral Induced Polarization, Nuclear Magnetic Resonance and Magnetic Methods" (DE-SC0007049) Executive Summary: Our research aimed to develop borehole measurement techniques capable of monitoring subsurface processes, such as changes in pore geometry and iron/sulfur geochemistry, associated with remediation of heavy metals and radionuclides. Previous work has demonstrated that geophysical method spectral induced polarization (SIP) can be used to assess subsurface contaminant remediation; however, SIP signals can be generated from multiple sources limiting their interpretation value. Integrating multiple geophysical methods, such as nuclear magnetic resonance (NMR) and magnetic susceptibility (MS), with SIP, could reduce the ambiguity of interpretation that might result from a single method. Our research efforts entails combining measurements from these methods, each sensitive to different mineral forms and/or mineral-fluid interfaces, providing better constraints on changes in subsurface biogeochemical processes and pore geometries significantly improving our understanding of processes impacting contaminant remediation. The Rifle Integrated Field Research Challenge (IFRC) site was used as a test location for our measurements. The Rifle IFRC site is located at a former uranium ore-processing facility in Rifle, Colorado. Leachate from spent mill tailings has resulted in residual uranium contamination of both groundwater and sediments within the local aquifer. Studies at the site include an ongoing acetate amendment strategy, native microbial populations are stimulated by introduction of carbon intended to alter redox conditions and immobilize uranium. To test the geophysical methods in the field, NMR and MS logging measurements were collected before, during, and after acetate amendment. Next, laboratory NMR, MS, and SIP measurements

  16. 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.

  17. 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.

  18. Caspase-independent cell death mediated by apoptosis-inducing factor (AIF) nuclear translocation is involved in ionizing radiation induced HepG2 cell death

    Energy Technology Data Exchange (ETDEWEB)

    Sun, Hengwen [Department of Radiation, Cancer Center of Guangdong General Hospital (Guangdong Academy of Medical Science), Guangzhou, 510080, Guangdong (China); Yang, Shana; Li, Jianhua [Department of Physiology, Guangzhou Medical University, Guangzhou, 510182, Guangdong (China); Zhang, Yajie [Department of Pathology, Guangzhou Medical University, Guangzhou, 510182, Guangdong (China); Gao, Dongsheng [Department of Oncology, Guangdong Medical College Affiliated Pengpai Memorial Hospital, Hai Feng, 516400, Gungdong (China); Zhao, Shenting, E-mail: zhaoshenting@126.com [Department of Physiology, Guangzhou Medical University, Guangzhou, 510182, Guangdong (China)

    2016-03-25

    Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. The aim of radiotherapy is to eradicate cancer cells with ionizing radiation. Except for the caspase-dependent mechanism, several lines of evidence demonstrated that caspase-independent mechanism is directly involved in the cell death responding to irradiation. For this reason, defining the contribution of caspase-independent molecular mechanisms represents the main goal in radiotherapy. In this study, we focused on the role of apoptosis-inducing factor (AIF), the caspase-independent molecular, in ionizing radiation induced hepatocellular carcinoma cell line (HepG2) cell death. We found that ionizing radiation has no function on AIF expression in HepG2 cells, but could induce AIF release from the mitochondria and translocate into nuclei. Inhibition of AIF could reduce ionizing radiation induced HepG2 cell death. These studies strongly support a direct relationship between AIF nuclear translocation and radiation induced cell death. What's more, AIF nuclear translocation is caspase-independent manner, but not caspase-dependent manner, in this process. These new findings add a further attractive point of investigation to better define the complex interplay between caspase-independent cell death and radiation therapy. - Highlights: • AIF nuclear translocation is involved in ionizing radiation induced hepatocellular carcinoma cell line HepG2 cell death. • AIF mediated cell death induced by ionizing radiation is caspase-independent. • Caspase-independent pathway is involved in ionzing radiation induced HepG2 cell death.

  19. Nuclear c-Abl-mediated tyrosine phosphorylation induces chromatin structural changes through histone modifications that include H4K16 hypoacetylation

    Energy Technology Data Exchange (ETDEWEB)

    Aoyama, Kazumasa; Fukumoto, Yasunori; Ishibashi, Kenichi; Kubota, Sho; Morinaga, Takao; Horiike, Yasuyoshi; Yuki, Ryuzaburo; Takahashi, Akinori; Nakayama, Yuji; Yamaguchi, Naoto, E-mail: nyama@p.chiba-u.ac.jp

    2011-12-10

    c-Abl tyrosine kinase, which is ubiquitously expressed, has three nuclear localization signals and one nuclear export signal and can shuttle between the nucleus and the cytoplasm. c-Abl plays important roles in cell proliferation, adhesion, migration, and apoptosis. Recently, we developed a pixel imaging method for quantitating the level of chromatin structural changes and showed that nuclear Src-family tyrosine kinases are involved in chromatin structural changes upon growth factor stimulation. Using this method, we show here that nuclear c-Abl induces chromatin structural changes in a manner dependent on the tyrosine kinase activity. Expression of nuclear-targeted c-Abl drastically increases the levels of chromatin structural changes, compared with that of c-Abl. Intriguingly, nuclear-targeted c-Abl induces heterochromatic profiles of histone methylation and acetylation, including hypoacetylation of histone H4 acetylated on lysine 16 (H4K16Ac). The level of heterochromatic histone modifications correlates with that of chromatin structural changes. Adriamycin-induced DNA damage stimulates translocation of c-Abl into the nucleus and induces chromatin structural changes together with H4K16 hypoacetylation. Treatment with trichostatin A, a histone deacetylase inhibitor, blocks chromatin structural changes but not nuclear tyrosine phosphorylation by c-Abl. These results suggest that nuclear c-Abl plays an important role in chromatin dynamics through nuclear tyrosine phosphorylation-induced heterochromatic histone modifications.

  20. Trichostatin A rescues the disrupted imprinting induced by somatic cell nuclear transfer in pigs.

    Directory of Open Access Journals (Sweden)

    Yanjun Huan

    Full Text Available Imprinting disorders induced by somatic cell nuclear transfer (SCNT usually lead to the abnormalities of cloned animals and low cloning efficiency. Histone deacetylase inhibitors have been shown to improve gene expression, genomic methylation reprogramming and the development of cloned embryos, however, the imprinting statuses in these treated embryos and during their subsequent development remain poorly studied. In this study, we investigated the dynamics of H19/Igf2 methylation and transcription in porcine cloned embryos treated with trichostatin A (TSA, and examined H19/Igf2 imprinting patterns in cloned fetuses and piglets. Our results showed that compared with the maintenance of H19/Igf2 methylation in fertilized embryos, cloned embryos displayed aberrant H19/Igf2 methylation and lower H19/Igf2 transcripts. When TSA enhanced the development of cloned embryos, the disrupted H19/Igf2 imprinting was largely rescued in these treated embryos, more similar to those detected in fertilized counterparts. Further studies displayed that TSA effectively rescued the disrupted imprinting of H19/Igf2 in cloned fetuses and piglets, prevented the occurrence of cloned fetus and piglet abnormalities, and enhanced the full-term development of cloned embryos. In conclusion, our results demonstrated that aberrant imprinting induced by SCNT led to the abnormalities of cloned fetuses and piglets and low cloning efficiency, and TSA rescued the disrupted imprinting in cloned embryos, fetuses and piglets, and prevented the occurrence of cloned fetus and piglet abnormalities, thereby improving the development of cloned embryos. This study would have important implications in improving cloning efficiency and the health of cloned animals.

  1. Obesity-induced endoplasmic reticulum stress suppresses nuclear factor-Y expression.

    Science.gov (United States)

    Liu, Yulan; Zhang, Yuwei; Zhang, Yanjie; Zhang, Jinlong; Liu, Yin; Feng, Peiqun; Su, Zhiguang

    2017-02-01

    Nuclear transcription factor Y (NF-Y) is an evolutionarily conserved transcription factor composed of three subunits, NF-YA, NF-YB, and NF-YC. NF-Y plays crucial roles in pre-adipocyte maintenance and/or commitment to adipogenesis. NF-YA dysfunction in adipocyte resulted in an age-dependent progressive loss of adipose tissue associated with metabolic complications. Endoplasmic reticulum (ER) stress has emerged as an important mediator in the pathogenesis of obesity. However, it is not known if NF-YA is involved in the ER stress-mediated pathogenesis of obesity. We first examined the effects of ER stress on the NF-YA expression in cultured 3T3-L1 adipocytes; then in ob/ob genetic obesity mice, we tested the effect of chemical chaperones alleviating ER stress on the expression levels of NF-YA. Subsequently, we inhibited the new mRNA synthesis using actinomycin D in 3T3-L1 cells to explore the mechanism modulating NF-YA expression. Finally, we evaluated the involvement of PPARg in the regulation of NF-YA expression by ER stress. We demonstrated that both obesity- and chemical chaperone -induced ER stress suppressed NF-YA expression and alleviation of ER stress by chemical chaperone could recover NF-YA expression in ob/ob mice. Moreover, we showed that ER stress suppressed NF-YA mRNA transcription through the involvement of peroxisome proliferator-activated receptor gamma (PPARg). Activation of PPARg ameliorates the ER stress-induced NF-YA suppression. Our findings may point to a possible role of NF-YA in stress conditions that occur in chronic obesity, ER stress might be involved in the pathogenesis of obesity through NF-YA depletion.

  2. Differentiation inducing factor-1 (DIF-1) induces gene and protein expression of the Dictyostelium nuclear calmodulin-binding protein nucleomorphin.

    Science.gov (United States)

    O'Day, Danton H; Poloz, Yekaterina; Myre, Michael A

    2009-02-01

    The nucleomorphin gene numA1 from Dictyostelium codes for a multi-domain, calmodulin binding protein that regulates nuclear number. To gain insight into the regulation of numA, we assessed the effects of the stalk cell differentiation inducing factor-1 (DIF-1), an extracellular signalling molecule, on the expression of numA1 RNA and protein. For comparison, the extracellular signalling molecules cAMP (mediates chemotaxis, prestalk and prespore differentiation) and ammonia (NH(3)/NH(4)(+); antagonizes DIF) were also studied. Starvation, which is a signal for multicellular development, results in a greater than 80% decrease in numA1 mRNA expression within 4 h. Treatment with ammonium chloride led to a greater than 90% inhibition of numA1 RNA expression within 2 h. In contrast, the addition of DIF-1 completely blocked the decrease in numA1 gene expression caused by starvation. Treatment of vegetative cells with cAMP led to decreases in numA1 RNA expression that were equivalent to those seen with starvation. Western blotting after various morphogen treatments showed that the maintenance of vegetative levels of numA1 RNA by DIF-1 in starved cells was reflected in significantly increased numA1 protein levels. Treatment with cAMP and/or ammonia led to decreased protein expression and each of these morphogens suppressed the stimulatory effects of DIF-1. Protein expression levels of CBP4a, a calcium-dependent binding partner of numA1, were regulated in the same manner as numA1 suggesting this potential co-regulation may be related to their functional relationship. NumA1 is the first calmodulin binding protein shown to be regulated by developmental morphogens in Dictyostelium being upregulated by DIF-1 and down-regulated by cAMP and ammonia.

  3. "Erythropoietin Utilization Evaluation And Two Brand Products Comparison, Eprex and Eposim "

    Directory of Open Access Journals (Sweden)

    H. Khalili

    2006-06-01

    Full Text Available Background and Aim: Anemia is one of the common problems in patients with chronic renal impairment. The most common cause of anemia in this patients is a decreased in erythropoietin hormone excretion, however other common cause include low life of red blood cells, loss of blood during dialysis, frequent blood sampling, uremia, iron, vitamin B12 and folic acid deficiency. Until introduction of erythropoietin in 1982, blood transfusion was an alternative for correction and maintaining hematocrit in normal range in dialyze patients. In current date, any dialyzed patient take rh-erythropoietin . Materials and Methods: The goal of this study is to evaluate erythropoietin utilization and comparing the effectiveness of the commercial product in the Iranian drugs market. The study was performed at nephrology and dialyze ward of Immam Khomeini hospital in a one year period. Results and Conclusion: Of the 30 patients' subject of study, 13 patients received eprex and 17 received epocim. Average dose of erythropoietin 2000IU was three times per week. The average plasma hemoglobin and hematocrit of patients prior to the treatment were 9.38 g/dl and 28% respectively. Increase in the hemoglobin and hematocrit in the group who received eprex was significantly higher than epocim group (p=0.001 and p=0.026 respectively. The incidents of side effects including hypertension, headache, pain at injection site, and influenza-like in eposim group were considerably higher than eprex.

  4. Activation cross sections on cadmium: Deuteron induced nuclear reactions up to 40 MeV

    Science.gov (United States)

    Tárkányi, F.; Király, B.; Ditrói, F.; Takács, S.; Csikai, J.; Hermanne, A.; Uddin, M. S.; Hagiwara, M.; Baba, M.; Ido, T.; Shubin, Yu. N.; Kovalev, S. F.

    2007-06-01

    Cross sections of deuteron induced nuclear reactions were measured up to 40 MeV using the standard stacked-foil irradiation method and high-resolution gamma-ray spectroscopy. Experimental cross sections and derived integral yields are reported for the reactions natCd(d,x)107g,108g,108m,109g,110g,110m,111g,112m,113m,114m,115m,116m1In, natCd(d,x)111m,115g,115m,117g,117mCd and natCd(d,x)105g,106m,110m,111gAg. No experimental data measured on natural cadmium have been found in the literature for the isotopes 107g,108g,108m,112m,115mIn, 111m,115m,117g,117mCd and 105g,106m,110m,111gAg. The experimental data are analyzed with and compared to the results of the theoretical model code ALICE-IPPE. Applications of the cross sections for data validation, medical radioisotope production, thin-layer activation and dose calculation are discussed.

  5. Monoenergetic proton emission from nuclear reaction induced by high intensity laser-generated plasmaa)

    Science.gov (United States)

    Torrisi, L.; Cavallaro, S.; Cutroneo, M.; Giuffrida, L.; Krasa, J.; Margarone, D.; Velyhan, A.; Kravarik, J.; Ullschmied, J.; Wolowski, J.; Szydlowski, A.; Rosinski, M.

    2012-02-01

    A 1016 W/cm2 Asterix laser pulse intensity, 1315 nm at the fundamental frequency, 300 ps pulse duration, was employed at PALS laboratory of Prague, to irradiate thick and thin primary CD2 targets placed inside a high vacuum chamber. The laser irradiation produces non-equilibrium plasma with deutons and carbon ions emission with energy of up to about 4 MeV per charge state, as measured by time-of-flight (TOF) techniques by using ion collectors and silicon carbide detectors. Accelerated deutons may induce high D-D cross section for fusion processes generating 3 MeV protons and 2.5 MeV neutrons, as measured by TOF analyses. In order to increase the mono-energetic proton yield, secondary CD2 targets can be employed to be irradiated by the plasma-accelerated deutons. Experiments demonstrated that high intensity laser pulses can be employed to promote nuclear reactions from which characteristic ion streams may be developed. Results open new scenario for applications of laser-generated plasma to the fields of ion sources and ion accelerators.

  6. Monoenergetic proton emission from nuclear reaction induced by high intensity laser-generated plasma.

    Science.gov (United States)

    Torrisi, L; Cavallaro, S; Cutroneo, M; Giuffrida, L; Krasa, J; Margarone, D; Velyhan, A; Kravarik, J; Ullschmied, J; Wolowski, J; Szydlowski, A; Rosinski, M

    2012-02-01

    A 10(16) W∕cm(2) Asterix laser pulse intensity, 1315 nm at the fundamental frequency, 300 ps pulse duration, was employed at PALS laboratory of Prague, to irradiate thick and thin primary CD(2) targets placed inside a high vacuum chamber. The laser irradiation produces non-equilibrium plasma with deutons and carbon ions emission with energy of up to about 4 MeV per charge state, as measured by time-of-flight (TOF) techniques by using ion collectors and silicon carbide detectors. Accelerated deutons may induce high D-D cross section for fusion processes generating 3 MeV protons and 2.5 MeV neutrons, as measured by TOF analyses. In order to increase the mono-energetic proton yield, secondary CD(2) targets can be employed to be irradiated by the plasma-accelerated deutons. Experiments demonstrated that high intensity laser pulses can be employed to promote nuclear reactions from which characteristic ion streams may be developed. Results open new scenario for applications of laser-generated plasma to the fields of ion sources and ion accelerators.

  7. Monoenergetic proton emission from nuclear reaction induced by high intensity laser-generated plasma

    Energy Technology Data Exchange (ETDEWEB)

    Torrisi, L. [INFN-LNS Via S. Sofia 44, 95123 Catania (Italy); Dip.to di Fisica, Universita di Messina, V.le F.S. D' Alcontres 31, 98166 S. Agata, Messina (Italy); Cavallaro, S.; Giuffrida, L. [INFN-LNS Via S. Sofia 44, 95123 Catania (Italy); Cutroneo, M. [Dip.to di Fisica, Universita di Messina, V.le F.S. D' Alcontres 31, 98166 S. Agata, Messina (Italy); Krasa, J.; Margarone, D.; Velyhan, A.; Ullschmied, J. [Institute of Physics, ASCR, v.v.i., 182 21 Prague 8 (Czech Republic); Kravarik, J. [Czech Technical University, Faculty of Electro-Engineering, Prague (Czech Republic); Wolowski, J.; Szydlowski, A.; Rosinski, M. [Institute of Plasma Physics and Laser Microfusion, IPPLM, 23 Hery Str., 01-497 Warsaw (Poland)

    2012-02-15

    A 10{sup 16} W/cm{sup 2} Asterix laser pulse intensity, 1315 nm at the fundamental frequency, 300 ps pulse duration, was employed at PALS laboratory of Prague, to irradiate thick and thin primary CD{sub 2} targets placed inside a high vacuum chamber. The laser irradiation produces non-equilibrium plasma with deutons and carbon ions emission with energy of up to about 4 MeV per charge state, as measured by time-of-flight (TOF) techniques by using ion collectors and silicon carbide detectors. Accelerated deutons may induce high D-D cross section for fusion processes generating 3 MeV protons and 2.5 MeV neutrons, as measured by TOF analyses. In order to increase the mono-energetic proton yield, secondary CD{sub 2} targets can be employed to be irradiated by the plasma-accelerated deutons. Experiments demonstrated that high intensity laser pulses can be employed to promote nuclear reactions from which characteristic ion streams may be developed. Results open new scenario for applications of laser-generated plasma to the fields of ion sources and ion accelerators.

  8. Deuterium–deuterium nuclear reaction induced by high intensity laser pulses

    Energy Technology Data Exchange (ETDEWEB)

    Torrisi, L., E-mail: lorenzo.torrisi@unime.it [INFN-LNS, Via S. Sofia 44, 95123 Catania (Italy); Dip.to di Fisica, Università di Messina, V.le F.S. D’Alcontres 31, 98166 S. Agata, Messina (Italy); Cavallaro, S.; Cutroneo, M.; Giuffrida, L. [INFN-LNS, Via S. Sofia 44, 95123 Catania (Italy); Dip.to di Fisica, Università di Messina, V.le F.S. D’Alcontres 31, 98166 S. Agata, Messina (Italy); Krasa, J.; Margarone, D.; Velyhan, A. [Institute of Physics, ASCR, v.v.i., 182 21 Prague 8 (Czech Republic); Kravarik, J. [Institute of Physics, ASCR, v.v.i., 182 21 Prague 8 (Czech Republic); Czech Technical University, Faculty of Electro-Engineering, Prague (Czech Republic); Ullschmied, J. [Institute of Physics, ASCR, v.v.i., 182 21 Prague 8 (Czech Republic); Wolowski, J.; Szydlowski, A.; Rosinski, M. [Institute of Plasma Physics and Laser Microfusion, IPPLM, 23 Hery Str., 01-497 Warsaw (Poland)

    2013-05-01

    A 10{sup 16} W/cm{sup 2} Asterix laser pulse intensity, 1315 nm wavelength, 300 ps pulse duration, was employed at PALS laboratory of Prague, to irradiate thick and thin primary CD{sub 2} targets placed into the high vacuum chamber. The laser irradiation produces non-equilibrium plasma with deuterons and carbon ions emission with energy up to about 4 MeV per charge state, as measured by time-of-flight (TOF) techniques by using ion collectors and silicon carbide detectors. Accelerated deuterium ions may induce high D–D cross section for fusion processes generating 3 MeV protons and 2.5 MeV neutrons, as measured by TOF analyses. In order to increase the mono-energetic proton yield, secondary CD{sub 2} targets can be availed to be irradiated by the plasma-accelerated deuterons. Experiments demonstrated that high intensity laser pulses can be employed to promote nuclear reactions from which characteristic ion streams may be developed. Results open new scenario for applications of laser-generated plasma to the fields of ion sources and ion accelerators.

  9. Deuterium-deuterium nuclear reaction induced by high intensity laser pulses

    Science.gov (United States)

    Torrisi, L.; Cavallaro, S.; Cutroneo, M.; Giuffrida, L.; Krasa, J.; Margarone, D.; Velyhan, A.; Kravarik, J.; Ullschmied, J.; Wolowski, J.; Szydlowski, A.; Rosinski, M.

    2013-05-01

    A 1016 W/cm2 Asterix laser pulse intensity, 1315 nm wavelength, 300 ps pulse duration, was employed at PALS laboratory of Prague, to irradiate thick and thin primary CD2 targets placed into the high vacuum chamber. The laser irradiation produces non-equilibrium plasma with deuterons and carbon ions emission with energy up to about 4 MeV per charge state, as measured by time-of-flight (TOF) techniques by using ion collectors and silicon carbide detectors. Accelerated deuterium ions may induce high D-D cross section for fusion processes generating 3 MeV protons and 2.5 MeV neutrons, as measured by TOF analyses. In order to increase the mono-energetic proton yield, secondary CD2 targets can be availed to be irradiated by the plasma-accelerated deuterons. Experiments demonstrated that high intensity laser pulses can be employed to promote nuclear reactions from which characteristic ion streams may be developed. Results open new scenario for applications of laser-generated plasma to the fields of ion sources and ion accelerators.

  10. Nuclear calcium controls the apoptotic-like cell death induced by d-erythro-sphinganine in tobacco cells.

    Science.gov (United States)

    Lachaud, Christophe; Da Silva, Daniel; Cotelle, Valérie; Thuleau, Patrice; Xiong, Tou Cheu; Jauneau, Alain; Brière, Christian; Graziana, Annick; Bellec, Yannick; Faure, Jean-Denis; Ranjeva, Raoul; Mazars, Christian

    2010-01-01

    Studies performed in animals have highlighted the major role of sphingolipids in regulating the balance between cell proliferation and cell death. Sphingolipids have also been shown to induce cell death in plants via calcium-based signalling pathways but the contribution of free cytosolic and/or nuclear calcium in the overall process has never been evaluated. Here, we show that increase in tobacco BY-2 cells of the endogenous content of Long Chain Bases (LCBs) caused by external application of d-erythro-sphinganine (DHS) is followed by immediate dose-dependent elevations of cellular free calcium concentration within the first minute in the cytosol and 10min later in the nucleus. Cells challenged with DHS enter a death process through apoptotic-like mechanisms. Lanthanum chloride, a general blocker of calcium entry, suppresses the cellular calcium variations and the PCD induced by DHS. Interestingly, dl-2-amino-5-phosphopentanoic acid (AP5) and [(+)-dizocilpine] (MK801), two inhibitors of animal and plant ionotropic glutamate receptors, suppress DHS-induced cell death symptoms by selectively inhibiting the variations of nuclear calcium concentration. The selective action of these compounds demonstrates the crucial role of nuclear calcium signature in controlling DHS-induced cell death in tobacco cells. 2009 Elsevier Ltd. All rights reserved.

  11. Erythropoietin and interleukin-2 activate distinct JAK kinase family members.

    Science.gov (United States)

    Barber, D L; D'Andrea, A D

    1994-01-01

    The erythropoietin (EPO) receptor and the interleukin-2 (IL-2) receptor beta-chain subunit are members of the cytokine receptor superfamily. They have conserved primary amino acid sequences in their cytoplasmic domains and activate phosphorylation of common substrates, suggesting common biochemical signaling mechanisms. We have generated a cell line, CTLL-EPO-R, that contains functional cell surface receptors for both EPO and IL-2. CTLL-EPO-R cells demonstrated similar growth kinetics in EPO and IL-2. Stimulation with EPO resulted in the rapid, dose-dependent tyrosine phosphorylation of JAK2. In contrast, stimulation with IL-2 or the related cytokine IL-4 resulted in the rapid, dose-dependent tyrosine phosphorylation of JAK1 and an additional 116-kDa protein. This 116-kDa protein was itself immunoreactive with a polyclonal antiserum raised against JAK2 and appears to be a novel member of the JAK kinase family. Immune complex kinase assays confirmed that IL-2 and IL-4 activated JAK1 and EPO activated JAK2. These results demonstrate that multiple biochemical pathways are capable of conferring a mitogenic signal in CTLL-EPO-R cells and that the EPO and IL-2 receptors interact with distinct JAK kinase family members within the same cellular background. Images PMID:7935373

  12. 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.

  13. 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.

  14. Effects of erythropoietin on angiogenesis after myocardial infarction in porcine.

    Science.gov (United States)

    Kawachi, Keisuke; Iso, Yoshitaka; Sato, Takatoshi; Wakabayashi, Kohei; Kobayashi, Youichi; Takeyama, Youichi; Suzuki, Hiroshi

    2012-01-01

    Erythropoietin (EPO) has recently been shown to confer cardioprotective effects via angiogenesis and antiapoptosis. The administration of EPO after myocardial infarction (MI) reduces infarct size and improves cardiac function in small animals. The purpose of this study is to investigate the protective effects of EPO in porcine MI. Each animal in the EPO group received four injections of recombinant human EPO (rhEPO; 6000 U per injection) at 2-day intervals, starting after coronary occlusion. Animals in the control group received saline. Left ventriculography was performed just after coronary occlusion and at 28 days. Time-course changes in serum levels of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and fibroblast growth factor (FGF) were measured. The number of vessels was calculated, and the mRNA expressions of VEGF and insulin-like growth factor (IGF) were examined. Left ventricular function was similar between the groups. The numbers of cells positive for anti-α-smooth muscle actin, von Willebrand factor, and c-kit were significantly higher in the EPO group than in the controls (P porcine MI.

  15. Implementation of a new energy-angular distribution of particles emitted by deuteron induced nuclear reaction in transport simulations

    Science.gov (United States)

    Sauvan, Patrick; Koning, Arjan; Ogando, Francisco; Sanz, Javier

    2017-09-01

    MCUNED code is an MCNPX extension able to handle evaluated nuclear data library for light ion transport simulations. In this work the MCUNED code is improved to describe more accurately the neutron emission during deuteron induced nuclear reaction. This code update consists in introducing a new methodology to take into account the angular distribution of neutron produced by deuteron breakup reaction. To carry out this work a new formulation for the angular distribution of neutrons produced by breakup reaction has been proposed. The implementation of this new methodology requires the use of extra parameters which are provided by the nuclear code TALYS and stored in the ENDF file. This new methodology shows significant improvement in comparison with the former treatment of neutron emission kinematics, these results are in good agreement with experimental data.

  16. Coal dust alters β-naphthoflavone-induced aryl hydrocarbon receptor nuclear translocation in alveolar type II cells

    Directory of Open Access Journals (Sweden)

    Castranova Vincent

    2009-08-01

    Full Text Available Abstract Background Many polycyclic aromatic hydrocarbons (PAHs can cause DNA adducts and initiate carcinogenesis. Mixed exposures to coal dust (CD and PAHs are common in occupational settings. In the CD and PAH-exposed lung, CD increases apoptosis and causes alveolar type II (AT-II cell hyperplasia but reduces CYP1A1 induction. Inflammation, but not apoptosis, appears etiologically associated with reduced CYP1A1 induction in this mixed exposure model. Many AT-II cells in the CD-exposed lungs have no detectable CYP1A1 induction after PAH exposure. Although AT-II cells are a small subfraction of lung cells, they are believed to be a potential progenitor cell for some lung cancers. Because CYP1A1 is induced via ligand-mediated nuclear translocation of the aryl hydrocarbon receptor (AhR, we investigated the effect of CD on PAH-induced nuclear translocation of AhR in AT-II cells isolated from in vivo-exposed rats. Rats received CD or vehicle (saline by intratracheal (IT instillation. Three days before sacrifice, half of the rats in each group started daily intraperitoneal injections of the PAH, β-naphthoflavone (BNF. Results Fourteen days after IT CD exposure and 1 day after the last intraperitoneal BNF injection, AhR immunofluorescence indicated that proportional AhR nuclear expression and the percentage of cells with nuclear AhR were significantly increased in rats receiving IT saline and BNF injections compared to vehicle controls. However, in CD-exposed rats, BNF did not significantly alter the nuclear localization or cytosolic expression of AhR compared to rats receiving CD and oil. Conclusion Our findings suggest that during particle and PAH mixed exposures, CD alters the BNF-induced nuclear translocation of AhR in AT-II cells. This provides an explanation for the modification of CYP1A1 induction in these cells. Thus, this study suggests that mechanisms for reduced PAH-induced CYP1A1 activity in the CD exposed lung include not only the

  17. Erythropoietin improves functional and histological recovery of traumatized skeletal muscle tissue.

    Science.gov (United States)

    Rotter, Robert; Menshykova, Marija; Winkler, Tobias; Matziolis, Georg; Stratos, Ioannis; Schoen, Matthias; Bittorf, Thomas; Mittlmeier, Thomas; Vollmar, Brigitte

    2008-12-01

    Apart from its hematopoietic effect, erythropoietin (EPO) is known as pleiotropic cytokine with anti-inflammatory and anti-apoptotic properties. Here, we evaluated for the first time the EPO-dependent regeneration capacity in an in vivo rat model of skeletal muscle trauma. A myoblast cell line was used to study the effect of EPO on serum deprivation-induced cell apoptosis in vitro. A crush injury was performed to the left soleus muscle in 80 rats treated with either EPO or saline. Muscle recovery was assessed by analysis of contraction capacities. Intravital microscopy, BrdU/laminin double immunohistochemistry and cleaved caspase-3 immunohistochemistry of muscle tissue on days 1, 7, 14, and 42 posttrauma served for assessment of local microcirculation, tissue integrity, and cell proliferation. Serum deprivation-induced myoblast apoptosis of 23.9 +/- 1.5% was reduced by EPO to 17.2 +/- 0.8%. Contraction force analysis in the EPO-treated animals revealed significantly improved muscle strength with 10-20% higher values of twitch and tetanic forces over the 42-day observation period. EPO-treated muscle tissue displayed improved functional capillary density as well as reduced leukocytic response and consecutively macromolecular leakage over day 14. Concomitantly, muscle histology showed significantly increased numbers of BrdU-positive satellite cells and interstitial cells as well as slightly lower counts of cleaved caspase-3-positive interstitial cells. EPO results in faster and better regeneration of skeletal muscle tissue after severe trauma and goes along with improved microcirculation. Thus, EPO, a compound established as clinically safe, may represent a promising therapeutic option to optimize the posttraumatic course of muscle tissue healing.

  18. Erythropoietin Attenuates Postoperative Cognitive Dysfunction by Shifting Macrophage Activation toward the M2 Phenotype

    Directory of Open Access Journals (Sweden)

    Jae Hoon Lee

    2017-11-01

    Full Text Available Postoperative cognitive dysfunction (POCD may be driven by transference of the innate immune response to the brain after aseptic surgical damage. Macrophages are key mediators of innate immunity that can display a pro-inflammatory M1 phenotype or an anti-inflammatory M2 phenotype. Erythropoietin (EPO is a hematopoietic hormone that exerts anti-inflammatory effects by influencing macrophage function. We hypothesized that EPO would prevent POCD by promoting macrophage phenotype switching to the M2 phenotype post-surgery. To evaluate the effects of EPO on POCD and macrophage polarization post-surgery, we administered EPO (5,000 U/kg with or without an arginase inhibitor (amino-6-boronohexanoic acid, 10 mg/kg to ICR mice before and after abdominal surgery. Forty-eight hours post-surgery, we assessed memory, synapse function, and macrophage/microglial phenotypes in the spleen and hippocampus. We also investigated M1/M2 phenotypes in RAW264.7 and BV2 cells stimulated with lipopolysaccharide and interferon-γ (M1 inducers in the presence or absence of EPO. EPO prevented POCD, decreased surgery-related synaptic dysfunction, and attenuated pro-inflammatory cytokine generation in the hippocampus. Moreover, EPO suppressed M1-related genes expression and promoted M2 genes expression in the spleen and hippocampus post-surgery. Furthermore, EPO decreased the proportions of macrophages/microglia expressing an M1 surface marker (CD40 and increased those expressing an M2 surface marker (CD206. Arginase inhibition abolished the beneficial effects of EPO on POCD. In vitro, EPO treatment promoted switching of RAW264.7 and BV2 cells stimulated with M1 inducers to an M2 phenotype. In conclusion, EPO prevents POCD by promoting macrophage phenotype switching toward the M2 phenotype.

  19. Absence of hematological side effects in acute and subacute nasal dosing of erythropoietin with a low content of sialic acid.

    Science.gov (United States)

    Lagarto, Alicia; Bueno, Viviana; Guerra, Isbel; Valdés, Odalys; Couret, Micaela; López, Raisel; Vega, Yamile

    2011-09-01

    The use of human recombinant erythropoietin (EPO) as a neuroprotective agent is limited due to its hematological side effects. An erythropoietin along with a low content of sialic acid (rhEPOb), similar to that produced in the brain during hypoxia, may be used as a neuroprotective agent without risk of thrombotic events. The objective of this investigation was to assess the toxicological potential of a nasal formulation with rhEPOb in acute, subacute and nasal irritation assays in rats. Healthy Wistar rats (Cenp:Wistar) were used for the assays. In an irritation test, animals received 15 μl of rhEPOb into the right nostril. Rats were sacrificed after 24 h and slides of the nasal mucosa tissues were examined. Control and treated groups showed signs of a minimal irritation consisting of week edema and vascular congestion in all animals. In the acute toxicity test, the dose of 47,143 UI/kg was administered by nasal route. Hematological patterns, body weight, relative organ weight, and organ integrity were not affected by single dosing with rhEPOb. In the subacute toxicity test, Wistar rats of both sexes received 6,600 UI/kg/day for 14 days. The toxicological endpoints examined included animal body weight, food consumption, hematological and biochemical patterns, selected tissue weights, and histopathological examinations. An increase of lymphocytes was observed in males that was considered to reflect an immune response to treatment. Histopathological examination of organs and tissues did not reveal treatment-induced changes. The administration of rhEPOb at daily doses of 6,600 UI/kg during 14 days did not produce hematological side effects. These results suggest that rhEPOb could offer the same neuroprotection as EPO, without hematological side effects. Copyright © 2010 Elsevier GmbH. All rights reserved.

  20. Steatosis-induced proteins adducts with lipid peroxidation products and nuclear electrophilic stress in hepatocytes.

    Science.gov (United States)

    Anavi, Sarit; Ni, Zhixu; Tirosh, Oren; Fedorova, Maria

    2015-01-01

    Accumulating evidence suggests that fatty livers are particularly more susceptible to several pathological conditions, including hepatic inflammation, cirrhosis and liver cancer. However the exact mechanism of such susceptibility is still largely obscure. The current study aimed to elucidate the effect of hepatocytes lipid accumulation on the nuclear electrophilic stress. Accumulation of intracellular lipids was significantly increased in HepG2 cells incubated with fatty acid (FA) complex (1mM, 2:1 oleic and palmitic acids). In FA-treated cells, lipid droplets were localized around the nucleus and seemed to induce mechanical force, leading to the disruption of the nucleus morphology. Level of reactive oxygen species (ROS) was significantly increased in FA-loaded cells and was further augmented by treatment with moderate stressor (CoCl2). Increased ROS resulted in formation of reactive carbonyls (aldehydes and ketones, derived from lipid peroxidation) with a strong perinuclear accumulation. Mass-spectroscopy analysis indicated that lipid accumulation per-se can results in modification of nuclear protein by reactive lipid peroxidation products (oxoLPP). 235 Modified proteins involved in transcription regulation, splicing, protein synthesis and degradation, DNA repair and lipid metabolism were identified uniquely in FA-treated cells. These findings suggest that steatosis can affect nuclear redox state, and induce modifications of nuclear proteins by reactive oxoLPP accumulated in the perinuclear space upon FA-treatment. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

  1. Steatosis-induced proteins adducts with lipid peroxidation products and nuclear electrophilic stress in hepatocytes

    Directory of Open Access Journals (Sweden)

    Sarit Anavi

    2015-04-01

    Full Text Available Accumulating evidence suggests that fatty livers are particularly more susceptible to several pathological conditions, including hepatic inflammation, cirrhosis and liver cancer. However the exact mechanism of such susceptibility is still largely obscure. The current study aimed to elucidate the effect of hepatocytes lipid accumulation on the nuclear electrophilic stress. Accumulation of intracellular lipids was significantly increased in HepG2 cells incubated with fatty acid (FA complex (1 mM, 2:1 oleic and palmitic acids. In FA-treated cells, lipid droplets were localized around the nucleus and seemed to induce mechanical force, leading to the disruption of the nucleus morphology. Level of reactive oxygen species (ROS was significantly increased in FA-loaded cells and was further augmented by treatment with moderate stressor (CoCl2. Increased ROS resulted in formation of reactive carbonyls (aldehydes and ketones, derived from lipid peroxidation with a strong perinuclear accumulation. Mass-spectroscopy analysis indicated that lipid accumulation per-se can results in modification of nuclear protein by reactive lipid peroxidation products (oxoLPP. 235 Modified proteins involved in transcription regulation, splicing, protein synthesis and degradation, DNA repair and lipid metabolism were identified uniquely in FA-treated cells. These findings suggest that steatosis can affect nuclear redox state, and induce modifications of nuclear proteins by reactive oxoLPP accumulated in the perinuclear space upon FA-treatment.

  2. 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.

  3. Erythropoietin production by a hepatic adenoma in a patient with severe erythrocytosis.

    Science.gov (United States)

    Vik, Anders; Cui, Guanglin; Isaksen, Vidar; Wik, Trude; Hansen, John-Bjarne

    2009-01-01

    A 53-year-old woman with severe erythrocytosis (hemoglobin concentration 19.5 g/dl and hematocrit 0.59) was admitted to our hospital because of fatigue and headache. The serum erythropoietin (Epo) concentration was 68.6 U/l (reference range; 3.7-31.5). Further investigations excluded polycythemia vera or any lung or heart disease. Radiological examination showed a tumor in the left hepatic lobe. Needle biopsies were performed and the histopathological diagnosis was hepatocellular adenoma. Immunohistochemistry demonstrated erythropoietin expression in the adenomatous cells. Liver adenoma is a rare cause of erythrocytosis. For the first time, we report erythropoietin-positive immunoreactivity in liver adenomatous cells in a patient with erythrocytosis. (c) 2009 S. Karger AG, Basel.

  4. Nuclear shape changes are induced by knockdown of the SWI/SNF ATPase BRG1 and are independent of cytoskeletal connections.

    Directory of Open Access Journals (Sweden)

    Karen M Imbalzano

    Full Text Available Changes in nuclear morphology occur during normal development and have been observed during the progression of several diseases. The shape of a nucleus is governed by the balance of forces exerted by nuclear-cytoskeletal contacts and internal forces created by the structure of the chromatin and nuclear envelope. However, factors that regulate the balance of these forces and determine nuclear shape are poorly understood. The SWI/SNF chromatin remodeling enzyme ATPase, BRG1, has been shown to contribute to the regulation of overall cell size and shape. Here we document that immortalized mammary epithelial cells show BRG1-dependent nuclear shape changes. Specifically, knockdown of BRG1 induced grooves in the nuclear periphery that could be documented by cytological and ultrastructural methods. To test the hypothesis that the observed changes in nuclear morphology resulted from altered tension exerted by the cytoskeleton, we disrupted the major cytoskeletal networks and quantified the frequency of BRG1-dependent changes in nuclear morphology. The results demonstrated that disruption of cytoskeletal networks did not change the frequency of BRG1-induced nuclear shape changes. These findings suggest that BRG1 mediates control of nuclear shape by internal nuclear mechanisms that likely control chromatin dynamics.

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

    Directory of Open Access Journals (Sweden)

    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.

  6. DIF-1 regulates Dictyostelium basal disc differentiation by inducing the nuclear accumulation of a bZIP transcription factor.

    Science.gov (United States)

    Yamada, Yoko; Nuñez-Corcuera, Beatriz; Williams, Jeffrey G

    2011-06-01

    Exposure of monolayer Dictyostelium cells to the signalling polyketide DIF-1 causes DimB, a bZIPtranscription factor, to accumulate in the nucleus where it induces prestalk gene expression. Here we analyse DimB signalling during normal development. In slugs DimB is specifically nuclear enriched in the pstB cells; a cluster of vital dye-staining cells located on the ventral surface of the posterior, prespore region. PstB cells move at culmination, to form the lower cup and the outer basal disc of the fruiting body, and DimB retains a high nuclear concentration in both these tissues. In a dimB null (dimB-) strain there are very few pstB or lower cup cells, as detected by neutral red staining, and it is known that the outer basal disc is absent or much reduced. In the dimB- strain ecmB, a marker of pstB differentiation, is not DIF inducible. Furthermore, ChIP analysis shows that DimB binds to the ecmB promoter in DIF-induced cells. These results suggest that the differentiation of pstB cells is caused by a high perceived level of DIF-1 signalling, leading to nuclear localization of DimB and direct activation of cell type-specific gene expression. Copyright © 2011 Elsevier Inc. All rights reserved.

  7. Productive and Penicillin-Stressed Chlamydia pecorum Infection Induces Nuclear Factor Kappa B Activation and Interleukin-6 Secretion In Vitro

    Directory of Open Access Journals (Sweden)

    Cory A. Leonard

    2017-05-01

    Full Text Available Nuclear factor kappa B (NFκB is an inflammatory transcription factor that plays an important role in the host immune response to infection. The potential for chlamydiae to activate NFκB has been an area of interest, however most work has focused on chlamydiae impacting human health. Given that inflammation characteristic of chlamydial infection may be associated with severe disease outcomes or contribute to poor overall fitness in farmed animals, we evaluated the ability of porcine chlamydiae to induce NFκB activation in vitro. C. pecorum infection induced both NFκB nuclear translocation and activation at 2 hours post infection (hpi, an effect strongly enhanced by suppression of host de novo protein synthesis. C. suis and C. trachomatis showed less capacity for NFκB activation compared to C. pecorum, suggesting a species-specific variation in NFκB activation. At 24 hpi, C. pecorum induced significant NFκB activation, an effect not abolished by penicillin (beta lactam-induced chlamydial stress. C. pecorum-dependent secretion of interleukin 6 was also detected in the culture supernatant of infected cells at 24 hpi, and this effect, too, was unchanged by penicillin-induced chlamydial stress. Taken together, these results suggest that NFκB participates in the early inflammatory response to C. pecorum and that stressed chlamydiae can promote inflammation.

  8. 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...

  9. Relativistic effects in the intermolecular interaction-induced nuclear magnetic resonance parameters of xenon dimer

    DEFF Research Database (Denmark)

    Hanni, Matti; Lantto, Perttu; Ilias, Miroslav

    2007-01-01

    Relativistic effects on the 129Xe nuclear magnetic resonance shielding and 131Xe nuclear quadrupole coupling (NQC) tensors are examined in the weakly bound Xe2 system at different levels of theory including the relativistic four-component Dirac-Hartree-Fock (DHF) method. The intermolecular intera...

  10. Excitation functions of proton induced nuclear reactions on natural copper using a medium-sized cyclotron

    Energy Technology Data Exchange (ETDEWEB)

    Al-Saleh, F.S.; Al-Harbi, A.A. [Physics Dept., Girls Coll. of Education in Riyadh, Scientific Dept., Riyadh (Saudi Arabia); Azzam, A. [Nuclear Physics Dept., Nuclear Recearch Center, A.E.A, Cairo (Egypt)

    2006-07-01

    Activation techniques have been used to measure the excitation functions of proton induced nuclear reactions on natural copper from their thresholds up to 27.5 MeV. The beam current was measured using a Faraday cup with secondary electron suppression, and the radioactivity of the products was determined via high-resolution gamma ray spectrometry. The data were compared with the data recommended by the IAEA wherever it was possible. A comparison of the new excitation functions with the theoretical calculations reported in the literature was undertaken to check the order of agreement between them. Good agreement was found for the results of {sup 63}Zn while the theoretical calculations overestimate the cross sections for {sup 61}Cu and {sup 62}Zn. The excitation function for the reaction {sup nat}Cu(p, x){sup 61}Co was measured for the first time during this work. The integral yields of the radionuclides {sup 62.63.65}Zn, {sup 61}Cu and {sup 61}Co were calculated. {sup 63}Zn and {sup 65}Zn are produced over the whole energy range of 3 to 27.5 MeV and the yield gets saturated above 20 MeV. {sup 62}Zn, {sup 61}Cu and {sup 61}Co are produced at relatively high energies and have integral yield values between those of {sup 63}Zn and {sup 65}Zn. The relatively high yield of {sup 62}Zn is useful for the production of {sup 62}Zn/{sup 62}Cu generator system. (orig.)

  11. Activation cross sections of $\\alpha$-particle induced nuclear reactions on hafnium and deuteron induced nuclear reaction on tantalum: production of $^{178}$W/$^{178m}$Ta generator

    CERN Document Server

    Tárk'anyi, F; Ditrói, F; Hermanne, A; Ignatyuk, A V; Uddin, M S

    2014-01-01

    In the frame of a systematic study of charged particle production routes of medically relevant radionuclei, the excitation function for indirect production of $^{178m}$Ta through $^{nat}$Hf($\\alpha$,xn)$^{178}$W-$^{178m}$Ta nuclear reaction was measured for the first time up to 40 MeV. In parallel, the side reactions $^{nat}$Hf($\\alpha$,x)$^{179,177,176,175}$W, $^{183,182,178g,177,176,175}$Ta, $^{179m,177m,175}$Hf were also assessed. Stacked foil irradiation technique and $\\gamma$-ray spectrometry were used. New experimental cross section data for the $^{nat}$Ta(d,xn)$^{178}$W reaction are also reported up to 40 MeV. The measured excitation functions are compared with the results of the ALICE-IPPE, and EMPIRE nuclear reaction model codes and with the TALYS 1.4 based data in the TENDL-2013 library. The thick target yields were deduced and compared with yields of other charged particle ((p,4n), (d,5n) and ($^3$He,x)) production routes for $^{178}$W.

  12. Erythropoietin for neuroprotection in neonatal encephalopathy: safety and pharmacokinetics.

    Science.gov (United States)

    Wu, Yvonne W; Bauer, Larry A; Ballard, Roberta A; Ferriero, Donna M; Glidden, David V; Mayock, Dennis E; Chang, Taeun; Durand, David J; Song, Dongli; Bonifacio, Sonia L; Gonzalez, Fernando F; Glass, Hannah C; Juul, Sandra E

    2012-10-01

    To determine the safety and pharmacokinetics of erythropoietin (Epo) given in conjunction with hypothermia for hypoxic-ischemic encephalopathy (HIE). We hypothesized that high dose Epo would produce plasma concentrations that are neuroprotective in animal studies (ie, maximum concentration = 6000-10000 U/L; area under the curve = 117000-140000 U*h/L). In this multicenter, open-label, dose-escalation, phase I study, we enrolled 24 newborns undergoing hypothermia for HIE. All patients had decreased consciousness and acidosis (pH score ≤ 5, or ongoing resuscitation at 10 minutes. Patients received 1 of 4 Epo doses intravenously: 250 (N = 3), 500 (N = 6), 1000 (N = 7), or 2500 U/kg per dose (N = 8). We gave up to 6 doses every 48 hours starting at <24 hours of age and performed pharmacokinetic and safety analyses. Patients received mean 4.8 ± 1.2 Epo doses. Although Epo followed nonlinear pharmacokinetics, excessive accumulation did not occur during multiple dosing. At 500, 1000, and 2500 U/kg Epo, half-life was 7.2, 15.0, and 18.7 hours; maximum concentration was 7046, 13780, and 33316 U/L, and total Epo exposure (area under the curve) was 50306, 131054, and 328002 U*h/L, respectively. Drug clearance at a given dose was slower than reported in uncooled preterm infants. No deaths or serious adverse effects were seen. Epo 1000 U/kg per dose intravenously given in conjunction with hypothermia is well tolerated and produces plasma concentrations that are neuroprotective in animals. A large efficacy trial is needed to determine whether Epo add-on therapy further improves outcome in infants undergoing hypothermia for HIE.

  13. Cooperative Effect of Erythropoietin and TGF-β Inhibition on Erythroid Development in Human Pluripotent Stem Cells.

    Science.gov (United States)

    Xie, Yinliang; Bai, Hao; Liu, Yanfeng; Hoyle, Dixie L; Cheng, Tao; Wang, Zack Z

    2015-12-01

    Patient-specific human induced-pluripotent stem cells (hiPSCs) represent important cell sources to treat patients with acquired blood disorders. To realize the therapeutic potential of hiPSCs, it is crucial to understand signals that direct hiPSC differentiation to a hematopoietic lineage fate. Our previous study demonstrated that CD34(+)CD31(+) cells derived from human pluripotent stem cells (hPSCs) contain hemato-endothelial progenitors (HEPs) that give rise to hematopoietic cells and endothelial cells. Here, we established a serum-free and feeder-free system to induce the differentiation of hPSC-derived CD34(+)CD31(+) progenitor cells to erythroid cells. We show that extracellular matrix (ECM) proteins promote the differentiation of CD34(+)CD31(+) progenitor cells into CD235a(+) erythroid cells through CD41(+)CD235a(+) megakaryocyte-erythroid progenitors (MEP). Erythropoietin (EPO) is a predominant factor for CD34(+)CD31(+) progenitor differentiation to erythroid cells, whereas transforming growth factor beta (TGF-β) inhibits the development of CD34(+)CD31(+) progenitor cells. Apoptosis of progenitor cells is induced by TGF-β in early erythroid differentiation. Suppression of TGF-β signaling by SB431542 at early stage of CD34(+)CD31(+) progenitor differentiation induces the erythroid cell generation. Together, these findings suggest that TGF-β suppression and EPO stimulation promote erythropoiesis of CD34(+)CD31(+) progenitor cells derived from hPSCs. © 2015 Wiley Periodicals, Inc.

  14. Investigation of activation cross-sections of deuteron induced nuclear reactions on natural Mo up to 50 MeV

    Energy Technology Data Exchange (ETDEWEB)

    Tarkanyi, F. [Institute of Nuclear Research of the Hungarian Academy of Sciences (ATOMKI), H-4026 Debrecen, Bem ter 18/c (Hungary); Ditroi, F., E-mail: ditroi@atomki.hu [Institute of Nuclear Research of the Hungarian Academy of Sciences (ATOMKI), H-4026 Debrecen, Bem ter 18/c (Hungary); Takacs, S.; Kiraly, B. [Institute of Nuclear Research of the Hungarian Academy of Sciences (ATOMKI), H-4026 Debrecen, Bem ter 18/c (Hungary); Hermanne, A. [Cyclotron Laboratory, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels (Belgium); Sonck, M. [Federal Agency for Nuclear Control, Ravenstein 36, 1000 Brussels (Belgium); Baba, M. [Cyclotron and Radioisotope Center (CYRIC), Tohoku University, Sendai 980-8578 (Japan); Ignatyuk, A.V. [Institute of Physics and Power Engineering (IPPE), Obninsk 249020 (Russian Federation)

    2012-03-01

    Highlights: Black-Right-Pointing-Pointer Excitation function measurement of deuteron induced reactions on molybdenum up to 50 MeV. Black-Right-Pointing-Pointer Model code calculations with EMPIRE-D, ALICE-D and TALYS. Black-Right-Pointing-Pointer Integral production yield calculation. Black-Right-Pointing-Pointer Medical radioisotope production; {sup 99m}Tc and {sup 99}Mo. - Abstract: Cross-sections of deuteron induced nuclear reactions on natural molybdenum have been studied in the frame of a systematic investigation of charged particle induced nuclear reactions on metals for different applications. The excitation functions of {sup 93,94g,94m,95g,95m,96,99m}Tc, {sup 90,93m,99}Mo, {sup 90,91m,92m,95m,95g,96}Nb and {sup 88,89}Zr were measured up to 50 MeV deuteron energy by using the stacked foil technique and activation method. The goal of this work was first of all to study the production possibility of the medically important {sup 99m}Tc, and its {sup 99}Mo parent, to get experimental data useful in accelerator technology, and for testing nuclear reaction theories. The thick target yields and production possibilities of {sup 99m}Tc and {sup 99}Mo were estimated up to 50 MeV deuteron energy, and it is shown that besides the proton induced reactions, deuteron induced reactions on enriched molybdenum target seem to be promising. For most of the reaction products published experimental data for excitation functions are available only up to 20 MeV, and our new values confirm and extend the dataset. The experimental data were compared with the results of model calculations obtained by using ALICE-IPPE-D, EMPIRE-II-D and two versions of the TALYS code resulting in moderate agreement.

  15. Nuclear Astrophysics

    CERN Document Server

    Langanke, K

    1999-01-01

    The manuscript reviews progress achieved in recent years in various aspects of nuclear astrophysics, including stellar nucleosynthesis, nuclear aspects of supernova collapse and explosion, neutrino-induced reactions and their possible role in the supernova mechanism and nucleosynthesis, explosive hydrogen burning in binary systems, and finally the observation of gamma-rays from supernova remnants.

  16. Cross sections of proton induced nuclear reactions on enriched 111Cd and 112Cd for the production of 111In for use in nuclear medicine.

    Science.gov (United States)

    Tárkányi, F; Szelecsényi, F; Kopecký, P; Molnár, T; Andó, L; Mikecz, P; Tóth, G Y; Rydl, A

    1994-02-01

    Proton induced nuclear reactions on enriched 111Cd and 112Cd have been studied up to 30 MeV in the context of routine production of the medically used isotope 111In with low and medium energy cyclotrons. The excitation functions of 111Cd(p,n)111m,gIn and 112Cd(p,2n)111m,gIn as production reactions and 111Cd(p,2n)110mIn, 111Cd(p,2n)110In, 111Cd(p,3n)109ml,m2,In, 112Cd(p,3n)110mIn, 112Cd(p,3n)110gIn as competing processes have been measured using the activation method involving the stacked-foil technique. The deduced thick target yields are compared with those obtained experimentally.

  17. Requirement of PML SUMO interacting motif for RNF4- or arsenic trioxide-induced degradation of nuclear PML isoforms.

    Directory of Open Access Journals (Sweden)

    Mohamed Ali Maroui

    Full Text Available PML, the organizer of nuclear bodies (NBs, is expressed in several isoforms designated PMLI to VII which differ in their C-terminal region due to alternative splicing of a single gene. This variability is important for the function of the different PML isoforms. PML NB formation requires the covalent linkage of SUMO to PML. Arsenic trioxide (As₂O₃ enhances PML SUMOylation leading to an increase in PML NB size and promotes its interaction with RNF4, a poly-SUMO-dependent ubiquitin E3 ligase responsible for proteasome-mediated PML degradation. Furthermore, the presence of a bona fide SUMO Interacting Motif (SIM within the C-terminal region of PML seems to be required for recruitment of other SUMOylated proteins within PML NBs. This motif is present in all PML isoforms, except in the nuclear PMLVI and in the cytoplasmic PMLVII. Using a bioluminescence resonance energy transfer (BRET assay in living cells, we found that As₂O₃ enhanced the SUMOylation and interaction with RNF4 of nuclear PML isoforms (I to VI. In addition, among the nuclear PML isoforms, only the one lacking the SIM sequence, PMLVI, was resistant to As₂O₃-induced PML degradation. Similarly, mutation of the SIM in PMLIII abrogated its sensitivity to As₂O₃-induced degradation. PMLVI and PMLIII-SIM mutant still interacted with RNF4. However, their resistance to the degradation process was due to their inability to be polyubiquitinated and to recruit efficiently the 20S core and the β regulatory subunit of the 11S complex of the proteasome in PML NBs. Such resistance of PMLVI to As₂O₃-induced degradation was alleviated by overexpression of RNF4. Our results demonstrate that the SIM of PML is dispensable for PML SUMOylation and interaction with RNF4 but is required for efficient PML ubiquitination, recruitment of proteasome components within NBs and proteasome-dependent degradation of PML in response to As₂O₃.

  18. Erythropoietin enhances nerve repair in anti-ganglioside antibody-mediated models of immune neuropathy.

    Directory of Open Access Journals (Sweden)

    Gang Zhang

    Full Text Available Guillain-Barré syndrome (GBS is a monophasic immune neuropathic disorder in which a significant proportion of patients have incomplete recovery. The patients with incomplete recovery almost always have some degree of failure of axon regeneration and target reinnervation. Anti-ganglioside antibodies (Abs are the most commonly recognized autoimmune markers in all forms of GBS and specific Abs are associated with the slow/poor recovery. We recently demonstrated that specific anti-ganglioside Abs inhibit axonal regeneration and nerve repair in preclinical models by activation of small GTPase RhoA and its downstream effectors. The objective of this study was to determine whether erythropoietin (EPO, a pleiotropic cytokine with neuroprotective and neurotrophic properties, enhances nerve regeneration in preclinical cell culture and animal models of autoimmune neuropathy/nerve repair generated with monoclonal and patient derived Abs. Primary neuronal cultures and a standardized sciatic crush nerve model were used to assess the efficacy of EPO in reversing inhibitory effects of anti-ganglioside Abs on nerve repair. We found that EPO completely reversed the inhibitory effects of anti-ganglioside Abs on axon regeneration in cell culture models and significantly improved nerve regeneration/repair in an animal model. Moreover, EPO-induced proregenerative effects in nerve cells are through EPO receptors and Janus kinase 2/Signal transducer and activator of transcription 5 pathway and not via early direct modulation of small GTPase RhoA. These preclinical studies indicate that EPO is a viable candidate drug to develop further for neuroprotection and enhancing nerve repair in patients with GBS.

  19. The Insect Ortholog of the Human Orphan Cytokine Receptor CRLF3 Is a Neuroprotective Erythropoietin Receptor

    Directory of Open Access Journals (Sweden)

    Nina Hahn

    2017-07-01

    Full Text Available The cytokine erythropoietin (Epo mediates various cell homeostatic responses to environmental challenges and pathological insults. While stimulation of vertebrate erythrocyte production is mediated by homodimeric “classical” Epo receptors, alternative receptors are involved in neuroprotection. However, their identity remains enigmatic due to complex cytokine ligand and receptor interactions and conflicting experimental results. Besides the classical Epo receptor, the family of type I cytokine receptors also includes the poorly characterized orphan cytokine receptor-like factor 3 (CRLF3 present in vertebrates including human and various insect species. By making use of the more simple genetic makeup of insect model systems, we studied whether CRLF3 is a neuroprotective Epo receptor in animals. We identified a single ortholog of CRLF3 in the beetle Tribolium castaneum, and established protocols for primary neuronal cell cultures from Tribolium brains and efficient in vitro RNA interference. Recombinant human Epo as well as the non-erythropoietic Epo splice variant EV-3 increased the survival of serum-deprived brain neurons, confirming the previously described neuroprotective effect of Epo in insects. Moreover, Epo completely prevented hypoxia-induced apoptotic cell death of primary neuronal cultures. Knockdown of CRLF3 expression by RNA interference with two different double stranded RNA (dsRNA fragments abolished the neuroprotective effect of Epo, indicating that CRLF3 is a crucial component of the insect Epo-responsive receptor. This suggests that a common urbilaterian ancestor of the orphan human and insect cytokine receptor CRLF3 served as a neuroprotective receptor for an Epo-like cytokine. Our work also suggests that vertebrate CRLF3, like its insect ortholog, might represent a tissue protection-mediating receptor.

  20. The nuclear charge distribution of fission products of thermal neutron induced fission of /sup 235/U

    CERN Document Server

    Wollnik, H; Greif, J; Siegert, G

    1976-01-01

    Nuclear charge distributions of mass separated light fission products, 79nuclear charge, the variance, the skewness, and the excess. The principles of the variations of the nuclear charge distributions due to varying kinetic energies are discussed. (20 refs).

  1. Strategic Role of Nuclear Inositide Signalling in Myelodysplastic Syndromes Therapy.

    Science.gov (United States)

    Manzoli, Lucia; Mongiorgi, Sara; Clissa, Cristina; Finelli, Carlo; Billi, Anna Maria; Poli, Alessandro; Quaranta, Marilisa; Cocco, Lucio; Follo, Matilde Y

    2014-10-13

    Nuclear inositide signalling is implicated in normal and pathological cell proliferation and differentiation in several distinct models. Among the key molecules of nuclear inositide pathways, phosphoinositide-phospholipase (PI-PLC) C β1 is essential for regulating hematopoiesis, particularly along myeloid and erythroid lineage. Moreover, Akt activation is associated with protein synthesis, via mTOR pathway, and with erythroid induction, through PI-PLCγ1 activation. Myelodysplastic syndromes (MDS) are a series of heterogeneous diseases characterized by ineffective hemopoiesis, with a variable risk of evolution into acute myeloid leukemia (AML). Therapeutic approaches for MDS include demethylating agents, such as azacitidine, aiming at reducing cell proliferation, and erythropoietin, useful for sustaining a normal erythropoiesis. In the last few years, a role for nuclear inositide signalling as a therapeutic target in MDS has been disclosed, in that PI-PLCβ1 increase is associated with azacitidine responsiveness, even when this drug is used in combination with other agents, and Akt is specifically activated in MDS at higher risk of AML evolution. On the other hand, recent data demonstrated that inositide signalling can also be involved in erythroid therapy, given the inhibitory effect of erythropoietin on PI-PLCβ1 and the activation of Akt/PI-PLCγ1 pathway, following the administration of erythropoietin. Here, we review the strategic role of nuclear inositide signalling in MDS, in pathogenesis and therapy.

  2. Activation of Nuclear Receptors RAR, RXR, and LXR Does Not Reduce Cuprizone-Induced Demyelination in Mice

    Directory of Open Access Journals (Sweden)

    Davina Kruczek

    2015-06-01

    Full Text Available Experiments with animal models of multiple sclerosis have shown that the expression of retinoid X receptors (RXR increases during demyelination and that RXR is involved in the regulation of remyelination. After ligand binding RXRs form heterodimeric transcription factors with other nuclear receptor (NR families including the retinoic acid receptors (RAR and liver X receptors (LXR. We tested whether activation of these nuclear receptor complexes reduces pathological demyelination using the cuprizone mouse model. Cuprizone, which causes oligodendrocyte degeneration, was given for three weeks as a food additive. For the activation of nuclear receptors mice were treated with daily i.p. injections of agonists for RXR (9-cis RA, RAR (all-trans RA, and LXR (T0901317. Myelin status, oligodendrocyte survival, astrogliosis, microglial activation, and axon density were monitored with immunohistochemistry and evaluated quantitatively. Three weeks of cuprizone feeding caused severe demyelination and significantly raised the number of Iba1 immunoreactive microglia cells in the caudal corpus callosum. This increase of microglia activity was reduced with 9-cis RA treatment but was enhanced with all-trans RA and was not affected by T0901317. Nuclear receptor activation did not influence the degree of demyelination, oligodendrocyte survival, astrogliosis, or axonal preservation. We conclude that RXR activation, although affecting Iba1-positive microglia, does not protect oligodendrocytes from cuprizone toxicity and does not induce compensatory mechanisms in the initial phase of demyelination.

  3. Nuclear Fragmentation Induced by Relativistic Projectiles Studied in the 4$\\pi$ Configuration of Plastic Track Detectors

    CERN Multimedia

    2002-01-01

    % EMU19 \\\\ \\\\ The collisions of heavy ions at relativistic energies have been studied to explore a number of questions related with hot and dense nuclear matter in order to extend our knowledge of nuclear equation-of-state. There are other aspects of these interactions which are studied to expound the process of projectile and/or target disintegrations. The disintegrations in question could be simply binary fissions or more complex processes leading to spallation or complete fragmentation. These important aspects of nuclear reactions are prone to investigations with nuclear track detectors. \\\\ \\\\One of the comparatively new track detector materials, CR-39, is sensitive enough to record particles of Z~$\\geq$~6 with almost 100\\% efficiency up to highly relativistic energies. The wide angle acceptance and exclusive measurements possible with plastic track detectors offer an opportunity to use them in a variety of situations in which high energy charged fragments are produced. The off-line nature of measuring tra...

  4. Novel nuclear-cytoplasmic interaction in wheat (Triticum aestivum) induces vigorous plants

    Science.gov (United States)

    Interspecific hybridization can be considered an accelerator of evolution, otherwise a slow process, solely dependent on mutation and recombination. Upon interspecific hybridization, several novel interactions between nuclear and cytoplasmic genomes emerge which provide additional sources of diversi...

  5. Activation cross-sections of deuteron induced nuclear reactions on neodymium up to 50 MeV

    Energy Technology Data Exchange (ETDEWEB)

    Tárkányi, F.; Takács, S. [Institute for Nuclear Research of the Hungarian Academy of Sciences (ATOMKI), Debrecen (Hungary); Ditrói, F., E-mail: ditroi@atomki.hu [Institute for Nuclear Research of the Hungarian Academy of Sciences (ATOMKI), Debrecen (Hungary); Hermanne, A. [Cyclotron Laboratory, Vrije Universiteit Brussel (VUB), Brussels (Belgium); Yamazaki, H.; Baba, M.; Mohammadi, A. [Cyclotron Radioisotope Center (CYRIC), Tohoku University, Sendai (Japan); Ignatyuk, A.V. [Institute of Physics and Power Engineering (IPPE), Obninsk (Russian Federation)

    2014-04-01

    Highlights: • Experimental excitation function of deuteron induced reactions on natural Nd. • Model code calculations with EMPIRE-D, ALICE-D and TALYS (TENDL-2012). • Physical yield calculation and comparison. • Discussion of medical and industrial applications. - Abstract: In the frame of a systematic study of activation cross sections of deuteron induced nuclear reactions on rare earths, the reactions on neodymium for production of therapeutic radionuclides were measured for the first time. The excitation functions of the {sup nat}Nd(d,x) {sup 151,150,149,148m,148g,146,144,143}Pm, {sup 149,147,139m}Nd, {sup 142}Pr and {sup 139g}Ce nuclear reactions were assessed by using the stacked foil activation technique and high resolution γ-spectrometry. The experimental excitation functions were compared to the theoretical predictions calculated with the modified model codes ALICE-IPPE-D and EMPIRE-II-D and with the data in the TENDL-2012 library based on latest version of the TALYS code. The application of the data in the field of medical isotope production and nuclear reaction theory is discussed.

  6. Nuclear Calcium Signaling Induces Expression of the Synaptic Organizers Lrrtm1 and Lrrtm2*

    Science.gov (United States)

    Hayer, Stefanie N.; Bading, Hilmar

    2015-01-01

    Calcium transients in the cell nucleus evoked by synaptic activity in hippocampal neurons function as a signaling end point in synapse-to-nucleus communication. As an important regulator of neuronal gene expression, nuclear calcium is involved in the conversion of synaptic stimuli into functional and structural changes of neurons. Here we identify two synaptic organizers, Lrrtm1 and Lrrtm2, as targets of nuclear calcium signaling. Expression of both Lrrtm1 and Lrrtm2 increased in a synaptic NMDA receptor- and nuclear calcium-dependent manner in hippocampal neurons within 2–4 h after the induction of action potential bursting. Induction of Lrrtm1 and Lrrtm2 occurred independently of the need for new protein synthesis and required calcium/calmodulin-dependent protein kinases and the nuclear calcium signaling target CREB-binding protein. Analysis of reporter gene constructs revealed a functional cAMP response element in the proximal promoter of Lrrtm2, indicating that at least Lrrtm2 is regulated by the classical nuclear Ca2+/calmodulin-dependent protein kinase IV-CREB/CREB-binding protein pathway. These results suggest that one mechanism by which nuclear calcium signaling controls neuronal network function is by regulating the expression of Lrrtm1 and Lrrtm2. PMID:25527504

  7. Nuclear calcium signaling induces expression of the synaptic organizers Lrrtm1 and Lrrtm2.

    Science.gov (United States)

    Hayer, Stefanie N; Bading, Hilmar

    2015-02-27

    Calcium transients in the cell nucleus evoked by synaptic activity in hippocampal neurons function as a signaling end point in synapse-to-nucleus communication. As an important regulator of neuronal gene expression, nuclear calcium is involved in the conversion of synaptic stimuli into functional and structural changes of neurons. Here we identify two synaptic organizers, Lrrtm1 and Lrrtm2, as targets of nuclear calcium signaling. Expression of both Lrrtm1 and Lrrtm2 increased in a synaptic NMDA receptor- and nuclear calcium-dependent manner in hippocampal neurons within 2-4 h after the induction of action potential bursting. Induction of Lrrtm1 and Lrrtm2 occurred independently of the need for new protein synthesis and required calcium/calmodulin-dependent protein kinases and the nuclear calcium signaling target CREB-binding protein. Analysis of reporter gene constructs revealed a functional cAMP response element in the proximal promoter of Lrrtm2, indicating that at least Lrrtm2 is regulated by the classical nuclear Ca(2+)/calmodulin-dependent protein kinase IV-CREB/CREB-binding protein pathway. These results suggest that one mechanism by which nuclear calcium signaling controls neuronal network function is by regulating the expression of Lrrtm1 and Lrrtm2. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  8. The analysis on the basic technology and radiation induced voltaic mechanism for nuclear battery

    Energy Technology Data Exchange (ETDEWEB)

    Hwang, Woan; Lee, B. O.; Min, B. T.; Kang, H. Y.; Kim, B. H.; Park, J. H.; Seo, H. S

    2000-12-01

    Present study is for nuclear battery technology directly converting radiation energy to electricity among various nuclear energy, and it is anticipated that an interest in direct conversion of nuclear energy into electricity shall be increased as the conversion efficiency enhances. The battery should promise cheap, reliable power from a package small and light enough to be mobile, and with energy density great enough for use as a space based power supply. Various radiation-electricity conversion mechanism so far have been reported since G.J. Moseley reported the operation of a high-voltage nuclear battery using radium. The most important conversion mechanisms are RTG (Radioisotope Thermoelectric Generator) converting the heat produced from radioisotope to electricity using the temperature difference, and NRG (Nuclear Resonance Generator) using free electrons from the collision between {alpha}, {beta}rays and copper coil. It is well known that RTG and NRG mechanisms are most practical way because their efficiencies high. The basic technology on radiation-electricity conversion mechanism, interaction mechanism between {beta} ray and material, shielding for {beta} ray, and technical backgrounds and a state of the art for RTG and NRG technologies, are analyzed in this report. Basic data on the conceptual design for the prototype of nuclear battery are prepared.

  9. Prediction of perinatal brain damage by cord plasma vasopressin, erythropoietin, and hypoxanthine values.

    Science.gov (United States)

    Ruth, V; Autti-Rämö, I; Granström, M L; Korkman, M; Raivio, K O

    1988-11-01

    For an assessment of whether cord plasma arginine vasopressin, erythropoietin, and hypoxanthine concentrations are predictors of perinatal brain damage, these concentrations were measured in 62 infants born after preeclampsia of pregnancy, 31 acutely asphyxiated infants, and 38 control infants. Follow-up at 2 years included neurologic examination and the determination of a Bayley mental score. Clear abnormality (death, cerebral palsy, or developmental delay) was found in four infants in the preeclampsia group and five in the asphyxia group; slight abnormality was found in 12 and 6 infants, respectively; and no abnormality was found in the remainder. Neither arginine vasopressin values nor hypoxanthine values predicted adverse outcome in either study group. A high erythropoietin level was found in infants born after preeclampsia regardless of outcome: normal outcome (geometric mean (GM), 102; 95% confidence interval [CI], 69 to 153 mU/ml), slightly abnormal outcome (GM, 100; 95% CI, 37 to 270 mU/ml) or clearly abnormal outcome (GM, 84; 95% CI, 19 to 378 mU/ml). However, asphyxiated infants with clearly abnormal outcome had higher erythropoietin values (GM, 67; 95% CI, 33 to 137 mU/ml; p less than 0.05) than the normal infants (GM, 37; 95% CI, 23 to 59 mU/ml). We conclude that a high erythropoietin level after normal pregnancy, but not after preeclampsia, indicates an increased risk for cerebral palsy or death.

  10. 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...

  11. How bio-questionable are the different recombinant human erythropoietin copy products in Thailand?

    NARCIS (Netherlands)

    Halim, Liem Andhyk|info:eu-repo/dai/nl/412608294; Brinks, Vera|info:eu-repo/dai/nl/31395979X; Jiskoot, Wim; Romeijn, Stefan; Praditpornsilpa, Kearkiat; Assawamakin, Anunchai; Schellekens, Huub|info:eu-repo/dai/nl/068406762

    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. 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 of...

  13. The Significance of Erythropoietin Receptor (EpoR) Acquisition by Breast Cancer Cells

    Science.gov (United States)

    2007-08-01

    CONTRACTING ORGANIZATION: Beth Israel Deaconess Medical Center...ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER Beth Israel Deaconess Medical Center Boston, MA 02215 9. SPONSORING...Arcasoy MO, Kirkpatrick JP, Vujaskovic Z, Dewhirst MW, Blackwell KL. Erythropoietin inhibits apoptosis in breast cancer cells via an Akt-dependent

  14. Early intervention with erythropoietin does not affect the outcome of acute kidney injury (the EARLYARF trial).

    Science.gov (United States)

    Endre, Zoltán H; Walker, Robert J; Pickering, John W; Shaw, Geoffrey M; Frampton, Christopher M; Henderson, Seton J; Hutchison, Robyn; Mehrtens, Jan E; Robinson, Jillian M; Schollum, John B W; Westhuyzen, Justin; Celi, Leo A; McGinley, Robert J; Campbell, Isaac J; George, Peter M

    2010-06-01

    We performed a double-blind placebo-controlled trial to study whether early treatment with erythropoietin could prevent the development of acute kidney injury in patients in two general intensive care units. As a guide for choosing the patients for treatment we measured urinary levels of two biomarkers, the proximal tubular brush border enzymes gamma-glutamyl transpeptidase and alkaline phosphatase. Randomization to either placebo or two doses of erythropoietin was triggered by an increase in the biomarker concentration product to levels above 46.3, with a primary outcome of relative average plasma creatinine increase from baseline over 4 to 7 days. Of 529 patients, 162 were randomized within an average of 3.5 h of a positive sample. There was no difference in the incidence of erythropoietin-specific adverse events or in the primary outcome between the placebo and treatment groups. The triggering biomarker concentration product selected patients with more severe illness and at greater risk of acute kidney injury, dialysis, or death; however, the marker elevations were transient. Early intervention with high-dose erythropoietin was safe but did not alter the outcome. Although these two urine biomarkers facilitated our early intervention, their transient increase compromised effective triaging. Further, our study showed that a composite of these two biomarkers was insufficient for risk stratification in a patient population with a heterogeneous onset of injury.

  15. 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.

  16. 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...

  17. 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...

  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. 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

    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

  20. 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

  1. Assessment of nuclear-reaction codes for proton-induced reactions on light nuclei below 250 MeV

    Science.gov (United States)

    Braunn, Benjamin; Boudard, Alain; David, Jean-Christophe; Koning, Arjan J.; Leprince, Anne; Leray, Sylvie; Mancusi, Davide

    2015-07-01

    We assess the suitability of nuclear-reaction codes for the generation of accurate cross-section libraries targeted at the simulation of the transport of high-energy protons (up to 250 MeV) in the human body, or in any material containing light nuclides. To this end we present an extensive study of elastic, reaction and fragmentation cross sections for proton-induced reactions on several nuclides. We compare TALYS evaluations against experimental data and, wherever applicable, against the predictions of the INCL/ABLA07 nuclear-reaction model. The TALYS evaluations have been cast in the form of a new cross-section library, which also includes evaluated proton-proton cross sections based on the NN-OnLine tool.

  2. Hepatitis C virus-induced cytoplasmic organelles use the nuclear transport machinery to establish an environment conducive to virus replication.

    Directory of Open Access Journals (Sweden)

    Christopher J Neufeldt

    2013-10-01

    Full Text Available Hepatitis C virus (HCV infection induces formation of a membranous web structure in the host cell cytoplasm where the viral genome replicates and virions assemble. The membranous web is thought to concentrate viral components and hide viral RNA from pattern recognition receptors. We have uncovered a role for nuclear pore complex proteins (Nups and nuclear transport factors (NTFs in the membranous web. We show that HCV infection leads to increased levels of cytoplasmic Nups that accumulate at sites enriched for HCV proteins. Moreover, we detected interactions between specific HCV proteins and both Nups and NTFs. We hypothesize that cytoplasmically positioned Nups facilitate formation of the membranous web and contribute to the compartmentalization of viral replication. Accordingly, we show that transport cargo proteins normally targeted to the nucleus are capable of entering regions of the membranous web, and that depletion of specific Nups or Kaps inhibits HCV replication and assembly.

  3. Activation cross-sections of deuteron induced nuclear reactions on gold up to 40 MeV

    Energy Technology Data Exchange (ETDEWEB)

    Tarkanyi, F. [Institute of Nuclear Research of the Hungarian Academy of Sciences (ATOMKI), Debrecen (Hungary); Ditroi, F., E-mail: ditroi@atomki.hu [Institute of Nuclear Research of the Hungarian Academy of Sciences (ATOMKI), Debrecen (Hungary); Hermanne, A. [Cyclotron Laboratory, Vrije Universiteit Brussel (VUB), Brussels (Belgium); Takacs, S.; Kiraly, B. [Institute of Nuclear Research of the Hungarian Academy of Sciences (ATOMKI), Debrecen (Hungary); Yamazaki, H.; Baba, M.; Mohammadi, A. [Cyclotron and Radioisotope Center (CYRIC), Tohoku University, Sendai (Japan); Ignatyuk, A.V. [Institute of Physics and Power Engineering (IPPE), Obninsk (Russian Federation)

    2011-06-15

    Cross-sections of deuteron induced nuclear reactions on gold were measured up to 40 MeV by using the standard stacked foil irradiation technique and high resolution gamma-ray spectroscopy. Experimental cross-sections and derived integral yields are reported for the {sup 197}Au(d,xn){sup 197m,197g,195m,195g}Hg and {sup 197}Au(d,x){sup 198g,196m,196g,195,194}Au nuclear reactions. The experimental data are analyzed and compared to literature and predictions of the ALICE-IPPE, EMPIRE and TALYS theoretical model codes. The application of the new cross-sections for accelerator technology, medical radioisotope production, thin layer activation and dose calculation is discussed.

  4. Earthquake-induced crustal deformation and consequences for fault displacement hazard analysis of nuclear power plants

    Energy Technology Data Exchange (ETDEWEB)

    Gürpinar, Aybars, E-mail: aybarsgurpinar2007@yahoo.com [Nuclear & Risk Consultancy, Anisgasse 4, 1221 Vienna (Austria); Serva, Leonello, E-mail: lserva@alice.it [Independent Consultant, Via dei Dauni 1, 00185 Rome (Italy); Livio, Franz, E-mail: franz.livio@uninsubria.it [Dipartimento di Scienza ed Alta Tecnologia, Università degli Studi dell’Insubria, Via Velleggio, 11, 22100 Como (Italy); Rizzo, Paul C., E-mail: paul.rizzo@rizzoasoc.com [RIZZO Associates, 500 Penn Center Blvd., Suite 100, Pittsburgh, PA 15235 (United States)

    2017-01-15

    Highlights: • A three-step procedure to incorporate coseismic deformation into PFDHA. • Increased scrutiny for faults in the area permanently deformed by future strong earthquakes. • These faults share with the primary structure the same time window for fault capability. • VGM variation may occur due to tectonism that has caused co-seismic deformation. - Abstract: Readily available interferometric data (InSAR) of the coseismic deformation field caused by recent seismic events clearly show that major earthquakes produce crustal deformation over wide areas, possibly resulting in significant stress loading/unloading of the crust. Such stress must be considered in the evaluation of seismic hazards of nuclear power plants (NPP) and, in particular, for the potential of surface slip (i.e., probabilistic fault displacement hazard analysis - PFDHA) on both primary and distributed faults. In this study, based on the assumption that slip on pre-existing structures can represent the elastic response of compliant fault zones to the permanent co-seismic stress changes induced by other major seismogenic structures, we propose a three-step procedure to address fault displacement issues and consider possible influence of surface faulting/deformation on vibratory ground motion (VGM). This approach includes: (a) data on the presence and characteristics of capable faults, (b) data on recognized and/or modeled co-seismic deformation fields and, where possible, (c) static stress transfer between source and receiving faults of unknown capability. The initial step involves the recognition of the major seismogenic structures nearest to the site and their characterization in terms of maximum expected earthquake and the time frame to be considered for determining their “capability” (as defined in the International Atomic Energy Agency - IAEA Specific Safety Guide SSG-9). Then a GIS-based buffer approach is applied to identify all the faults near the NPP, possibly influenced by

  5. Cell and nuclear enlargement of SW480 cells induced by a plant lignan, arctigenin: evaluation of cellular DNA content using fluorescence microscopy and flow cytometry.

    Science.gov (United States)

    Kang, Kyungsu; Lee, Hee Ju; Yoo, Ji-Hye; Jho, Eun Hye; Kim, Chul Young; Kim, Minkyun; Nho, Chu Won

    2011-08-01

    Arctigenin is a natural plant lignan previously shown to induce G(2)/M arrest in SW480 human colon cancer cells as well as AGS human gastric cancer cells, suggesting its use as a possible cancer chemopreventive agent. Changes in cell and nuclear size often correlate with the functionality of cancer-treating agents. Here, we report that arctigenin induces cell and nuclear enlargement of SW480 cells. Arctigenin clearly induced the formation of giant nuclear shapes in SW480, as demonstrated by fluorescence microscopic observation and quantitative determination of nuclear size. Cell and nuclear size were further assessed by flow cytometric analysis of light scattering and fluorescence pulse width after propidium iodide staining. FSC-H and FL2-W values (parameters referring to cell and nuclear size, respectively) significantly increased after arctigenin treatment; the mean values of FSC-H and FL2-W in arctigenin-treated SW480 cells were 572.6 and 275.1, respectively, whereas those of control cells were 482.0 and 220.7, respectively. Our approach may provide insights into the mechanism behind phytochemical-induced cell and nuclear enlargement as well as functional studies on cancer-treating agents.

  6. Aberrant phenotypes of transgenic mice expressing dimeric human erythropoietin

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    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

  7. 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

  8. Application of Nuclear Volume Measurements to Comprehend the Cell Cycle in Root-Knot Nematode-Induced Giant Cells

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    José Dijair Antonino de Souza Junior

    2017-06-01

    Full Text Available Root-knot nematodes induce galls that contain giant-feeding cells harboring multiple enlarged nuclei within the roots of host plants. It is recognized that the cell cycle plays an essential role in the set-up of a peculiar nuclear organization that seemingly steers nematode feeding site induction and development. Functional studies of a large set of cell cycle genes in transgenic lines of the model host Arabidopsis thaliana have contributed to better understand the role of the cell cycle components and their implication in the establishment of functional galls. Mitotic activity mainly occurs during the initial stages of gall development and is followed by an intense endoreduplication phase imperative to produce giant-feeding cells, essential to form vigorous galls. Transgenic lines overexpressing particular cell cycle genes can provoke severe nuclei phenotype changes mainly at later stages of feeding site development. This can result in chaotic nuclear phenotypes affecting their volume. These aberrant nuclear organizations are hampering gall development and nematode maturation. Herein we report on two nuclear volume assessment methods which provide information on the complex changes occurring in nuclei during giant cell development. Although we observed that the data obtained with AMIRA tend to be more detailed than Volumest (Image J, both approaches proved to be highly versatile, allowing to access 3D morphological changes in nuclei of complex tissues and organs. The protocol presented here is based on standard confocal optical sectioning and 3-D image analysis and can be applied to study any volume and shape of cellular organelles in various complex biological specimens. Our results suggest that an increase in giant cell nuclear volume is not solely linked to increasing ploidy levels, but might result from the accumulation of mitotic defects.

  9. Activation of nuclear β-catenin/c-Myc axis promotes oxidative stress injury in streptozotocin-induced diabetic cardiomyopathy.

    Science.gov (United States)

    Liu, Peng; Su, Jianfang; Song, Xixi; Wang, Shixiao

    2017-12-02

    Myocardial oxidative stress injury plays a crucial role in the pathogenesis of diabetic cardiomyopathy (DCM). Wnt/β-catenin signaling has been reported to involve in various heart diseases. However, the underlying mechanism associated with β-catenin in DCM remains elusive. This study intended to explore the effect of β-catenin on oxidative damage of DCM by establishing streptozotocin (STZ)-induced diabetic mouse model and hydrogen peroxide (H 2 O 2 )-treated myocardial cell model. Cardiac oxidative stress in DCM was detected by measurements of lipid peroxidation and anti-oxidative enzyme activities as well as DHE staining. Nuclear β-catenin activity and oxidative damage degree were measured by western blotting, qPCR, MTT assay and TUNEL staining. Cardiac function and morphology were evaluated by echocardiography and histopathology. Under diabetic oxidative stress or H 2 O 2 stimulation, nuclear β-catenin accumulation upregulated downstream c-Myc and further facilitated DNA damage and p53-mediated apoptosis as well as cell viability reduction, followed by phenotypic changes of cardiac dysfunction, interstitial fibrosis deposition and myocardial atrophy. Conversely, through directly inhibiting nuclear β-catenin/c-Myc axis, not only did siRNA knockdown of β-catenin or c-Myc attenuate cell injury in H 2 O 2 -stimulated cardiomyocytes, but also diabetic cardiac-specific β-catenin-knockout mice displayed the same prevention of heart injury as insulin-treated diabetic mice. The present study demonstrated that activated nuclear β-catenin/c-Myc axis was responsible for oxidative cardiac impairment of DCM. Therefore, repressing functional nuclear β-catenin may provide a hopeful therapeutic strategy for DCM. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Novel nuclear-cytoplasmic interaction in wheat (Triticum aestivum) induces vigorous plants.

    Science.gov (United States)

    Soltani, Ali; Kumar, Ajay; Mergoum, Mohamed; Pirseyedi, Seyed Mostafa; Hegstad, Justin B; Mazaheri, Mona; Kianian, Shahryar F

    2016-03-01

    Interspecific hybridization can be considered an accelerator of evolution, otherwise a slow process, solely dependent on mutation and recombination. Upon interspecific hybridization, several novel interactions between nuclear and cytoplasmic genomes emerge which provide additional sources of diversity. The magnitude and essence of intergenomic interactions between nuclear and cytoplasmic genomes remain unknown due to the direction of many crosses. This study was conducted to address the role of nuclear-cytoplasmic interactions as a source of variation upon hybridization. Wheat (Triticum aestivum) alloplasmic lines carrying the cytoplasm of Aegilops mutica along with an integrated approach utilizing comparative quantitative trait locus (QTL) and epigenome analysis were used to dissect this interaction. The results indicate that cytoplasmic genomes can modify the magnitude of QTL controlling certain physiological traits such as dry matter weight. Furthermore, methylation profiling analysis detected eight polymorphic regions affected by the cytoplasm type. In general, these results indicate that novel nuclear-cytoplasmic interactions can potentially trigger an epigenetic modification cascade in nuclear genes which eventually change the genetic network controlling physiological traits. These modified genetic networks can serve as new sources of variation to accelerate the evolutionary process. Furthermore, this variation can synthetically be produced by breeders in their programs to develop epigenomic-segregating lines.

  11. Neutron-induced nuclear data for the MYRRHA fast spectrum facility

    Directory of Open Access Journals (Sweden)

    Romojaro Pablo

    2017-01-01

    Full Text Available The MYRRHA (Multi-purpose hYbrid Research Reactor for High-tech Applications concept is a flexible experimental lead-bismuth cooled and mixed-oxide (MOX fueled fast spectrum facility designed to operate both in sub-critical (accelerator driven and critical modes. One of the key issues for the safe operation of the reactor is the uncertainty assessment during the design works. The main objective of the European project CHANDA (solving CHAllenges in Nuclear DAta Work Package 10 is to improve MYRRHA relevant nuclear data in order to reduce the reactor parameter uncertainties derived from them. In order to achieve this goal, several tasks have been undertaken. First, a sensitivity study of MYRRHA integral parameters, such as energy dependent cross sections, fission spectra and neutron multiplicities, to nuclear data has been conducted resulting in a list of MYRRHA relevant quantities (nuclides and reactions. On the second task, an analysis of the existing experimental data and evaluations for the quantities included in the list has been carried out. In this framework, the impact on the multiplication factor of quantities from different nuclear data libraries for different nuclides, reactions and energy regions has been investigated on the MYRRHA MOX critical core model. As the next step, new experiments and evaluations will be performed in order to improve existing nuclear data libraries.

  12. Neutron-induced nuclear data for the MYRRHA fast spectrum facility

    Science.gov (United States)

    Romojaro, Pablo; Žerovnik, Gašper; Álvarez-Velarde, Francisco; Stankovskiy, Alexey; Kodeli, Ivan; Fiorito, Luca; Díez, Carlos Javier; Cabellos, Óscar; García-Herranz, Nuria; Heyse, Jan; Paradela, Carlos; Schillebeeckx, Peter; Eynde, Gert Van den

    2017-09-01

    The MYRRHA (Multi-purpose hYbrid Research Reactor for High-tech Applications) concept is a flexible experimental lead-bismuth cooled and mixed-oxide (MOX) fueled fast spectrum facility designed to operate both in sub-critical (accelerator driven) and critical modes. One of the key issues for the safe operation of the reactor is the uncertainty assessment during the design works. The main objective of the European project CHANDA (solving CHAllenges in Nuclear DAta) Work Package 10 is to improve MYRRHA relevant nuclear data in order to reduce the reactor parameter uncertainties derived from them. In order to achieve this goal, several tasks have been undertaken. First, a sensitivity study of MYRRHA integral parameters, such as energy dependent cross sections, fission spectra and neutron multiplicities, to nuclear data has been conducted resulting in a list of MYRRHA relevant quantities (nuclides and reactions). On the second task, an analysis of the existing experimental data and evaluations for the quantities included in the list has been carried out. In this framework, the impact on the multiplication factor of quantities from different nuclear data libraries for different nuclides, reactions and energy regions has been investigated on the MYRRHA MOX critical core model. As the next step, new experiments and evaluations will be performed in order to improve existing nuclear data libraries.

  13. Synaptic activity and nuclear calcium signaling protect hippocampal neurons from death signal-associated nuclear translocation of FoxO3a induced by extrasynaptic N-methyl-D-aspartate receptors.

    Science.gov (United States)

    Dick, Oliver; Bading, Hilmar

    2010-06-18

    Synaptic activity and the generation of nuclear calcium signals promote neuronal survival through a transcription-dependent process that is not fully understood. Here we show that one mechanism of activity-induced acquired neuroprotection involves the Forkhead transcription factor, FoxO3a, which is known to induce genomic death responses upon translocation from the cytosol to the nucleus. Depletion of endogenous FoxO3a using RNA interference renders hippocampal neurons more resistant to excitotoxic cell death. Using a FoxO3a-green fluorescent protein (GFP) fusion protein to monitor in real time the localization of FoxO3a in hippocampal neurons, we found that several cell death inducing stimuli, including the stimulation of extrasynaptic N-methyl-D-aspartate receptors, growth factor withdrawal, and oxygen-glucose deprivation, caused a swift translocation of FoxO3a-GFP from the cytosol to the cell nucleus. This translocation was inhibited in hippocampal neurons that had undergone prolonged periods of synaptic activity before exposure to cell death-inducing conditions. The activity-dependent protection from death signal-induced FoxO3a-GFP nuclear translocation required synaptic N-methyl-D-aspartate receptor activation and was dependent on nuclear calcium signaling and calcium/calmodulin-dependent protein kinase IV. The modulation of nucleo-cytoplasmic shuttling of FoxO3a may represent one mechanism through which nuclear calcium-induced genomic responses affect cell death processes.

  14. Synaptic Activity and Nuclear Calcium Signaling Protect Hippocampal Neurons from Death Signal-associated Nuclear Translocation of FoxO3a Induced by Extrasynaptic N-Methyl-d-aspartate Receptors*

    Science.gov (United States)

    Dick, Oliver; Bading, Hilmar

    2010-01-01

    Synaptic activity and the generation of nuclear calcium signals promote neuronal survival through a transcription-dependent process that is not fully understood. Here we show that one mechanism of activity-induced acquired neuroprotection involves the Forkhead transcription factor, FoxO3a, which is known to induce genomic death responses upon translocation from the cytosol to the nucleus. Depletion of endogenous FoxO3a using RNA interference renders hippocampal neurons more resistant to excitotoxic cell death. Using a FoxO3a-green fluorescent protein (GFP) fusion protein to monitor in real time the localization of FoxO3a in hippocampal neurons, we found that several cell death inducing stimuli, including the stimulation of extrasynaptic N-methyl-d-aspartate receptors, growth factor withdrawal, and oxygen-glucose deprivation, caused a swift translocation of FoxO3a-GFP from the cytosol to the cell nucleus. This translocation was inhibited in hippocampal neurons that had undergone prolonged periods of synaptic activity before exposure to cell death-inducing conditions. The activity-dependent protection from death signal-induced FoxO3a-GFP nuclear translocation required synaptic N-methyl-d-aspartate receptor activation and was dependent on nuclear calcium signaling and calcium/calmodulin-dependent protein kinase IV. The modulation of nucleo-cytoplasmic shuttling of FoxO3a may represent one mechanism through which nuclear calcium-induced genomic responses affect cell death processes. PMID:20404335

  15. A key role for stress-induced satellite III transcripts in the relocalization of splicing factors into nuclear stress granules.

    Science.gov (United States)

    Metz, Alexandra; Soret, Johann; Vourc'h, Claire; Tazi, Jamal; Jolly, Caroline

    2004-09-01

    Exposure of cells to stressful conditions results in the rapid synthesis of a subset of specialized proteins termed heat shock proteins (HSPs) which function in protecting the cell against damage. The stress-induced activation of hsp genes is controlled by the heat shock transcription factor 1 (HSF1). At the cellular level, one of the most striking effects of stress is the rapid and reversible redistribution of HSF1 into a few nuclear structures termed nuclear stress granules which form primarily on the 9q12 locus in humans. Within these structures, HSF1 binds to satellite III repeated elements and drives the RNA polymerase II-dependent transcription of these sequences into stable RNAs which remain associated with the 9q12 locus for a certain time after synthesis. Other proteins, in particular splicing factors, were also shown to relocalize to the granules upon stress. Here, we investigated the role of stress-induced satellite III transcripts in the relocalization of splicing factors to the granules. We show that the recruitment of the two serine/arginine-rich (SR) proteins SF2/ASF and SRp30c requires the presence of stress-induced satellite III transcripts. In agreement with these findings, we identified the second RNA-recognition motif (RRM2) of hSF2/ASF as the motif required for the targeting to the granules, and we showed by immunoprecipitation that the endogenous hSF2/ASF protein is present in a complex with satellite III transcripts in stressed cells in vivo. Interestingly, satellite III transcripts also immunoprecipitate together with small nuclear ribonucleoproteins (snRNPs) in vivo whereas the intronless hsp70 transcripts do not, supporting the proposal that these transcripts are subject to splicing. Altogether, these data highlight the central role for satellite III transcripts in the targeting and/or retention of splicing factors into the granules upon stress.

  16. Generation of Induced Pluripotent Stem (iPS Cells by Nuclear Reprogramming

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    Dilip Dey

    2011-01-01

    Full Text Available During embryonic development pluripotency is progressively lost irreversibly by cell division, differentiation, migration and organ formation. Terminally differentiated cells do not generate other kinds of cells. Pluripotent stem cells are a great source of varying cell types that are used for tissue regeneration or repair of damaged tissue. The pluripotent stem cells can be derived from inner cell mass of blastocyte but its application is limited due to ethical concerns. The recent discovery of iPS with defined reprogramming factors has initiated a flurry of works on stem cell in various laboratories. The pluripotent cells can be derived from various differentiated adult cells as well as from adult stem cells by nuclear reprogramming, somatic cell nuclear transfer etc. In this review article, different aspects of nuclear reprogramming are discussed.

  17. Steam explosions-induced containment failure studies for Swiss nuclear power plants

    Energy Technology Data Exchange (ETDEWEB)

    Zuchuat, O.; Schmocker, U. [Swiss Federal Nuclear Safety Inspectorate, Villigen (Switzerland); Esmaili, H.; Khatib-Rahbar, M.

    1998-01-01

    The assessment of the consequences of both in-vessel and ex-vessel energetic fuel-coolant interaction for Beznau (a Westinghouse pressurized water reactor with a large, dry containment), Goesgen (a Siemens/KWU pressurized water reactor with a large, dry containment) and Leibstadt (a General Electric boiling water reactor-6 with a free standing steel, MARK-III containment) nuclear power plants is presented in this paper. The Conditional Containment Failure Probability of the steel containment of these Swiss nuclear power plants is determined based on different probabilistic approaches. (author)

  18. Fluctuation-induced heat release from temperature-quenched nuclear spins near a quantum critical point.

    Science.gov (United States)

    Kim, Y H; Kaur, N; Atkins, B M; Dalal, N S; Takano, Y

    2009-12-11

    At a quantum critical point (QCP)--a zero-temperature singularity in which a line of continuous phase transition terminates--quantum fluctuations diverge in space and time, leading to exotic phenomena that can be observed at nonzero temperatures. Using a quantum antiferromagnet, we present calorimetric evidence that nuclear spins frozen in a high-temperature nonequilibrium state by temperature quenching are annealed by quantum fluctuations near the QCP. This phenomenon, with readily detectable heat release from the nuclear spins as they are annealed, serves as an excellent marker of a quantum critical region around the QCP and provides a probe of the dynamics of the divergent quantum fluctuations.

  19. Research on fission induced plasmas and nuclear pumped lasers at the Los Alamos Scientific Laboratory

    Science.gov (United States)

    Helmick, H. H.

    1979-01-01

    A program of research on gaseous uranium and uranium plasmas is being conducted at The Los Alamos Scientific Laboratory under sponsorship of the National Aeronautics and Space Administration. The objective of this work is twofold: (1) to demonstrate the proof of principle of a gaseous uranium fueled reactor, and (2) pursue fundamental research on nuclear pumped lasers. The relevancy of the two parallel programs is embodied in the possibility of a high-performance uranium plasma reactor being used as the power supply for a nuclear pumped laser system. The accomplishments in the two above fields are summarized

  20. 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

  1. Quercetin suppresses heat shock-induced nuclear translocation of Hsp72

    Directory of Open Access Journals (Sweden)

    Antoni Gawron

    2011-08-01

    Full Text Available The effect of quercetin and heat shock on the Hsp72 level and distribution in HeLa cells was studied by Western blotting, indirect immunofluorescence and immunogold electron microscopy. In control cells and after quercetin treatment, Hsp72 was located both in the cytoplasm and in the nucleus in comparable amounts. After hyperthermia, the level of nuclear Hsp72 raised dramatically. Expression of Hsp72 in cytoplasm was also higher but not to such extent as that observed in the nucleus. Preincubation of heated cells with quercetin inhibited strong Hsp72 expression observed after hyperthermia and changed the intracellular Hsp72 distribution. The cytoplasmic level of protein exceeded the nuclear one, especially around the nucleus, where the coat of Hsp72 was noticed. Observations indicating that quercetin was present around and in the nuclear envelope suggested an involvement of this drug in the inhibition of nuclear translocation. Our results indicate that pro-apoptotic activity of quercetin may be correlated not only with the inhibition of Hsp72 expression but also with suppression of its migration to the nucleus.

  2. Varicella-zoster virus induces the formation of dynamic nuclear capsid aggregates

    Energy Technology Data Exchange (ETDEWEB)

    Lebrun, Marielle [University of Liege (ULg), GIGA-Infection Immunity and Inflammation, Laboratory of Virology and Immunology, Liege (Belgium); Thelen, Nicolas; Thiry, Marc [University of Liege (ULg), GIGA-Neurosciences, Laboratory of Cellular and Tissular Biology, Liege (Belgium); Riva, Laura; Ote, Isabelle; Condé, Claude; Vandevenne, Patricia [University of Liege (ULg), GIGA-Infection Immunity and Inflammation, Laboratory of Virology and Immunology, Liege (Belgium); Di Valentin, Emmanuel [University of Liege (ULg), GIGA-Viral Vectors Platform, Liege (Belgium); Bontems, Sébastien [University of Liege (ULg), GIGA-Infection Immunity and Inflammation, Laboratory of Virology and Immunology, Liege (Belgium); Sadzot-Delvaux, Catherine, E-mail: csadzot@ulg.ac.be [University of Liege (ULg), GIGA-Infection Immunity and Inflammation, Laboratory of Virology and Immunology, Liege (Belgium)

    2014-04-15

    The first step of herpesviruses virion assembly occurs in the nucleus. However, the exact site where nucleocapsids are assembled, where the genome and the inner tegument are acquired, remains controversial. We created a recombinant VZV expressing ORF23 (homologous to HSV-1 VP26) fused to the eGFP and dually fluorescent viruses with a tegument protein additionally fused to a red tag (ORF9, ORF21 and ORF22 corresponding to HSV-1 UL49, UL37 and UL36). We identified nuclear dense structures containing the major capsid protein, the scaffold protein and maturing protease, as well as ORF21 and ORF22. Correlative microscopy demonstrated that the structures correspond to capsid aggregates and time-lapse video imaging showed that they appear prior to the accumulation of cytoplasmic capsids, presumably undergoing the secondary egress, and are highly dynamic. Our observations suggest that these structures might represent a nuclear area important for capsid assembly and/or maturation before the budding at the inner nuclear membrane. - Highlights: • We created a recombinant VZV expressing the small capsid protein fused to the eGFP. • We identified nuclear dense structures containing capsid and procapsid proteins. • Correlative microscopy showed that the structures correspond to capsid aggregates. • Procapsids and partial capsids are found within the aggregates of WT and eGFP-23 VZV. • FRAP and FLIP experiments demonstrated that they are dynamic structures.

  3. CacyBP/SIP nuclear translocation induced by gastrin promotes gastric cancer cell proliferation.

    Science.gov (United States)

    Zhai, Hui-Hong; Meng, Juan; Wang, Jing-Bo; Liu, Zhen-Xiong; Li, Yuan-Fei; Feng, Shan-Shan

    2014-08-07

    To investigate the role of nuclear translocation of calcyclin binding protein, also called Siah-1 interacting protein (CacyBP/SIP), in gastric carcinogenesis. The expression of CacyBP/SIP protein in gastric cancer cell lines was detected by Western blot. Immunofluorescence experiments were performed on gastric cancer cell lines that had been either unstimulated or stimulated with gastrin. To confirm the immunofluorescence findings, the relative abundance of CacyBP/SIP in nuclear and cytoplasmic compartments was assessed by Western blot. The effect of nuclear translocation of CacyBP/SIP on cell proliferation was examined using MTT assay. The colony formation assay was used to measure clonogenic cell survival. The effect of CacyBP/SIP nuclear translocation on cell cycle progression was investigated. Two CacyBP/SIP-specific siRNA vectors were designed and constructed to inhibit CacyBP/SIP expression in order to reduce the nuclear translocation of CacyBP/SIP, and the expression of CacyBP/SIP in stably transfected cells was determined by Western blot. The effect of inhibiting CacyBP/SIP nuclear translocation on cell proliferation was then assessed. CacyBP/SIP protein was present in most of gastric cancer cell lines. In unstimulated cells, CacyBP/SIP was distributed throughout the cytoplasm; while in stimulated cells, CacyBP/SIP was found mainly in the perinuclear region. CacyBP/SIP nuclear translocation generated a growth-stimulatory effect on cells. The number of colonies in the CacyBP/SIP nuclear translocation group was significantly higher than that in the control group. The percentage of stimulated cells in G1 phase was significantly lower than that of control cells (69.70% ± 0.46% and 65.80% ± 0.60%, control cells and gastrin-treated SGC7901 cells, P = 0.008; 72.99% ± 0.46% and 69.36% ± 0.51%, control cells and gastrin-treated MKN45 cells, P = 0.022). CacyBP/SIPsi1 effectively down-regulated the expression of CacyBP/SIP, and cells stably transfected by Cacy

  4. Nucleolar disruption and cajal body disassembly are nuclear hallmarks of DNA damage-induced neurodegeneration in purkinje cells.

    Science.gov (United States)

    Baltanás, Fernando C; Casafont, Iñigo; Weruaga, Eduardo; Alonso, José R; Berciano, María T; Lafarga, Miguel

    2011-07-01

    The Purkinje cell (PC) degeneration (pcd) phenotype results from mutation in nna1 gene and is associated with the degeneration and death of PCs during the postnatal life. Although the pcd mutation is a model of the ataxic mouse, it shares clinical and pathological characteristics of inherited human spinocerebellar ataxias. PC degeneration in pcd mice provides a useful neuronal system to study nuclear mechanisms involved in DNA damage-dependent neurodegeneration, particularly the contribution of nucleoli and Cajal bodies (CBs). Both nuclear structures are engaged in housekeeping functions for neuronal survival, the biogenesis of ribosomes and the maturation of snRNPs and snoRNPs required for pre-mRNA and pre-rRNA processing, respectively. In this study, we use ultrastructural analysis, in situ transcription assay and molecular markers for DNA damage, nucleoli and CB components to demonstrate that PC degeneration involves the progressive accumulation of nuclear DNA damage associated with disruption of nucleoli and CBs, disassembly of polyribosomes into monoribosomes, ribophagy and shut down of nucleolar and extranucleolar transcription. Microarray analysis reveals that four genes encoding repressors of nucleolar rRNA synthesis (p53, Rb, PTEN and SNF2) are upregulated in the cerebellum of pcd mice. Collectively, these data support that nucleolar and CB alterations are hallmarks of DNA damage-induced neurodegeneration. © 2010 The Authors. Brain Pathology © 2010 International Society of Neuropathology.

  5. The feed-back regulation of erythropoietin production in healthy humans

    Energy Technology Data Exchange (ETDEWEB)

    Klausen, T

    1998-10-01

    The proposed oxygen-dependent feed-back loop regulation of EPO (erythropoietin) production is mainly supported by data from studies in animals and cell cultures. The feed-back loop and its dependence on oxygen was therefore challenged by studies in healthy humans: Exposure of humans to different levels of acute and continued altitude hypobaria provided evidence for an oxygen dependence of the EPO response. This response is consistent with the proposed feed-back loop regulation of EPO production; Exposure to continued altitude hypobaria demonstrated that the decline in human EPO production is initiated before an EPO-induced erythopoiesis is detectable, and that this decline is related to a concomitant decrease in the haemoglobin-oxygen affinity. Contrary to the feed-back loop, this time-relation indicate that the feed-back regulation of EPO production during continued hypobaric hypoxia is exerted primarily through a decrease in the haemoglobin-oxygen affinity, rather than by the effects of an EPO-stimulated erythropoiesis; Increased circulating levels of the proinflammatory cytokine IL-6 was found in healthy humans during four days of altitude exposure as compared with sea level. The other proinflammatory cytokines IL-1 beta, and TNF alpha remained unchanged, and the increased serum IL-6 did not induce production of c-reactive protein; Comparable circadian variations in human EPO production were shown in sedentary subjects, athletes, and healthy but hypoxaemic subjects. Human EPO production could not be triggered by one hour of high-intensity exercise, whereas longitudinal changes in exercise showed a trend of relation between human EPO production, serum concentration of free testosterone, and indices of body composition. These results have demonstrated and endogenous, probably hormonal, and oxygen-independent regulation of human EPO production, which is at variance with the oxygen dependent feed-back loop regulation of EPO production. Conclusively, the present

  6. Extension of activation cross section data of deuteron induced nuclear reactions on rhodium up to 50 MeV

    Energy Technology Data Exchange (ETDEWEB)

    Hermanne, A. [Cyclotron Laboratory, Vrije Universiteit Brussel, Brussels (Belgium); Tárkányi, F.; Takács, S.; Ditrói, F. [Institute of Nuclear Research of the Hungarian Academy of Sciences, Debrecen (Hungary)

    2015-11-01

    In the frame of the systematical study of light ion induced nuclear reactions activation cross sections for deuteron induced reactions on monoisotopic {sup 103}Rh were extended to 50 MeV incident energy. Excitation functions were measured in the 49.8–36.6 MeV energy range for the {sup 103}Rh(d,xn){sup 100,101}Pd, {sup 103}Rh(d,pxn){sup 99m,99g,100,101m,101g,102m,102g}Rh and {sup 103}Rh(d,x){sup 97,103}Ru reactions by using the stacked foil irradiation technique and off-line high resolution γ-ray spectrometry. The experimental results are compared to our previous results and to the theoretical predictions in the TENDL-2014 library (TALYS 1.6 code).

  7. Low Energy Nuclear Transmutation in Condensed Matter Induced by D2 Gas Permeation Through pd Complexes:. Correlation Between Deuterium Flux and Nuclear Products

    Science.gov (United States)

    Iwamura, Y.; Itoh, T.; Sakano, M.; Sakai, S.; Kuribayashi, S.

    2005-12-01

    Observations of low energy nuclear reactions induced by D2 gas permeation through Pd complexes (Pd/CaO/Pd) were presented at ICCF-91 and in a paper2 published in the Japanese Journal of Applied Physics. When Cs was added on the surface of a Pd complex, Pr emerged on the surface while Cs decreased after the Pd complex was subjected to D2 gas permeation. When Sr was added to the surface, Mo emerged while the Sr decreased after D2 gas permeation. The isotopic composition of the detected Mo was different from the natural abundance. In this paper, recent progress of our research is described. The detected Pr was confirmed by various methods such as TOF-SIMS, XANES, X-ray Fluorescence Spectrometry and ICP-MS. Analysis of the depth profile of Pr indicated that a very thin surface region up to 100 Å was the active transmutation zone. Many experimental results showed that the quantity of Pr was proportional to the deuterium flux through Pd complex. The cross-section of transmutation of Cs into Pr can be roughly estimated at 1 barn if we consider the deuterium flux as an ultra low energy deuteron beam.

  8. Production cross sections of radioisotopes from (3)He-particle induced nuclear reactions on natural titanium.

    Science.gov (United States)

    Szelecsényi, F; Kovács, Z; Nagatsu, K; Zhang, M-R; Suzuki, K

    2017-01-01

    Excitation functions were measured using the stacked-foil method for the (nat)Ti((3)He,x)(44m)Sc, (46m+g)Sc, (47)Sc, (48)Sc, (48)V and (48)Cr nuclear processes up to 68MeV. Our new cross-section data were compared with the earlier reported values as well as the evaluated theoretical predictions by means of the TALYS 1.6 code as compiled in the TENDL-2015 library. The new data show acceptable agreement with the previous experimental values in the overlapping energy regions, however only a partial agreement was found in the case of the results of the nuclear reaction model code. The present work not only strengthens the experimental datasets of the above processes but also provides new cross-section values above 36MeV where only one dataset is available for each reaction. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Folate rescues vitamin B12 depletion-induced inhibition of nuclear thymidylate biosynthesis and genome instability.

    Science.gov (United States)

    Palmer, Ashley M; Kamynina, Elena; Field, Martha S; Stover, Patrick J

    2017-05-16

    Clinical vitamin B12 deficiency can result in megaloblastic anemia, which results from the inhibition of DNA synthesis by trapping folate cofactors in the form of 5-methyltetrahydrofolate (5-methylTHF) and subsequent inhibition of de novo thymidylate (dTMP) biosynthesis. In the cytosol, vitamin B12 functions in the remethylation of homocysteine to methionine, which regenerates THF from 5-methylTHF. In the nucleus, THF is required for de novo dTMP biosynthesis, but it is not understood how 5-methylTHF accumulation in the cytosol impairs nuclear dTMP biosynthesis. The impact of vitamin B12 depletion on nuclear de novo dTMP biosynthesis was investigated in methionine synthase-null human fibroblast and nitrous oxide-treated HeLa cell models. The nucleus was the most sensitive cellular compartment to 5-methylTHF accumulation, with levels increasing greater than fourfold. Vitamin B12 depletion decreased de novo dTMP biosynthesis capacity by 5-35%, whereas de novo purine synthesis, which occurs in the cytosol, was not affected. Phosphorylated histone H2AX (γH2AX), a marker of DNA double-strand breaks, was increased in vitamin B12 depletion, and this effect was exacerbated by folate depletion. These studies also revealed that 5-formylTHF, a slow, tight-binding inhibitor of serine hydroxymethyltransferase (SHMT), was enriched in nuclei, accounting for 35% of folate cofactors, explaining previous observations that nuclear SHMT is not a robust source of one-carbons for de novo dTMP biosynthesis. These findings indicate that a nuclear 5-methylTHF trap occurs in vitamin B12 depletion, which suppresses de novo dTMP biosynthesis and causes DNA damage, accounting for the pathophysiology of megaloblastic anemia observed in vitamin B12 and folate deficiency.

  10. Modeled Neutron Induced Nuclear Reaction Cross Sections for Radiochemsitry in the region of Thulium, Lutetium, and Tantalum I. Results of Built in Spherical Symmetry in a Deformed Region

    Energy Technology Data Exchange (ETDEWEB)

    Hoffman, R. D. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2013-09-06

    We have developed a set of modeled nuclear reaction cross sections for use in radiochemical diagnostics. Systematics for the input parameters required by the Hauser-Feshbach statistical model were developed and used to calculate neutron induced nuclear reaction cross sections for targets ranging from Terbium (Z = 65) to Rhenium (Z = 75). Of particular interest are the cross sections on Tm, Lu, and Ta including reactions on isomeric targets.

  11. UVB-induced nuclear translocation of TC-PTP by AKT/14-3-3σ axis inhibits keratinocyte survival and proliferation.

    Science.gov (United States)

    Kim, Mihwa; Morales, Liza D; Baek, Minwoo; Slaga, Thomas J; DiGiovanni, John; Kim, Dae Joon

    2017-10-31

    Understanding protein subcellular localization is important to determining the functional role of specific proteins. T-cell protein tyrosine phosphatase (TC-PTP) contains bipartite nuclear localization signals (NLSI and NLSII) in its C-terminus. We previously have demonstrated that the nuclear form of TC-PTP (TC45) is mainly localized to the cytoplasm in keratinocytes and it is translocated to the nucleus following UVB irradiation. Here, we report that TC45 is translocated by an AKT/14-3-3σ-mediated mechanism in response to UVB exposure, resulting in increased apoptosis and decreased keratinocyte proliferation. We demonstrate that UVB irradiation increased phosphorylation of AKT and induced nuclear translocation of 14-3-3σ and TC45. However, inhibition of AKT blocked nuclear translocation of TC45 and 14-3-3σ. Site-directed mutagenesis of 14-3-3σ binding sites within TC45 showed that a substitution at Threonine 179 (TC45/T179A) effectively blocked UVB-induced nuclear translocation of ectopic TC45 due to the disruption of the direct binding between TC45 and 14-3-3σ. Overexpression of TC45/T179A in keratinocytes resulted in a decrease of UVB-induced apoptosis which corresponded to an increase in nuclear phosphorylated STAT3, and cell proliferation was higher in TC45/T179A-overexpressing keratinocytes compared to control keratinocytes following UVB irradiation. Furthermore, deletion of TC45 NLSII blocked its UVB-induced nuclear translocation, indicating that both T179 and NLSII are required. Taken together, our findings suggest that AKT and 14-3-3σ cooperatively regulate TC45 nuclear translocation in a critical step of an early protective mechanism against UVB exposure that signals the deactivation of STAT3 in order to promote keratinocyte cell death and inhibit keratinocyte proliferation.

  12. Lectin-binding assays for the isoforms of human erythropoietin: comparison of urinary and four recombinant erythropoietins.

    Science.gov (United States)

    Storring, P L; Tiplady, R J; Gaines Das, R E; Rafferty, B; Mistry, Y G

    1996-09-01

    Assays have been developed for the isoforms of erythropoietin (EPO) based on their binding to eight different lectins. These assays were used to compare the isoform compositions of two preparations of human urinary EPO (uEPO) and four preparations of recombinant DNA-derived human EPO (rEPO), which had been shown to differ in their biological and immunological properties and in their isoform composition as judged by isoelectric focusing and electrophoresis. Agarose-bound Ricinus communis agglutinin I (RCA), Erythrina cristagalli agglutinin (ECA), Maackia amurensis leukoagglutinin (MAL), Sambucus nigra agglutinin (SNA), Lycopersicon esculentum agglutinin (LEA), concanavalin A (Con A), Phaseolus vulgaris agglutinin-L4 (L-PHA) and Agaricus bisporus agglutinin (ABA) were used to bind EPO isoforms possessing: N-glycans containing non-sialylated outer Gal beta 1-4GlcNAc (RCA and ECA), NeuAc alpha 2-3Gal beta 1-4GlcNAc (MAL), NeuAc alpha 2-6Gal (SNA), or repeating Gal beta 1-4GlcNAc sequences (LEA); biantennary N-glycans (Con A); tetraantennary and 2,6-branched triantennary N-glycans (L-PHA); and O-glycans containing NeuAc alpha 2-6GalNAc (SNA) and Gal beta 1-3GalNAc (ABA). Free EPO was measured by mouse spleen cell bioassay or immunoassay. Estimates from most lectin-binding assays were reproducible between assays and batches of lectin-agarose, although batches of MAL- and ABA-agarose, and to a lesser extent LEA-agarose, differed in their EPO-binding. Lectin-binding assays showed differences between the isoform compositions of all EPOs, including the two Chinese hamster ovary cell-derived rEPOs, with RCA- and ECA-binding assays being the most discriminating. Lectin-binding estimates provided evidence that uEPO differs from these rEPOs in its lower content of isoforms with biantennary N-glycans and higher content of those with multiantennary N-glycans, and in its lower content of isoforms with N-glycans possessing repeating Gal beta 1-4GlcNAc sequences and of those with O

  13. v-Src-induced nuclear localization of YAP is involved in multipolar spindle formation in tetraploid cells.

    Science.gov (United States)

    Kakae, Keiko; Ikeuchi, Masayoshi; Kuga, Takahisa; Saito, Youhei; Yamaguchi, Naoto; Nakayama, Yuji

    2017-01-01

    The protein-tyrosine kinase, c-Src, is involved in a variety of signaling events, including cell division. We have reported that v-Src, which is a mutant variant of the cellular proto-oncogene, c-Src, causes delocalization of Aurora B kinase, resulting in a furrow regression in cytokinesis and the generation of multinucleated cells. However, the effect of v-Src on mitotic spindle formation is unknown. Here we show that v-Src-expressing HCT116 and NIH3T3 cells undergo abnormal cell division, in which cells separate into more than two cells. Upon v-Src expression, the proportion of multinucleated cells is increased in a time-dependent manner. Flow cytometry analysis revealed that v-Src increases the number of cells having a ≥4N DNA content. Microscopic analysis showed that v-Src induces the formation of multipolar spindles with excess centrosomes. These results suggest that v-Src induces multipolar spindle formation by generating multinucleated cells. Tetraploidy activates the tetraploidy checkpoint, leading to a cell cycle arrest of tetraploid cells at the G1 phase, in which the nuclear exclusion of the transcription co-activator YAP plays a critical role. In multinucleated cells that are induced by cytochalasin B and the Plk1 inhibitor, YAP is excluded from the nucleus. However, v-Src prevents this nuclear exclusion of YAP through a decrease in the phosphorylation of YAP at Ser127 in multinucleated cells. Furthermore, v-Src decreases the expression level of p53, which also plays a critical role in the cell cycle arrest of tetraploid cells. These results suggest that v-Src promotes abnormal spindle formation in at least two ways: generation of multinucleated cells and a weakening of the tetraploidy checkpoint. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. 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.

  15. 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......: Erythropoietin (Eprex) 100 IU/kg were administered subcutaneously weekly for 3 months prior to surgery in two cryptorchid boys, 6 months old and 1 year 9 months old, respectively, with renal function impairment. RESULTS: The number of spermatogonia per tubular cross-section in testicular biopsies was unusually...... 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...

  16. Bortezomib induces the formation of nuclear poly(A) RNA granules enriched in Sam68 and PABPN1 in sensory ganglia neurons.

    Science.gov (United States)

    Casafont, Iñigo; Berciano, Maria T; Lafarga, Miguel

    2010-02-01

    The ubiquitin-dependent proteasome system (UPS) is the major pathway responsible for selective nuclear and cytoplasmic protein degradation. Bortezomib, a boronic acid dipeptide, is a reversible 20S proteasome inhibitor used as novel anticancer drug, particularly in the treatment of multiple myeloma and certain lymphomas. Bortezomib-induced peripheral neuropathy (BIPN) is a widely recognized dose-limiting neurotoxicity of this proteasome inhibitor, which causes a significant negative impact on the quality of life. The pathogenic mechanisms underlying bortezomib neurotoxicity are little known. In this study a rat was used as our animal model to investigate the bortezomib-induced nuclear changes in dorsal root ganglia (DRG) neurons. Our results indicate that this neuronal population is an important target of bortezomib neurotoxicity. Nuclear changes include accumulation of ubiquitin-protein conjugates, reduction of transcriptional activity, and nuclear retention of poly(A) RNAs in numerous spherical or ring-shaped dense granules. They also contained the RNA-binding proteins PABPN1 (poly(A) binding protein nuclear 1) and Sam68, but lacked the mRNA nuclear export factors REF and Y14. At the cytoplasmic level, most neurons exhibited chromatolysis, supporting the inhibition of mRNA translation. Our results indicate that bortezomib interferes with transcription, nuclear processing and transport, and cytoplasmic translation of mRNAs in DRG neurons. They also support that this neuronal dysfunction is an essential pathogenic mechanism in the BIPN, which is characterized by sensory impairment including sensory ataxia.

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

    Science.gov (United States)

    2013-11-01

    Reserve University, Cleveland, OH. 2002 Acute Complications of Pericardial Disease or Injury. February 19th. Acute Complications of Diabetes Mellitus...Chile. [Arterial and venous prostagladin E2 levels in patients with valvular disease ]. Guarda E, Zamorano B, Gazmuri RJ, Escobar E. 1988 Best...AD Award Number: W81XWH-11-2-0019 TITLE: “Intraosseous Erythropoietin for Acute Tissue Protection in Battlefield Casualties

  18. 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...... no statistically significant group differences in the primary or secondary outcome measures. EPO was well tolerated. CONCLUSIONS: Beneficial effects of EPO in patients with SAH cannot be excluded or concluded on the basis of this study and larger scale trials are warranted....

  19. Erythropoietin in the critically ill: do we ask the right questions?

    OpenAIRE

    McCook, Oscar; Georgieff, Michael; Scheuerle, Angelika; M?ller, Peter; Thiemermann, Christoph; Radermacher, Peter

    2012-01-01

    There is a plethora of experimental data on the potential therapeutic benefits of recombinant human erythropoietin (rhEPO) and its synthetic derivatives in critical care medicine, in particular in ischemia/reperfusion injury. Most of the recent clinical trials have not shown clear benefits, and, in some patients, EPO-aggravated morbidity and mortality was even reported. Treatment with rhEPO has been successfully used in patients with anemia resulting from chronic kidney disease, but even a su...

  20. Short-term intra-nasal erythropoietin administration with low sialic acid content is without toxicity or erythropoietic effects.

    Science.gov (United States)

    Lagarto, Alicia; Bueno, Viviana; Sanchez, Jose A; Couret, Micaela; Valdes, Odalys; Barzaga, Pedro; Lopez, Raisell; Guerra, Isbel; Gabilondo, Tatiana; Vega, Yamile; Beausoleil, Irene

    2012-11-01

    The objective of this investigation was to assess the toxicological potential of nasal formulation of erythropoietin with low sialic acid content (Neuro EPO) after 28 days of intra-nasal dosing in rats besides to evaluate the immunogenicity and erythropoietic effect of the test substance. Healthy Wistar rats of both sexes were used for 28 days subacute toxicity and immunogenicity assays. Doses evaluated were 3450, 4830 and 6900 UI/kg/day. The toxicological endpoints examined included animal body weight, food consumption, hematological and biochemical patterns, antibodies determination, selected tissue weights and histopathological examination. Reversibility of toxic effects was evaluated at high dose 14 days after treatment period. Female B6D2F1 mice were used for evaluated erythropoietic effect of the nasal formulation. Hematological endpoints were examined every week during 28 days of intra-nasal dosing of 6900 UI/kg/day. Variations of hematological patterns were not observed after 28 days of intranasal dosing. A slight increase in glucose level of treated animals within the normal range was observed. This effect was not dose related and was reversible. Antibody formation was not observed in any of the test doses. Histopathological examination of organs and tissues did not reveal treatment induced changes. The administration of Neuro EPO in normocythaemic mice did not produce erythropoietic effect. These results suggest that Neuro EPO could be used as a neuroprotective agent, without significant systemic haematological side effects.

  1. Renal Anemia Model Mouse Established by Transgenic Rescue with an Erythropoietin Gene Lacking Kidney-Specific Regulatory Elements

    Science.gov (United States)

    Hirano, Ikuo; Suzuki, Norio; Yamazaki, Shun; Sekine, Hiroki; Minegishi, Naoko

    2016-01-01

    ABSTRACT The erythropoietin (Epo) gene is under tissue-specific inducible regulation. Because the kidney is the primary EPO-producing tissue in adults, impaired EPO production in chronic kidney disorders results in serious renal anemia. The Epo gene contains a liver-specific enhancer in the 3′ region, but the kidney-specific enhancer for gene expression in renal EPO-producing (REP) cells remains elusive. Here, we examined a conserved upstream element for renal Epo regulation (CURE) region that spans 17.4 kb to 3.6 kb upstream of the Epo gene and harbors several phylogenetically conserved elements. We prepared various Epo gene-reporter constructs utilizing a bacterial artificial chromosome and generated a number of transgenic-mouse lines. We observed that deletion of the CURE region (δCURE) abrogated Epo gene expression in REP cells. Although transgenic expression of the δCURE construct rescued Epo-deficient mice from embryonic lethality, the rescued mice had severe EPO-dependent anemia. These mouse lines serve as an elaborate model for the search for erythroid stimulatory activity and are referred to as AnRED (anemic model with renal EPO deficiency) mice. We also dissected the CURE region by exploiting a minigene harboring four phylogenetically conserved elements in reporter transgenic-mouse analyses. Our analyses revealed that Epo gene regulation in REP cells is a complex process that utilizes multiple regulatory influences. PMID:27920250

  2. Stabilization and encapsulation of recombinant human erythropoietin into PLGA microspheres using human serum albumin as a stabilizer.

    Science.gov (United States)

    He, Jintian; Feng, Meiyan; Zhou, Xianglian; Ma, Shufen; Jiang, Yang; Wang, Ying; Zhang, Hongxia

    2011-09-15

    The aim of this study was to prepare recombinant human erythropoietin (rhEPO) loaded poly(lactic-co-glycolic acid) (PLGA) microspheres using human serum albumin (HSA) as a stabilizer. Prior to encapsulation, the rhEPO-HSA mixture microparticles were fabricated using a modified freezing-induced phase separation method. The microparticles were subsequently encapsulated into PLGA microspheres. Process optimization revealed that the polymer concentration in the organic phase and the sodium chloride (NaCl) concentration in the outer water phase of the s/o/w emulsion played critical roles in determining the properties of the resultant microspheres. An in vitro release test showed that rhEPO was released from PLGA microspheres in a sustained manner up to 30 days. A single injection of rhEPO-loaded PLGA microspheres in Sprague-Dawley rats resulted in elevated hemoglobin and red blood cell concentrations for about 33 days. The stability of the rhEPO within the PLGA microspheres was systematically investigated by size-exclusion high-performance liquid chromatography (SEC-HPLC), SDS-PAGE, western blot and in vivo biological activity assay. The stability of rhEPO released from rhEPO-loaded microspheres was also examined by western blot. The results suggested that the integrity of rhEPO was successfully protected during the encapsulation process and the release period from polymeric matrices. Copyright © 2011 Elsevier B.V. All rights reserved.

  3. Cytokine combination therapy with erythropoietin and granulocyte colony stimulating factor in a porcine model of acute myocardial infarction.

    Science.gov (United States)

    Angeli, Franca S; Amabile, Nicolas; Shapiro, Mia; Mirsky, Rachel; Bartlett, Lauren; Zhang, Yan; Virmani, Renu; Chatterjee, Kanu; Boyle, Andrew; Grossman, William; Yeghiazarians, Yerem

    2010-12-01

    Erythropoietin (EPO) and granulocyte colony stimulating factor (GCSF) have generated interest as novel therapies after myocardial infarction (MI), but the effect of combination therapy has not been studied in the large animal model. We investigated the impact of prolonged combination therapy with EPO and GCSF on cardiac function, infarct size, and vascular density after MI in a porcine model. MI was induced in pigs by a 90 min balloon occlusion of the left anterior descending coronary artery. 16 animals were treated with EPO+GCSF, or saline (control group). Cardiac function was assessed by echocardiography and pressure-volume measurements at baseline, 1 and 6 weeks post-MI. Histopathology was performed 6 weeks post-MI. At week 6, EPO+GCSF therapy stabilized left ventricular ejection fraction, (41 ± 1% vs. 33 ± 1%, p < 0.01) and improved diastolic function compared to the control group. Histopathology revealed increased areas of viable myocardium and vascular density in the EPO+GCSF therapy, compared to the control. Despite these encouraging results, in a historical analysis comparing combination therapy with monotherapy with EPO or GCSF, there were no significant additive benefits in the LVEF and volumes overtime using the combination therapy. Our findings indicate that EPO+GCSF combination therapy promotes stabilization of cardiac function after acute MI. However, combination therapy does not seem to be superior to monotherapy with either EPO or GCSF.

  4. Wear measurement using radioactive tracer technique based on proton, deuteron and {alpha}-particle induced nuclear reactions on molybdenum

    Energy Technology Data Exchange (ETDEWEB)

    Ditroi, F., E-mail: ditroi@atomki.hu [Institute of Nuclear Research of the Hungarian Academy of Sciences (ATOMKI), H-4026 Debrecen, Bem ter 18/c (Hungary); Tarkanyi, F.; Takacs, S. [Institute of Nuclear Research of the Hungarian Academy of Sciences (ATOMKI), H-4026 Debrecen, Bem ter 18/c (Hungary)

    2012-11-01

    Highlights: Black-Right-Pointing-Pointer Proton, deuteron, {sup 3}He and {alpha}-particle activation of Mo. Black-Right-Pointing-Pointer TLA (thin layer activation). Black-Right-Pointing-Pointer Wear measurement. Black-Right-Pointing-Pointer Integral production yields. Black-Right-Pointing-Pointer Wear curves (specific activity versus penetration depth). - Abstract: Excitation functions of light ion induced nuclear reactions on natural molybdenum have been studied in the frame of a systematic investigation of charged particle induced nuclear reactions on metals for various applications. Excitation functions of {sup 93,94g,94m,95g,95m,96,99m}Tc, {sup 90,93m,99}Mo, {sup 90,91m,92m,95m,95g,96}Nb and {sup 88,89}Zr were measured up to 50 MeV deuteron energy Tarkanyi et al., 2012 [1], {sup 93m,93g,94m,94g,95m,95g,96g,99m}Tc, {sup 90,93m,99}Mo, {sup 90,92m,95m,95g,96}Nb and {sup 88,89}Zr were measured up to 40 MeV proton energy Tarkanyi et al., 2012 [2] and {sup 93m,93g,94m,94g,95m,95g,96g,99m}Tc, {sup 93m,99}Mo, {sup 90}Nb, {sup 94,95,97,103}Ru and {sup 88}Zr were measured up to 40 MeV alpha energy Ditroi et al., 2012 [3] by using the stacked foil technique and activation method. The results for {sup 3}He induced reactions on natural Mo were taken from the literature Comparetto and Qaim, 1980 [4]. According to their half-lives, from the above listed radionuclides the {sup 95m,96}Tc, {sup 91m,92m,95m,95g}Nb, {sup 99}Mo, {sup 103,97}Ru and {sup 88}Zr are suitable candidates for wear measurement by using thin layer activation (TLA) method. The goal of this work was to determine the necessary nuclear data for TLA of the above radionuclides and to prove their applicability for wear measurements.

  5. Effects of acute exercise on plasma erythropoietin levels in trained runners.

    Science.gov (United States)

    Bodary, P F; Pate, R R; Wu, Q F; McMillan, G S

    1999-04-01

    The purpose of this study was to investigate further the influence of exercise on erythropoietin. We observed the effects of high intensity running on plasma erythropoietin concentration in competitive distance runners. A repeated measures design was used to compare the responses of intermittent high intensity (HIGH) exercise to continuous moderate intensity (MOD) exercise and rest (REST). The HIGH treatment consisted of 60 min of exercise alternating 5 min of running at approximately 90% of VO2max with 5 min of brisk walking. The MOD treatment consisted of a continuous 60-min run on the treadmill at 60% of VO2max. Blood samples were collected immediately before the exercise (PRE), immediately following the exercise (POST), and 4 (heart rate (4HR), 12 (12HR), 24 (24HR), and 48 (48HR)) h following the exercise. The variables examined included plasma erythropoietin concentration ([EPO]), hemoglobin (Hb) concentration ([Hb]), hematocrit (Hct), red blood cell count (RBC), and mean corpuscular volume (MCV). ANOVA revealed the expected treatment-by-time interaction for Hct and [Hb] suggesting a hemodilution at 24 and 48 h postexercise for the MOD and HIGH treatments. However, no significant treatment-by-time interactions were observed for [EPO], RBC, or MCV. These results indicate that intermittent high intensity exercise does not have a significant effect on [EPO] in trained distance runners.

  6. The role of cytochrome c on apoptosis induced by Anagrapha falcifera multiple nuclear polyhedrosis virus in insect Spodoptera litura cells.

    Directory of Open Access Journals (Sweden)

    Kaiyu Liu

    Full Text Available There are conflicting reports on the role of cytochrome c during insect apoptosis. Our previous studies have showed that cytochrome c released from the mitochondria was an early event by western blot analysis and caspase-3 activation was closely related to cytochrome c release during apoptosis induced by baculovirus in Spodoptera litura cells (Sl-1 cell line. In the present study, alteration in mitochondrial morphology was observed by transmission electron microscopy, and cytochrome c release from mitochondria in apoptotic Sl-1 cells induced with Anagrapha falcifera multiple nuclear polyhedrosis virus (AfMNPV has further been confirmed by immunofluoresence staining protocol, suggesting that structural disruption of mitochondria and the release of cytochrome c are important events during Lepidoptera insect cell apoptosis. We also used Sl-1 cell-free extract system and the technique of RNA interference to further investigate the role of cytochrome c in apoptotic Sl-1 cells induced by AfMNPV. Caspase-3 activity in cell-free extracts supplemented with exogenous cytochrome c was determined and showed an increase with the extension of incubation time. DsRNA-mediated silencing of cytochrome c resulted in the inhibition of apoptosis and protected the cells from AfMNPV-induced cell death. Silencing of expression of cytochrome c had a remarkable effect on pro-caspase-3 and pro-caspase-9 activation and resulted in the reduction of caspase-3 and caspase-9 activity in Sl-1 cells undergoing apoptosis. Caspase-9 inhibitor could inhibit activation of pro-caspase-3, and the inhibition of the function of Apaf-1 with FSBA blocked apoptosis, hinting that Apaf-1 could be involved in Sl-1 cell apoptosis induced by AfMNPV. Taken together, these results strongly demonstrate that cytochrome c plays an important role in apoptotic signaling pathways in Lepidopteran insect cells.

  7. Specific binding of sup 125 I-rErythropoietin to Friend polycythemia virus-transformed erythroleukemia cells purified by centrifugal elutriation

    Energy Technology Data Exchange (ETDEWEB)

    Correa, P.N.; Bard, V.; Axelrad, A.A. (Univ. of Toronto (Canada))

    1990-01-01

    We have used countercurrent centrifugal elutriation (CCE) to determine the distribution of cells with respect to cell volume and buoyant density for an erythroleukemia cell line (JG6) transformed by the polycythemia strain of Friend virus (FV-P), and to determine the effect of inducing the cells to differentiate with dimethylsulfoxide (DMSO) on this distribution. CCE made it possible to obtain suspensions of modal JG6 populations virtually free of dead cells and uniform with respect to volume and buoyant density. These modal populations were assayed for specific binding of erythropoietin (Epo). Between 500 and 550 Epo receptors per cell were detected. These belonged to a single class having a dissociation constant of 0.36 nM. DMSO induction of differentiation of the JG6 cells had no effect on the number of Epo receptors expressed.

  8. 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

  9. Pycnogenol Induces Nuclear Translocation of Apoptosis-inducing Factor and Caspase-independent Apoptosis in MC-3 Human Mucoepidermoid Carcinoma Cell Line.

    Science.gov (United States)

    Yang, In-Hyoung; Shin, Ji-Ae; Cho, Sung-Dae

    2014-12-01

    Pycnogenol is extracted from the pine bark of a tree known as Pinus pinaster that has variety biological effects. However, its anticancer activity has not yet been completely studied. The aim of this study is to investigate anticancer effect of pycnogenol in MC-3 human mucoepidermoid carcinoma (MEC) cell line. We describe the effect of anti-cancer of pycnogenol in MC-3 human oral MEC cells using trypan blue exclusion assay, 3-(4,5-dimethylthiazol-2-yl)-(3-carboxymethoxyphenyl)-2-(4-sulphophenyl)-2H-tetrazolium (MTS) assay, Western blot, preparation of cytosolic and nuclear fractions, immunocytochemistry and reverse transcriptase polymerase chain reaction. Pycnogenol significantly decreased cell viability and also induced caspase-independent apoptosis. We confirmed that pycnogenol induced the translocation of apoptosis-inducing factor into nucleus and regulated apoptosis. Also, Bak protein stability was partly enhanced by pycnogenol to elevate the expression level of Bak protein. Overall, pycnogenol may be a fascinating therapeutic drug candidate for the treatment of MEC.

  10. Matrine induces caspase-independent program cell death in hepatocellular carcinoma through bid-mediated nuclear translocation of apoptosis inducing factor.

    Science.gov (United States)

    Zhou, Huan; Xu, Minying; Gao, Ya; Deng, Zhigang; Cao, Hanwei; Zhang, Wenqing; Wang, Qiao; Zhang, Bing; Song, Gang; Zhan, Yanyan; Hu, Tianhui

    2014-03-16

    Matrine, a clinical drug in China, has been used to treat viral hepatitis, cardiac arrhythmia and skin inflammations. Matrine also exhibits chemotherapeutic potential through its ability to trigger cancer cell death. However, the mechanisms involved are still largely unknown. The objective of this study was to investigate the major determinant for the cell death induced by matrine in human hepatocellular carcinoma. We use human hepatocellular carcinoma cell line HepG2 and human hepatocellular carcinoma xenograft in nude mice as models to study the action of matrine in hepatocellular cancers. We found that caspase-dependent and -independent Program Cell Death (PCD) occurred in matrine-treated HepG2 cells, accompanied by the decreasing of mitochondrial transmembrane potential and the increasing ROS production. Further studies showed that AIF released from the mitochondria to the nucleus, and silencing of AIF reduced the caspase-independent PCD induced by matrine. What's more, AIF nuclear translocation, and the subsequent cell death as well, was prevented by Bid inhibitor BI-6C9, Bid-targeted siRNA and ROS scavenger Tiron. In the in vivo study, matrine significantly attenuated tumor growth with AIF release from mitochondria into nucleus in nude mice. These data imply that matrine potently induce caspase-independent PCD in HepG2 cells through Bid-mediated AIF translocation.

  11. Nuclear expression of hypoxia-inducible factor-1alpha in clear cell renal cell carcinoma is involved in tumor progression.

    Science.gov (United States)

    Di Cristofano, Claudio; Minervini, Andrea; Menicagli, Michele; Salinitri, Giuseppe; Bertacca, Gloria; Pefanis, Gerasimos; Masieri, Lorenzo; Lessi, Francesca; Collecchi, Paola; Minervini, Riccardo; Carini, Marco; Bevilacqua, Generoso; Cavazzana, Andrea

    2007-12-01

    The most frequent genomic abnormality in clear cell renal cell carcinoma (cc-RCC) is inactivation of Von Hippel-Lindau gene (VHL). pVHL19 is a ligase promoting proteosomal degradation of hypoxia-inducible factor-1alpha (HIF-1alpha); pVHL30 is associated with microtubules. VHL exert its oncogenetic action both directly and through HIF-1alpha activation. TNM classification is unable to define a correct prognostic evaluation of intracapsular cc-RCC. The nucleo-cytoplasmic trafficking in VHL/HIF-1alpha pathway could be relevant in understanding the molecular pathogenesis of renal carcinogenesis. This study analyzes VHL/HIF-1alpha proteins in a large series of intracapsular cc-RCCs, correlating their expression and cellular localization with prognosis. Two anti-pVHL (clones Ig32 and Ig33) and 1 anti-HIF-1alpha were used on tissue microarrays from 136 intracapsular cc-RCCs (mean follow-up: 74 mo). Clone 32 recognizes both pVHLs, whereas clone 33 only pVHL30. Results were matched with clinicopathologic variables and tumor-specific survival (TSS). A strong cytoplasmic positivity was found for all antibodies in the largest part of cases, associated to a strong nuclear localization in the case of HIF-1alpha. All pVHL-negative cases were associated with high HIF-1alpha expression. pVHL negativity and HIF-1alpha nuclear positivity significantly correlated with shorter TSS. In multivariate analysis both pVHL negativity and HIF-1alpha nuclear expression were independent predictors of TSS. The localization of the proteins well matches with their role and with the supposed tumor molecular pathways. The correlation with prognosis of VHL/HIF-1alpha alterations confirms the relevance of their molecular pathway and of the cellular trafficking of their products in the pathogenesis of renal cancer.

  12. Nuclear Dependence of Proton-Induced Drell-Yan Dimuon Production at 120 GeV at Seaquest

    Energy Technology Data Exchange (ETDEWEB)

    Dannowitz, Bryan P. [Illinois U., Urbana

    2016-01-01

    A measurement of the atomic mass (A) dependence of p + A → µ+µ- + X Drell-Yan dimuons produced by 120 GeV protons is presented here. The data was taken by the SeaQuest experiment at Fermilab using a proton beam extracted from its Main Injector. Over 61,000 dimuon pairs were recorded with invariant mass 4.2 < Mγ* < 10 GeV and target parton momentum fraction 0.1 ≤ x2 ≤ 0.5 for nuclear targets 1H, 2H, C, Fe, and W . The ratio of dimuon yields per nucleon (Y ) for heavy nuclei versus 2H, RDY = 2 2 Y (A)/Y ( H) ≈ u¯(A)(x)/u¯( H)(x), is sensitive to modifications in the anti-quark sea distributions in nuclei for the case of proton-induced Drell-Yan. The data analyzed here and in the future of SeaQuest will provide tighter constraints on various models that attempt to define the anomalous behavior of nuclear modification as seen in deep inelastic lepton scattering, a phenomenon generally known as the EMC effect.

  13. Transmutation prospect of long-lived nuclear waste induced by high-charge electron beam from laser plasma accelerator

    Science.gov (United States)

    Wang, X. L.; Xu, Z. Y.; Luo, W.; Lu, H. Y.; Zhu, Z. C.; Yan, X. Q.

    2017-09-01

    Photo-transmutation of long-lived nuclear waste induced by a high-charge relativistic electron beam (e-beam) from a laser plasma accelerator is demonstrated. A collimated relativistic e-beam with a high charge of approximately 100 nC is produced from high-intensity laser interaction with near-critical-density (NCD) plasma. Such e-beam impinges on a high-Z convertor and then radiates energetic bremsstrahlung photons with flux approaching 1011 per laser shot. Taking a long-lived radionuclide 126Sn as an example, the resulting transmutation reaction yield is the order of 109 per laser shot, which is two orders of magnitude higher than obtained from previous studies. It is found that at lower densities, a tightly focused laser irradiating relatively longer NCD plasmas can effectively enhance the transmutation efficiency. Furthermore, the photo-transmutation is generalized by considering mixed-nuclide waste samples, which suggests that the laser-accelerated high-charge e-beam could be an efficient tool to transmute long-lived nuclear waste.

  14. Ultrafast x-ray-induced nuclear dynamics in diatomic molecules using femtosecond x-ray-pump–x-ray-probe spectroscopy

    Energy Technology Data Exchange (ETDEWEB)

    Lehmann, C. S.; Picón, A.; Bostedt, C.; Rudenko, A.; Marinelli, A.; Moonshiram, D.; Osipov, T.; Rolles, D.; Berrah, N.; Bomme, C.; Bucher, M.; Doumy, G.; Erk, B.; Ferguson, K. R.; Gorkhover, T.; Ho, P. J.; Kanter, E. P.; Krässig, B.; Krzywinski, J.; Lutman, A. A.; March, A. M.; Ray, D.; Young, L.; Pratt, S. T.; Southworth, S. H.

    2016-07-01

    The availability at x-ray free electron lasers of generating two intense, femtosecond x-ray pulses with controlled time delay opens the possibility of performing time-resolved experiments for x-ray induced phenomena. We have applied this capability to molecular dynamics. In diatomic molecules composed of low-Z elements, K-shell ionization creates a core-hole state in which the main decay is an Auger process involving two electrons in the valence shell. After Auger decay, the nuclear wavepackets of the transient two-valence-hole states continue evolving on the femtosecond timescale, leading either to separated atomic ions or long-lived quasi-bound states. By using an x-ray pump and an x-ray probe pulse tuned above the K-shell ionization threshold of the nitrogen molecule, we are able to observe ion dissociation in progress by measuring the time-dependent kinetic energy releases of different breakup channels. We simulated the measurements on N2 with a molecular dynamics model that accounts for K-shell ionization, Auger decay, and time evolution of the nuclear wavepackets. In addition to explaining the time-dependent feature in the measured kinetic energy release distributions from the dissociative states, the simulation also reveals the contributions of quasi-bound states.

  15. Nuclear transcriptome profiling of induced pluripotent stem cells and embryonic stem cells identify non-coding loci resistant to reprogramming.

    Science.gov (United States)

    Fort, Alexandre; Yamada, Daisuke; Hashimoto, Kosuke; Koseki, Haruhiko; Carninci, Piero

    2015-01-01

    Identification of functionally relevant differences between induced pluripotent stem cells (iPSC) and reference embryonic stem cells (ESC) remains a central question for therapeutic applications. Differences in gene expression between iPSC and ESC have been examined by microarray and more recently with RNA-SEQ technologies. We here report an in depth analyses of nuclear and cytoplasmic transcriptomes, using the CAGE (cap analysis of gene expression) technology, for 5 iPSC clones derived from mouse lymphocytes B and 3 ESC lines. This approach reveals nuclear transcriptomes significantly more complex in ESC than in iPSC. Hundreds of yet not annotated putative non-coding RNAs and enhancer-associated transcripts specifically transcribed in ESC have been detected and supported with epigenetic and chromatin-chromatin interactions data. We identified super-enhancers transcriptionally active specifically in ESC and associated with genes implicated in the maintenance of pluripotency. Similarly, we detected non-coding transcripts of yet unknown function being regulated by ESC specific super-enhancers. Taken together, these results demonstrate that current protocols of iPSC reprogramming do not trigger activation of numerous cis-regulatory regions. It thus reinforces the need for already suggested deeper monitoring of the non-coding transcriptome when characterizing iPSC clones. Such differences in regulatory transcript expression may indeed impact their potential for clinical applications.

  16. Cross section measurements of deuteron induced nuclear reactions on natural tungsten up to 34 MeV.

    Science.gov (United States)

    Duchemin, C; Guertin, A; Haddad, F; Michel, N; Métivier, V

    2015-03-01

    (186g)Re is a β-/γ emitter of great interest for nuclear medicine. It has shown successful results on bone metastases palliation and has similar chemical properties as (99m)Tc, the most commonly used imaging agent. (186g)Re is routinely produced using rhenium target in nuclear reactor. Higher specific activity could be obtained using accelerators. In this paper, production cross section values are presented for the (nat)W(d,x)(186g)Re reaction up to 34MeV, using the stacked-foils method and gamma spectrometry. From this data set, the thick target production yield of (186g)Re is determined and compared with the validated values of the IAEA and also with the proton route. The production cross sections of the (nat)W(d,x)(183,182g,184m,184g,181)Re and (nat)W(d,x)(187)W reactions have also been determined. A good agreement is found with the literature. Our data are compared with the version 1.6 (December 2013) of the TALYS code which shows discrepancies both on the shape and on the amplitude for these deuteron induced reactions. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. Erythropoietin activates the phosporylated cAMP [adenosine 3'5' cyclic monophosphate] response element-binding protein pathway and attenuates delayed paraplegia after ischemia-reperfusion injury.

    Science.gov (United States)

    Mares, Joshua M; Foley, Lisa S; Bell, Marshall T; Bennett, Daine T; Freeman, Kirsten A; Meng, Xianzhong; Weyant, Michael J; Cleveland, Joseph C; Fullerton, David A; Puskas, Ferenc; Reece, Thomas Brett

    2015-03-01

    Paraplegia remains a devastating complication of complex aortic surgery. Erythropoietin (EPO) has been shown to prevent paraplegia after ischemia reperfusion, but the protective mechanism remains poorly described in the spinal cord. We hypothesized that EPO induces the CREB (cAMP [adenosine 3'5' cyclic monophosphate] response element-binding protein) pathway and neurotrophin production in the murine spinal cord, attenuating functional and cellular injury. Adult male mice were subjected to 4 minutes of spinal cord ischemia via an aortic and left subclavian cross-clamp. Experimental groups included EPO treatment 4 hours before incision (n = 7), ischemic control (n = 7), and shams (n = 4). Hind-limb function was assessed using the Basso motor score for 48 hours after reperfusion. Spinal cords were harvested and analyzed for neuronal viability using histology and staining with a fluorescein derivative. Expression of phosphorylated (p)AKT (a serine/threonine-specific kinase), pCREB, B-cell lymphoma 2, and brain-derived neurotrophic factor were determined using immunoblotting. By 36 hours of reperfusion, EPO significantly preserved hind-limb function after ischemia-reperfusion injury (P < .01). Histology demonstrated preserved cytoarchitecture in the EPO treatment group. Cords treated with EPO expressed significant increases in pAKT (P = .021) and pCREB (P = .038). Treatment with EPO induced expression of both of the neurotrophins, B-cell lymphoma 2, and brain-derived neurotrophic factor, beginning at 12 hours. Erythropoietin-mediated induction of the CREB pathway and production of neurotrophins is associated with improved neurologic function and increased neuronal viability following spinal cord ischemia reperfusion. Further elucidation of EPO-derived neuroprotection will allow for expansion of adjunct mechanisms for spinal cord protection in high-risk thoracoabdominal aortic intervention. Copyright © 2015 The American Association for Thoracic Surgery. Published by

  18. Heavy component of spent nuclear fuel: Efficiency of model-substance ionization by electron-induced discharge

    Energy Technology Data Exchange (ETDEWEB)

    Antonov, N. N., E-mail: antonovnickola@gmail.com; Gavrikov, A. V.; Samokhin, A. A.; Smirnov, V. P. [Russian Academy of Sciences, High Energy Density Research Center, Joint Institute for High Temperatures (Russian Federation)

    2016-12-15

    The method of plasma separation of spent nuclear fuel can be tested with a model substance which has to be transformed from the condensed to plasma state. For this purpose, electron-induced discharge in lead vapor injected into the interelectrode gap is simulated using the kinetic approach. The ionization efficiency, the electrostatic-potential distribution, and those of the ion and electron densities in the discharge gap are derived as functions of the discharge-current density and concentration of the vapor of the model substance. Given a discharge-current density of 3.5 A/cm{sup 2} and a lead-vapor concentration of 2 × 10{sup 12} cm{sup –3}, the simulated ionization efficiency proves to be nearly 60%. The discharge in lead vapor is also investigated experimentally.

  19. AN EVALUATION OF HYDROGEN INDUCED CRACKING SUSCEPTIBILITY OF TITANIUM ALLOYS IN US HIGH-LEVEL NUCLEAR WASTE REPOSITORY ENVIRONMENTS

    Energy Technology Data Exchange (ETDEWEB)

    G. De; K. Mon; G. Gordon; D. Shoesmith; F. Hua

    2006-02-21

    This paper evaluates hydrogen-induced cracking (HIC) susceptibility of titanium alloys in environments anticipated in the Yucca Mountain nuclear waste repository with particular emphasis on the. effect of the oxide passive film on the hydrogen absorption process of titanium alloys being evaluated. The titanium alloys considered in this review include Ti 2, 5 , 7, 9, 11, 12, 16, 17, 18, 24 and 29. In general, the concentration of hydrogen in a titanium alloy can increase due to absorption of atomic hydrogen produced from passive general corrosion of that alloy or galvanic coupling of it to a less noble metal. It is concluded that under the exposure conditions anticipated in the Yucca Mountain repository, the HIC of titanium drip shield will not occur because there will not be sufficient hydrogen in the metal even after 10,000 years of emplacement. Due to the conservatisms adopted in the current evaluation, this assessment is considered very conservative.

  20. Cross sections of proton induced nuclear reactions on natural cadmium leading to the formation of radionuclides of indium

    Energy Technology Data Exchange (ETDEWEB)

    Al-Saleh, F.S. [Physics Dept., Girls Coll. of Education, Riyadh Univ. for Women, Riyadh (Saudi Arabia)

    2008-07-01

    Cross sections of proton induced nuclear reactions on {sup nat}Cd, leading to the formation of {sup 110g}In,{sup 111}In,{sup 113m}In, and {sup 116ml}In for energies up to 14.7 MeV were measured using the stacked-foil irradiation technique and high resolution gamma-ray spectroscopy. Our experimental data were analyzed and the excitation functions for the studied radionuclides were compared with the previously reported data. Model codes ALICE-IPPE and EMPIRE-II were used for calculating the excitation functions theoretically. Integral yields of the radionuclides {sup 110g}In,{sup 111}In,{sup 113m}In and {sup 116ml}In were also calculated. (orig.)

  1. Boron-Proton Nuclear-Fusion Enhancement Induced in Boron-Doped Silicon Targets by Low-Contrast Pulsed Laser

    Directory of Open Access Journals (Sweden)

    A. Picciotto

    2014-08-01

    Full Text Available We show that a spatially well-defined layer of boron dopants in a hydrogen-enriched silicon target allows the production of a high yield of alpha particles of around 10^{9} per steradian using a nanosecond, low-contrast laser pulse with a nominal intensity of approximately 3×10^{16}  W cm^{−2}. This result can be ascribed to the nature of the long laser-pulse interaction with the target and with the expanding plasma, as well as to the optimal target geometry and composition. The possibility of an impact on future applications such as nuclear fusion without production of neutron-induced radioactivity and compact ion accelerators is anticipated.

  2. Thapsigargin-induced nuclear calcium signals in rat basophilic leukaemia cells.

    OpenAIRE

    Horikoshi, Y; Furuno, T; Teshima, R; Sawada, J; Nakanishi, M

    1994-01-01

    By a confocal fluorescence microscope with an argon-ion laser (488 nm) and a He-Cd laser (325 nm) we have studied thapsigargin-induced calcium signals in individual rat basophilic leukaemia (RBL-2H3) cells. In the presence or absence of external calcium ions, thapsigargin-induced calcium signals were transferred to the nucleus as well as to the cytoplasm of RBL-2H3 cells. The calcium signals were generally much stronger in the nucleus than in the cytoplasm. However, some of the RBL-2H3 cells ...

  3. Erythropoietin attenuates pulmonary vascular remodeling in experimental pulmonary arterial hypertension through interplay between endothelial progenitor cells and heme-oxygenase

    Directory of Open Access Journals (Sweden)

    Rosa L.E. Loon

    2015-08-01

    Full Text Available BackgroundPulmonary 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 progenitor cells (EPCs and activation of the cytoprotective enzyme heme oxygenase-1 (HO1.MethodsRats with flow-associated PAH, resembling pediatric PAH, were treated with HO-1 inducer EPO in the presence or absence of the selective HO-activity-inhibitor tin-mesoporphyrin (SnMP. HO-activity, circulating EPCs and pulmonary vascular lesions were assessed after 3 weeks.ResultsIn PAH-rats, circulating EPCs were decreased and HO-activity was increased compared to control. EPO-treatment restored circulating EPCs and improved pulmonary vascular remodeling, as shown by a reduced wall thickness and occlusion rate of the intra-acinar vessels. Inhibition of HO-activity with SnMP aggravated PAH. Moreover, SnMP treatment abrogated EPO-induced amelioration of pulmonary vascular remodeling, while surprisingly further increasing circulating EPCs as compared with EPO alone.ConclusionsIn experimental PAH, EPO treatment restored the number of circulating EPC’s to control level, improved pulmonary vascular remodeling, and showed important interplay with HO-activity. Inhibition of increased HO-activity in PAH-rats exacerbated progression of pulmonary vascular remodeling, despite the presence of restored numbers of circulating EPC’s. We suggest that both EPO-induced HO1 and EPCs are promising targets to ameliorate the pulmonary vasculature in PAH.

  4. Real-time mode detection of heavy ion-induced nuclear reaction products

    CERN Document Server

    Tsyganov, Yu S; Polyakov, A N; Yakushev, A B; Vakatov, V I

    2002-01-01

    Design of spectrometers of two nuclear research facilities, the Dubna Gas-filled Recoil Separator and KHIPTI is reviewed. The sources of backgrounds are discussed and techniques used to suppress these backgrounds in one-event detection experiments aimed at the synthesis of heavy elements are presented. The first system was used in 1998 in experiments on Z=114 superheavy element. We consider the possibility of detection of rare time and position correlated recoil-alpha and alpha-alpha sequences in real-time mode as basic techniques to suppress beam and target-like associated backgrounds. Fields of application of such a technique are discussed from the viewpoint of synthesis of heavy elements and by studying their chemical properties.

  5. Nuclear receptor CAR represses TNFalpha-induced cell death by interacting with the anti-apoptotic GADD45B.

    Directory of Open Access Journals (Sweden)

    Yukio Yamamoto

    2010-04-01

    Full Text Available Phenobarbital (PB is the most well-known among numerous non-genotoxic carcinogens that cause the development of hepatocellular carcinoma (HCC. PB activates nuclear xenobiotic receptor Constitutive Active/Androstane Receptor (CAR; NR1I3 and this activation is shown to determine PB promotion of HCC in mice. The molecular mechanism of CAR-mediated tumor promotion, however, remains elusive at the present time. Here we have identified Growth Arrest and DNA Damage-inducible 45beta (GADD45B as a novel CAR target, through which CAR represses cell death.PB activation of nuclear xenobiotic receptor CAR is found to induce the Gadd45b gene in mouse liver throughout the development of HCC as well as in liver tumors. Given the known function of GADD45B as a factor that represses Mitogen-activated protein Kinase Kinase 7 - c-Jun N-terminal Kinase (MKK7-JNK pathway-mediated apoptosis, we have now demonstrated that CAR interacts with GADD45B to repress Tumor Necrosis Factor alpha ( TNFalpha-induced JNK1 phosphorylation as well as cell death. Primary hepatocytes, prepared from Car(+/+, Car(-/-, Gadd45b(+/+ and Gadd45b(-/- mice, were treated with TNFalpha and Actinomycin D to induce phosphorylation of JNK1 and cell death. Co-treatment with the CAR activating ligand TCPOBOP (1,4 bis[2-(3,5-dichloropyridyloxy]benzene has resulted in repression of both phosphorylation and cell death in the primary hepatocytes from Car(+/+ but not Car(-/- mice. Repression by TCPOBOP was not observed in those prepared from Gadd45b(-/- mice. In vitro protein-protein interaction and phosphorylation assays have revealed that CAR interacts with MKK7 and represses the MKK7-mediated phosphorylation of JNK1.CAR can form a protein complex with GADD45B, through which CAR represses MKK7-mediated phosphorylation of JNK1. In addition to activating the Gadd45b gene, CAR may repress death of mouse primary hepatocytes by forming a GADD45B complex and repressing MKK7-mediated phosphorylation of JNK1

  6. Review: Placental perturbations induce the developmental abnormalities often observed in bovine somatic cell nuclear transfer.

    Science.gov (United States)

    Chavatte-Palmer, P; Camous, S; Jammes, H; Le Cleac'h, N; Guillomot, M; Lee, R S F

    2012-02-01

    Since the first success in cloning sheep, the production of viable animals by somatic cell nuclear transfer (SCNT) has developed significantly. Cattle are by far the most successfully cloned species but, despite this, the technique is still associated with a high incidence of pregnancy failure and accompanying placental and fetal pathologies. Pre- and early post-implantation losses can affect up to 70% of the pregnancies. In the surviving pregnancies, placentomegaly and fetal overgrowth are commonly observed, but the incidence varies widely, depending on the genotype of the nuclear donor cell and differences in SCNT procedures. In all cases, the placenta is central to the onset of the pathologies. Although cellular organisation of the SCNT placenta appears normal, placental vascularisation is modified and fetal-to-maternal tissue ratios are slightly increased in the SCNT placentomes. In terms of functionality, steroidogenesis is perturbed and abnormal estrogen production and metabolism probably play an important part in the increased gestation length and lack of preparation for parturition observed in SCNT recipients. Maternal plasma concentrations of pregnancy-associated glycoproteins are increased, mostly due to a reduction in turnover rate rather than increased placental production. Placental glucose transport and fructose synthesis appear to be modified and hyperfructosemia has been observed in neonatal SCNT calves. Gene expression analyses of the bovine SCNT placenta show that multiple pathways and functions are affected. Abnormal epigenetic re-programming appears to be a key component of the observed pathologies, as shown by studies on the expression of imprinted genes in SCNT placenta. Copyright © 2012. Published by Elsevier Ltd.

  7. Experimental and numerical characterization of wind-induced pressure coefficients on nuclear buildings and chimney exhausts

    Energy Technology Data Exchange (ETDEWEB)

    Ricciardi, Laurent, E-mail: laurent.ricciardi@irsn.fr; Gélain, Thomas; Soares, Sandrine

    2015-10-15

    Highlights: • Experiments on scale models of nuclear buildings and chimney exhausts were performed. • Pressure coefficient fields on buildings are shown for various wind directions. • Evolution of pressure coefficient vs U/W ratio is given for various chimney exhausts. • RANS simulations using SST k–ω turbulence model were performed on most studied cases. • A good agreement is overall observed, with Root Mean Square Deviation lower than 0.15. - Abstract: Wind creates pressure effects on different surfaces of buildings according to their exposure to the wind, in particular at external communications. In nuclear facilities, these effects can change contamination transfers inside the building and can even lead to contamination release into the environment, especially in damaged (ventilation stopped) or accidental situations. The diversity of geometries of facilities requires the use of a validated code for predicting pressure coefficients, which characterize the wind effect on the building walls and the interaction between the wind and chimney exhaust. The first aim of a research program launched by the French Institut de Radioprotection et de Sûreté Nucléaire (IRSN), was therefore to acquire experimental data of the mean pressure coefficients for different geometries of buildings and chimneys through wind tunnel tests and then to validate a CFD code (ANSYS CFX) from these experimental results. The simulations were performed using a steady RANS approach and a two-equation SST k–ω turbulence model. After a mesh sensitivity study for one configuration of building and chimney, a comparison was carried out between the numerical and experimental values for other studied configurations. This comparison was generally satisfactory, averaged over all measurement points, with values of Root Mean Square Deviations lower than 0.15 for most cases.

  8. Nuclear receptors and myokines : mediators of exercise-induced skeletal muscle metabolism

    NARCIS (Netherlands)

    van Gogh, IJA

    2016-01-01

    Skeletal muscle is a crucial organ in mediating (exercise-induced) beneficial health effects. In this thesis we gained important knowledge on the molecular biology of the muscle. With our focus on the muscle, we investigated the crosstalk with other organs, the regulation of myokines and the role of

  9. Status of experimental data of proton-induced reactions for intermediate-energy nuclear data evaluation

    Energy Technology Data Exchange (ETDEWEB)

    Watanabe, Yukinobu; Kawano, Toshihiko [Kyushu Univ., Fukuoka (Japan); Yamano, Naoki; Fukahori, Tokio

    1998-11-01

    The present status of experimental data of proton-induced reactions is reviewed, with particular attention to total reaction cross section, elastic and inelastic scattering cross section, double-differential particle production cross section, isotope production cross section, and activation cross section. (author)

  10. The nuclear receptor NR4A1 induces a form of cell death dependent on autophagy in mammalian cells.

    Directory of Open Access Journals (Sweden)

    Jimena Bouzas-Rodríguez

    Full Text Available The control of cell death is a biological process essential for proper development, and for preventing devastating pathologies like cancer and neurodegeneration. On the other hand, autophagy regulation is essential for protein and organelle degradation, and its dysfunction is associated with overlapping pathologies like cancer and neurodegeneration, but also for microbial infection and aging. In the present report we show that two evolutionarily unrelated receptors--Neurokinin 1 Receptor (NK(1R, a G-protein coupled receptor, and Insulin-like Growth Factor 1 Receptor (IGF1R, a tyrosine kinase receptor--both induce non-apoptotic cell death with autophagic features and requiring the activity of the autophagic core machinery proteins PI3K-III, Beclin-1 and Atg7. Remarkably, this form of cell death occurs in apoptosis-competent cells. The signal transduction pathways engaged by these receptors both converged on the activation of the nuclear receptor NR4A1, which has previously been shown to play a critical role in some paradigms of apoptosis and in NK(1R-induced cell death. The activity of NR4A1 was necessary for IGF1R-induced cell death, as well as for a canonical model of cell death by autophagy induced by the presence of a pan-caspase inhibitor, suggesting that NR4A1 is a general modulator of this kind of cell death. During cell death by autophagy, NR4A1 was transcriptionally competent, even though a fraction of it was present in the cytoplasm. Interestingly, NR4A1 interacts with the tumor suppressor p53 but not with Beclin-1 complex. Therefore the mechanism to promote cell death by autophagy might involve regulation of gene expression, as well as protein interactions. Understanding the molecular basis of autophagy and cell death mediation by NR4A1, should provide novel insights and targets for therapeutic intervention.

  11. Comparison of Umbilical Serum Copeptin Relative to Erythropoietin and S100B as Asphyxia Biomarkers at Birth.

    Science.gov (United States)

    Summanen, Milla; Seikku, Laura; Rahkonen, Petri; Stefanovic, Vedran; Teramo, Kari; Andersson, Sture; Kaila, Kai; Rahkonen, Leena

    2017-01-01

    Birth asphyxia, estimated to account for a million neonatal deaths annually, can cause a wide variety of neurodevelopmental impairments. There is a need to develop new, swift methods to identify those neonates who would benefit from neuroprotective treatments such as hypothermia. To examine the utility of cord serum copeptin, a stable byproduct of arginine vasopressin release, as a biomarker of birth asphyxia based on a comparison with 2 biomarkers of hypoxia and brain trauma: erythropoietin and S100B. The study population consisted of 140 singleton, term neonates: 113 controls and 27 with birth asphyxia (2/3 criteria met: umbilical artery pH Copeptin, S100B, and erythropoietin levels in umbilical artery samples were measured by immunoassays. Copeptin correlated in the entire study population more strongly with umbilical artery base excess than S100B and erythropoietin, and only copeptin correlated with arterial pH. Furthermore, only copeptin levels were significantly higher in cases of birth asphyxia, and in vaginally born neonates they were found to increase as a function of labor duration. Copeptin was elevated in neonates born via vacuum extraction, whereas erythropoietin levels showed a slight increase after emergency cesarean section. In this study population, S100B and erythropoietin were not valid biomarkers of birth asphyxia. In contrast, our work suggests that copeptin has high potential to become a routinely used biomarker for acute birth asphyxia and neonatal distress. © 2017 S. Karger AG, Basel.

  12. Analysis of Muon Induced Neutrons in Detecting High Z Nuclear Materials

    Science.gov (United States)

    2015-03-01

    the muon-induced neu- tron yield in lead,” Astroparticle Physics , vol. 47, 2013. 24. G. Knoll, Radiation Detection and Measurement. Hoboken, New...Presented to the Faculty Department of Engineering Physics Graduate School of Engineering and Management Air Force Institute of Technology Air University...pyramids for hidden chambers [4]. A similar technique could be applied to weapons inspection procedures to probe the unobservable physics package for

  13. Nuclear Shape, Mechanics, and Mechanotransduction

    National Research Council Canada - National Science Library

    Dahl, Kris Noel; Ribeiro, Alexandre J.S; Lammerding, Jan

    2008-01-01

    .... Here, we discuss the effect of intra- and extracellular forces on nuclear shape and structure and how these force-induced changes could be implicated in nuclear mechanotransduction, ie, force-induced...

  14. Ethanol Extracts of Fresh Davallia formosana (WL1101) Inhibit Osteoclast Differentiation by Suppressing RANKL-Induced Nuclear Factor-κB Activation

    Science.gov (United States)

    Lin, Tzu-Hung; Yang, Rong-Sen; Wang, Kuan-Chin; Lu, Dai-Hua; Liou, Houng-Chi; Ma, Yun; Chang, Shao-Han; Fu, Wen-Mei

    2013-01-01

    The rhizome of Davallia formosana is commonly used to treat bone disease including bone fracture, arthritis, and osteoporosis in Chinese herbal medicine. Here, we report the effects of WL1101, the ethanol extracts of fresh rhizomes of Davallia formosana on ovariectomy-induced osteoporosis. In addition, excess activated bone-resorbing osteoclasts play crucial roles in inflammation-induced bone loss diseases, including rheumatoid arthritis and osteoporosis. In this study, we examined the effects of WL1101 on receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis. Treatment with WL1101 significantly inhibited RANKL-stimulated osteoclastogenesis. Two isolated active compounds, ((−)-epicatechin) or WL14 (4-hydroxy-3-aminobenzoic acid) could also inhibit RANKL-induced osteoclastogenesis. WL1101 suppressed the RANKL-induced nuclear factor-κB (NF-κB) activation and nuclear translocation, which is the key process during osteoclastogenesis, by inhibiting the activation of IκB kinase (IKK) and IκBα. In animal model, oral administration of WL1101 (50 or 200 mg/kg/day) effectively decreased the excess bone resorption and significantly antagonized the trabecular bone loss in ovariectomized rats. Our results demonstrate that the ethanol extracts of fresh rhizomes of Davallia formosana inhibit osteoclast differentiation via the inhibition of NF-κB activation and effectively ameliorate ovariectomy-induced osteoporosis. WL1101 may thus have therapeutic potential for the treatment of diseases associated with excessive osteoclastic activity. PMID:24191169

  15. Ethanol Extracts of Fresh Davallia formosana (WL1101 Inhibit Osteoclast Differentiation by Suppressing RANKL-Induced Nuclear Factor-κB Activation

    Directory of Open Access Journals (Sweden)

    Tzu-Hung Lin

    2013-01-01

    Full Text Available The rhizome of Davallia formosana is commonly used to treat bone disease including bone fracture, arthritis, and osteoporosis in Chinese herbal medicine. Here, we report the effects of WL1101, the ethanol extracts of fresh rhizomes of Davallia formosana on ovariectomy-induced osteoporosis. In addition, excess activated bone-resorbing osteoclasts play crucial roles in inflammation-induced bone loss diseases, including rheumatoid arthritis and osteoporosis. In this study, we examined the effects of WL1101 on receptor activator of nuclear factor-κB ligand (RANKL-induced osteoclastogenesis. Treatment with WL1101 significantly inhibited RANKL-stimulated osteoclastogenesis. Two isolated active compounds, ((−-epicatechin or WL14 (4-hydroxy-3-aminobenzoic acid could also inhibit RANKL-induced osteoclastogenesis. WL1101 suppressed the RANKL-induced nuclear factor-κB (NF-κB activation and nuclear translocation, which is the key process during osteoclastogenesis, by inhibiting the activation of IκB kinase (IKK and IκBα. In animal model, oral administration of WL1101 (50 or 200 mg/kg/day effectively decreased the excess bone resorption and significantly antagonized the trabecular bone loss in ovariectomized rats. Our results demonstrate that the ethanol extracts of fresh rhizomes of Davallia formosana inhibit osteoclast differentiation via the inhibition of NF-κB activation and effectively ameliorate ovariectomy-induced osteoporosis. WL1101 may thus have therapeutic potential for the treatment of diseases associated with excessive osteoclastic activity.

  16. Curcumin Induces Nrf2 Nuclear Translocation and Prevents Glomerular Hypertension, Hyperfiltration, Oxidant Stress, and the Decrease in Antioxidant Enzymes in 5/6 Nephrectomized Rats

    Directory of Open Access Journals (Sweden)

    Edilia Tapia

    2012-01-01

    Full Text Available Renal injury resulting from renal ablation induced by 5/6 nephrectomy (5/6NX is associated with oxidant stress, glomerular hypertension, hyperfiltration, and impaired Nrf2-Keap1 pathway. The purpose of this work was to know if the bifunctional antioxidant curcumin may induce nuclear translocation of Nrf2 and prevents 5/6NX-induced oxidant stress, renal injury, decrease in antioxidant enzymes, and glomerular hypertension and hyperfiltration. Four groups of rats were studied: (1 control, (2 5/6NX, (3 5/6NX +CUR, and (4 CUR (n=8–10. Curcumin was given by gavage to NX5/6 +CUR and CUR groups (60 mg/kg/day starting seven days before surgery. Rats were studied 30 days after NX5/6 or sham surgery. Curcumin attenuated 5/6NX-induced proteinuria, systemic and glomerular hypertension, hyperfiltration, glomerular sclerosis, interstitial fibrosis, interstitial inflammation, and increase in plasma creatinine and blood urea nitrogen. This protective effect was associated with enhanced nuclear translocation of Nrf2 and with prevention of 5/6NX-induced oxidant stress and decrease in the activity of antioxidant enzymes. It is concluded that the protective effect of curcumin against 5/6NX-induced glomerular and systemic hypertension, hyperfiltration, renal dysfunction, and renal injury was associated with the nuclear translocation of Nrf2 and the prevention of both oxidant stress and the decrease of antioxidant enzymes.

  17. Proteasome inhibition induces DNA damage and reorganizes nuclear architecture and protein synthesis machinery in sensory ganglion neurons.

    Science.gov (United States)

    Palanca, Ana; Casafont, Iñigo; Berciano, María T; Lafarga, Miguel

    2014-05-01

    Bortezomib is a reversible proteasome inhibitor used as an anticancer drug. However, its clinical use is limited since it causes peripheral neurotoxicity. We have used Sprague-Dawley rats as an animal model to investigate the cellular mechanisms affected by both short-term and chronic bortezomib treatments in sensory ganglia neurons. Proteasome inhibition induces dose-dependent alterations in the architecture, positioning, shape and polarity of the neuronal nucleus. It also produces DNA damage without affecting neuronal survival, and severe disruption of the protein synthesis machinery at the central cytoplasm accompanied by decreased expression of the brain-derived neurotrophic factor. As a compensatory or adaptive survival response against proteotoxic stress caused by bortezomib treatment, sensory neurons preserve basal levels of transcriptional activity, up-regulate the expression of proteasome subunit genes, and generate a new cytoplasmic perinuclear domain for protein synthesis. We propose that proteasome activity is crucial for controlling nuclear architecture, DNA repair and the organization of the protein synthesis machinery in sensory neurons. These neurons are primary targets of bortezomib neurotoxicity, for which reason their dysfunction may contribute to the pathogenesis of the bortezomib-induced peripheral neuropathy in treated patients.

  18. Prolonged induced hypothermia in hemorrhagic shock is associated with decreased muscle metabolism: a nuclear magnetic resonance-based metabolomics study.

    Science.gov (United States)

    Lusczek, Elizabeth R; Lexcen, Daniel R; Witowski, Nancy E; Determan, Charles; Mulier, Kristine E; Beilman, Greg

    2014-01-01

    Hemorrhagic shock is a leading cause of trauma-related death in war and is associated with significant alterations in metabolism. Using archived serum samples from a previous study, the purpose of this work was to identify metabolic changes associated with induced hypothermia in a porcine model of hemorrhagic shock. Twelve Yorkshire pigs underwent a standardized hemorrhagic shock and resuscitation protocol to simulate battlefield injury with prolonged evacuation to definitive care in cold environments. Animals were randomized to receive either hypothermic (33°C) or normothermic (39°C) limited resuscitation for 8 h, followed by standard resuscitation. Proton nuclear magnetic resonance spectroscopy was used to evaluate serum metabolites from these animals at intervals throughout the hypothermic resuscitation period. Animals in the hypothermic group had a significantly higher survival rate (P = 0.02) than normothermic animals. Using random forest analysis, a difference in metabolic response between hypothermic and normothermic animals was identified. Hypothermic resuscitation was characterized by decreased concentrations of several muscle-related metabolites including taurine, creatine, creatinine, and amino acids. This study suggests that a decrease in muscle metabolism as a result of induced hypothermia is associated with improved survival.

  19. Role of aromatic amino acids in carbohydrate binding of plant lectins : Laser photo chemically induced dynamic nuclear polarization study of hevein domain-containing lectins

    NARCIS (Netherlands)

    Siebert, HC; vonderLieth, CW; Kaptein, R; Beintema, JJ; Dijkstra, K; vanNuland, N; Soedjanaatmadja, UMS; Rice, A; Vliegenthart, JFG; Wright, CS; Gabius, HJ

    Carbohydrate recognition by lectins often involves the side chains of tyrosine, tryptophan, and histidine residues. These moieties are able to produce chemically induced dynamic nuclear polarization (CIDNP) signals after laser irradiation in the presence of a suitable radical pair-generating dye.

  20. Pseudopregnancy induces the expression of hepatocyte nuclear factor-1 beta and its target gene aminopeptidase N in rabbit endometrium via the epithelial promoter

    DEFF Research Database (Denmark)

    Classen-Linke, I; Sjöström, H; Norén, O

    1995-01-01

    APN promoter and is increased in human-choriogonadotropin-induced pseudopregnancy. Cloning and sequencing of the rabbit APN epithelial promoter revealed conservation of the upstream footprint (UF), hepatocyte nuclear factor-1 (HNF1) and Sp1 elements known to be present in the pig and human promoters...

  1. Involvement of laser photo-CIDNP (chemically induced dynamic nuclear polarization)-reactive amino acid side chains in ligand binding by galactoside-specific lectins in solution

    NARCIS (Netherlands)

    Vliegenthart, J.F.G.; Siebert, H.-C; Adar, R.; Arango, R.; Burchert, M.; Kaltner, H.; Kayser, G.; Tajkhorshid, C.-W.

    1997-01-01

    For proteins in solution the validity of certain crystallographic parameters can be ascertained by a combination of molecular-dynamics (MD) simulations and NMR spectroscopy. Using the laser photoCIDNP (chemically induced dynamic nuclear polarization) technique as a measure for surface accessibility

  2. D-D nuclear fusion processes induced in polyethylene foams by TW Laser-generated plasma

    Directory of Open Access Journals (Sweden)

    Torrisi L.

    2015-01-01

    Full Text Available Deuterium-Deuterium fusion processes were generated by focusing the 3 TW PALS Laser on solid deuterated polyethylene targets placed in vacuum. Deuterium ion acceleration of the order of 4 MeV was obtained using laser irradiance Iλ2 ∼ 5 × 1016 W μm2/cm2 on the target. Thin and thick targets, at low and high density, were irradiated and plasma properties were monitored “on line” and “off line”. The ion emission from plasma was monitored with Thomson Parabola Spectrometer, track detectors and ion collectors. Fast semiconductor detectors based on SiC and fast plastic scintillators, both employed in time-of-flight configuration, have permitted to detect the characteristic 3.0 MeV protons and 2.45 MeV neutrons emission from the nuclear fusion reactions. From massive absorbent targets we have evaluated the neutron flux by varying from negligible values up to about 5 × 107 neutrons per laser shot in the case of foams targets, indicating a reaction rate of the order of 108 fusion events per laser shot using “advanced targets”.

  3. D-D nuclear fusion processes induced in polyethylene foams by TW Laser-generated plasma

    Science.gov (United States)

    Torrisi, L.; Cutroneo, M.; Cavallaro, S.; Ullschmied, J.

    2015-06-01

    Deuterium-Deuterium fusion processes were generated by focusing the 3 TW PALS Laser on solid deuterated polyethylene targets placed in vacuum. Deuterium ion acceleration of the order of 4 MeV was obtained using laser irradiance Iλ2 ˜ 5 × 1016 W μm2/cm2 on the target. Thin and thick targets, at low and high density, were irradiated and plasma properties were monitored "on line" and "off line". The ion emission from plasma was monitored with Thomson Parabola Spectrometer, track detectors and ion collectors. Fast semiconductor detectors based on SiC and fast plastic scintillators, both employed in time-of-flight configuration, have permitted to detect the characteristic 3.0 MeV protons and 2.45 MeV neutrons emission from the nuclear fusion reactions. From massive absorbent targets we have evaluated the neutron flux by varying from negligible values up to about 5 × 107 neutrons per laser shot in the case of foams targets, indicating a reaction rate of the order of 108 fusion events per laser shot using "advanced targets".

  4. Nuclear factor-kappa B inhibition can enhance apoptosis of differentiated thyroid cancer cells induced by 131I.

    Directory of Open Access Journals (Sweden)

    Zhaowei Meng

    Full Text Available OBJECTIVE: To evaluate changes of nuclear factor-kappa B (NF-κB during radioiodine 131 ((131I therapy and whether NF-κB inhibition could enhance (131I-induced apoptosis in differentiated thyroid cancer (DTC cells in a synergistic manner. METHODS: Three human DTC cell lines were used. NF-κB inhibition was achieved by using a NF-κB inhibitor (Bay 11-7082 or by p65 siRNA transfection. Methyl-thiazolyl-tetrazolium assay was performed for cell viability assessment. DNA-binding assay, luciferase reporter assay, and Western blot were adopted to determine function and expression changes of NF-κB. Then NF-κB regulated anti-apoptotic factors XIAP, cIAP1, and Bcl-xL were measured. Apoptosis was analyzed by Western blot for caspase 3 and PARP, and by flow cytometry as well. An iodide uptake assay was performed to determine whether NF-κB inhibition could influence radioactive iodide uptake. RESULTS: The methyl-thiazolyl-tetrazolium assay showed significant decrease of viable cells by combination therapy than by mono-therapies. The DNA-binding assay and luciferase reporter assay showed enhanced NF-κB function and reporter gene activities due to (131I, yet significant suppression was achieved by NF-κB inhibition. Western blot proved (131I could increase nuclear NF-κB concentration, while NF-κB inhibition reduced NF-κB concentration. Western blot also demonstrated significant up-regulation of XIAP, cIAP1, and Bcl-xL after (131I therapy. And inhibition of NF-κB could significantly down-regulate these factors. Finally, synergism induced by combined therapy was displayed by significant enhancements of cleaved caspase 3 and PARP from Western blot, and of Annexin V positively staining from flow cytometry. The iodine uptake assay did not show significant changes when NF-κB was inhibited. CONCLUSION: We demonstrated that (131I could induce NF-κB activation, which would attenuate (131I efficacy in DTC cells. NF-κB inhibition by Bay 11-7082 or by p65 si

  5. Comparison of the effects of erythropoietin and anakinra on functional recovery and gene expression in a traumatic brain injury model

    Directory of Open Access Journals (Sweden)

    Gail D Anderson

    2013-10-01

    Full Text Available The goal of this study was to compare the effects of two inflammatory modulators, erythropoietin (EPO and anakinra, on functional recovery and brain gene expression following a cortical contusion impact (CCI injury. Dosage regimens were designed to provide serum concentrations in the range obtained with clinically approved doses. Functional recovery was assessed using both motor and spatial learning tasks and neuropathological measurements conducted in the cortex and hippocampus. Microarray-based transcriptional profiling was used to determine the effect on gene expression at 24 h, 72 h and 7 days post-CCI. Ingenuity Pathway Analysis was used to evaluate the effect on relevant functional categories. EPO and anakinra treatment resulted in significant changes in brain gene expression in the CCI model demonstrating acceptable brain penetration. At all three time points, EPO treatment resulted in significantly more differentially expressed genes than anakinra. For anakinra at 24 h and EPO at 24 h, 72 h and 7 days, the genes in the top 3 functional categories were involved in cellular movement, inflammatory response and cell-to-cell signaling. For EPO, the majority of the genes in the top 10 canonical pathways identified were associated with inflammatory and immune signaling processes. This was true for anakinra only at 24 h post-traumatic brain injury (TBI. The immunomodulation effects of EPO and anakinra did not translate into positive effects on functional behavioral and lesion studies. Treatment with either EPO or anakinra failed to induce significant beneficial effects on recovery of function or produce any significant effects on the prevention of injury induced tissue loss at 30 days post-injury. In conclusion, treatment with EPO or anakinra resulted in significant effects on gene expression in the brain without affecting functional outcome. This suggests that targeting these inflammatory processes alone may not be sufficient for preventing

  6. AMPK-KLF2 signaling pathway mediates the proangiogenic effect of erythropoietin in endothelial colony forming cells.

    Science.gov (United States)

    Wang, Dawei; Song, Yimeng; Zhang, Jianshu; Pang, Wei; Wang, Xian; Zhu, Yi; Li, Xiaoxia

    2017-10-04

    Endothelial colony forming cells (ECFCs) were proved to take part in post-natal vasculogenesis and injury repair. The angiogenic properties of ECFCs could be influenced by various cytokines, chemokines, and growth factors. Erythropoietin (EPO) is a promising cytokine participating in angiogenesis. However, the mechanisms for EPO's proangiogenic effect still remain largely elusive. Here, we investigated the role of AMP-activated protein kinase (AMPK)-Krüppel-like factor 2 (KLF2) signaling pathway in the proangiogenic effect of EPO in ECFCs. Human ECFCs were isolated from cord blood and cultured. EPO significantly enhanced the migration and tube formation capacities of ECFCs and markedly increased the expression of endothelial markers and vascular endothelial growth factor (VEGF). Further, EPO caused the phosphorylation of AMPK and endothelial nitric oxide synthase (eNOS), in which process KLF2 was also up-regulated on both mRNA and protein levels. The up-regulation of KLF2 was blocked by inhibiting AMPK with Compound C or Ad-AMPK-DN, a recombinant adenovirus which encoded a dominant negative mutant of AMPK. Furthermore, knockdown of KLF2 showed no effect on AMPK but abolished the EPO-enhanced migration and tube formation capacities of ECFCs. Of note, knockdown of KLF2 also diminished the EPO-induced expression of endothelial markers and VEGF; overexpression of KLF2 promoted the expression of endothelial markers and VEGF and enhanced the migration and tube formation capacities of ECFCs. These data suggest that up-regulation of KLF2 by AMPK plays an essential role in EPO-induced angiogenesis. Copyright © 2017, American Journal of Physiology-Cell Physiology.

  7. Subretinal transplantation of rat MSCs and erythropoietin gene modified rat MSCs for protecting and rescuing degenerative retina in rats.

    Science.gov (United States)

    Guan, Y; Cui, L; Qu, Z; Lu, L; Wang, F; Wu, Y; Zhang, J; Gao, F; Tian, H; Xu, L; Xu, G; Li, W; Jin, Y; Xu, G-T

    2013-11-01

    For degenerative retinal diseases, like the acquired form exemplified by age-related macular degeneration (AMD), there is currently no cure. This study was to explore a stem cell therapy and a stem cell based gene therapy for sodium iodate (SI)-induced retinal degeneration in rats. Three cell types, i.e., rat mesenchymal stem cells (rMSCs) alone, erythropoietin (EPO) gene modified rMSCs (EPO-rMSCs) or doxycycline (DOX) inducible EPO expression rMSCs (Tet-on EPO-rMSCs), were transplanted into the subretinal spaces of SI-treated rats. The rMSCs were prepared for transplantation after 3 to 5 passages or modified with EPO gene. During the 8 weeks after the transplantation, the rats treated with rMSCs alone or with two types of EPO-rMSCs were all monitored with fundus examination, fundus fluorescein angiography (FFA) and electroretinogram. The transplantation efficiency of donor cells was examined for their survival, integration and differentiation. Following the transplantation, labeled donor cells were observed in subretinal space and adopted RPE morphology. EPO concentration in vitreous and retina of SI-treated rats which were transplanted with EPO-rMSCs or Tet-on EPO-rMSCs was markedly increased, in parallel with the improvement of retinal morphology and function. These findings suggest that rMSCs transplantation could be a new therapy for degenerative retinal diseases since it can protect and rescue RPE and retinal neurons, while EPO gene modification to rMSCs could be an even better option.

  8. Nuclear marginalization of host cell chromatin associated with expansion of two discrete virus-induced subnuclear compartments during baculovirus infection.

    Science.gov (United States)

    Nagamine, Toshihiro; Kawasaki, Yu; Abe, Atsushi; Matsumoto, Shogo

    2008-07-01

    Chromatin structure is strictly regulated during the cell cycle. DNA viruses occasionally disturb the spatial organization of the host cell chromatin due to formation of the viral DNA replication compartment. To examine chromatin behavior in baculovirus-infected cells, we constructed recombinant plasmids expressing fluorescent protein-tagged histone H4 molecules and visualized the intracellular localization of chromatin by their transient expression in live infected cells. Similar to other DNA viruses, the baculovirus Bombyx mori nucleopolyhedrovirus induced marginal relocation of chromatin within the nuclei of BmN cells, simultaneously with expansion of the viral DNA replication compartment, the virogenic stroma (VS). In the late stage of infection, however, the peristromal region (PR), another virus-induced subnuclear compartment, was also excluded from the chromatin-localizing area. Provided that late-gene products such as PR proteins (e.g., envelope proteins of the occlusion-derived virus) were expressed, blockage of viral DNA synthesis failed to inhibit chromatin relocation, despite abrogation of VS expansion. Instead, chromatin became marginalized concomitantly with PR expansion, suggesting that the PR contributes directly to chromatin replacement. In addition, chromatin was excluded from relatively large subnuclear structures that were induced in uninfected cells by cotransfection with four baculovirus genes, ie1, lef3, p143, and hr. Omission of any of the four genes, however, failed to result in formation of the large structures or chromatin exclusion. This correlation between compartmentalization and chromatin exclusion suggests the possibility that a chromatin-exclusive property of viral molecules, at least in part, supports nuclear compartmentalization of virus-infected cells.

  9. Nuclear Marginalization of Host Cell Chromatin Associated with Expansion of Two Discrete Virus-Induced Subnuclear Compartments during Baculovirus Infection▿

    Science.gov (United States)

    Nagamine, Toshihiro; Kawasaki, Yu; Abe, Atsushi; Matsumoto, Shogo

    2008-01-01

    Chromatin structure is strictly regulated during the cell cycle. DNA viruses occasionally disturb the spatial organization of the host cell chromatin due to formation of the viral DNA replication compartment. To examine chromatin behavior in baculovirus-infected cells, we constructed recombinant plasmids expressing fluorescent protein-tagged histone H4 molecules and visualized the intracellular localization of chromatin by their transient expression in live infected cells. Similar to other DNA viruses, the baculovirus Bombyx mori nucleopolyhedrovirus induced marginal relocation of chromatin within the nuclei of BmN cells, simultaneously with expansion of the viral DNA replication compartment, the virogenic stroma (VS). In the late stage of infection, however, the peristromal region (PR), another virus-induced subnuclear compartment, was also excluded from the chromatin-localizing area. Provided that late-gene products such as PR proteins (e.g., envelope proteins of the occlusion-derived virus) were expressed, blockage of viral DNA synthesis failed to inhibit chromatin relocation, despite abrogation of VS expansion. Instead, chromatin became marginalized concomitantly with PR expansion, suggesting that the PR contributes directly to chromatin replacement. In addition, chromatin was excluded from relatively large subnuclear structures that were induced in uninfected cells by cotransfection with four baculovirus genes, ie1, lef3, p143, and hr. Omission of any of the four genes, however, failed to result in formation of the large structures or chromatin exclusion. This correlation between compartmentalization and chromatin exclusion suggests the possibility that a chromatin-exclusive property of viral molecules, at least in part, supports nuclear compartmentalization of virus-infected cells. PMID:18434402

  10. The role of constitutive nitric-oxide synthase in ultraviolet B light-induced nuclear factor κB activity.

    Science.gov (United States)

    Tong, Lingying; Wu, Shiyong

    2014-09-19

    NF-κB is a transcription factor involved in many signaling pathways that also plays an important role in UV-induced skin tumorigenesis. UV radiation can activate NF-κB, but the detailed mechanism remains unclear. In this study, we provided evidence that the activation of constitutive nitric-oxide synthase plays a role in regulation of IκB reduction and NF-κB activation in human keratinocyte HaCaT cells in early phase (within 6 h) post-UVB. Treating the cells with l-NAME, a selective inhibitor of constitutive nitric-oxide synthase (cNOS), can partially reverse the IκB reduction and inhibit the DNA binding activity as well as nuclear translocation of NF-κB after UVB radiation. A luciferase reporter assay indicates that UVB-induced NF-κB activation is totally diminished in cNOS null cells. The cNOS-mediated reduction of IκB is likely due to the imbalance of nitric oxide/peroxynitrite because treating the cells with lower (50 μm), but not higher (100-500 μm), concentration of S-nitroso-N-acetylpenicillamine (SNAP) can reverse the effect of l-NAME in partial restore IκB level post-UVB. Our data also showed that NF-κB activity was required for maintaining a stable IκB kinase α subunit (IKKα) level because treating the cells with NF-κB or cNOS inhibitors could reduce IKKα level upon UVB radiation. In addition, our data demonstrated that although NF-κB protects cells from UVB-induced death, its pro-survival activity was likely neutralized by the pro-death activity of peroxynitrite after UVB radiation. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  11. Epigenetic Regulation of αA-crystallin in High Myopia-Induced Dark Nuclear Cataract

    Science.gov (United States)

    Zhang, Ke-Ke; Yang, Jin; Luo, Yi; Lu, Yi

    2013-01-01

    Purpose To assess the etiology of early-onset dark nucleus in high-myopic patients and its relationship with the epigenetic regulation of αA-crystallin (CRYAA). Methods We reviewed clinical data from patients who underwent cataract surgery at our center in 2012. Lens epithelial samples were collected during capsulorhexis, whereas young lens epithelium was donated. Cataract type and severity were graded according to the Lens Opacity Classification System III (LOCS III). DNA methylation was analyzed by pyrosequencing the CpG islands of the CRYAA promoter in the following groups: Age-Related Cataract (ARC) Nuclear Color (NC) 2–3; High-Myopic Cataract (HMC) NC2–3; ARC NC5–6; HMC NC5–6; and in young lenses graded NC1. We analyzed CRYAA expression by real-time polymerase chain reaction (PCR), reverse transcription PCR, and immunohistochemistry. Results The odds ratio of dark nucleus in high-myopic patients was 5.16 (95% confidence interval: 3.98–6.69; p<0.001). CpG islands in lens epithelial CRYAA promoter in the HMC NC5–6 Group exhibited the highest methylation of all the groups, but no statistically significant differences were evident between the HMC NC2–3 and ARC NC2–3 Groups. Likewise, CRYAA mRNA and protein levels in the HMC NC5–6 Group were significantly lower than the ARC NC5–6 Group and high-myopic controls. Conclusions High myopia is a risk factor for dark nucleus. Downregulation of CRYAA via the hypermethylation of CpG islands in its promoter could underlie the earlier onset of dark nucleus in high-myopic patients. PMID:24312600

  12. Heart failure induces significant changes in nuclear pore complex of human cardiomyocytes.

    Directory of Open Access Journals (Sweden)

    Estefanía Tarazón

    Full Text Available AIMS: The objectives of this study were to analyse the effect of heart failure (HF on several proteins of nuclear pore complex (NPC and their relationship with the human ventricular function. METHODS AND RESULTS: A total of 88 human heart samples from ischemic (ICM, n = 52 and dilated (DCM, n = 36 patients undergoing heart transplant and control donors (CNT, n = 9 were analyzed by Western blot. Subcellular distribution of nucleoporins was analysed by fluorescence and immunocytochemistry. When we compared protein levels according to etiology, ICM showed significant higher levels of NDC1 (65%, p<0.0001, Nup160 (88%, p<0.0001 and Nup153 (137%, p = 0.004 than those of the CNT levels. Furthermore, DCM group showed significant differences for NDC1 (41%, p<0.0001, Nup160 (65%, p<0.0001, Nup153 (155%, p = 0.006 and Nup93 (88%, p<0.0001 compared with CNT. However, Nup155 and translocated promoter region (TPR did not show significant differences in their levels in any etiology. Regarding the distribution of these proteins in cell nucleus, only NDC1 showed differences in HF. In addition, in the pathological group we obtained good relationship between the ventricular function parameters (LVEDD and LVESD and Nup160 (r = -0382, p = 0.004; r = -0.290, p = 0.033; respectively. CONCLUSIONS: This study shows alterations in specific proteins (NDC1, Nup160, Nup153 and Nup93 that compose NPC in ischaemic and dilated human heart. These changes, related to ventricular function, could be accompanied by alterations in the nucleocytoplasmic transport. Therefore, our findings may be the basis for a new approach to HF management.

  13. Experimental study to explore the $\\rm ^8Be$ induced nuclear reaction via the Trojan Horse Method

    CERN Document Server

    Qun-Gang, Wen; Shu-Hua, Zhou; Irgaziev, Bakhadir; Yuan-Yong, Fu; Spitaleri, Claudio; La Cognata, Marco; Jing, Zhou; Qiu-Ying, Meng; Lamia, Livio; Lattuada, Marcello

    2014-01-01

    To explore a possible indirect method for $\\rm ^8Be$ induced astrophysical reactions, the $\\rm ^9Be=({}^8Be+\\it n)$ cluster structure was studied via the Trojan Horse Method. It is the first time to study a super short life nucleus $\\rm ^8Be$ via the Trojan Horse Method, and it is the first time to make a valid test for $l=1$ Trojan-horse nucleus. The $\\rm ^9Be$ nucleus is assumed to have a ($\\rm {}^8Be+\\it n$) cluster structure and used as the Trojan-horse nucleus. The $\\rm ^8Be$ nucleus acts as a participant, while the neutron is a spectator to the virtual $\\rm ^8Be +{\\it d}\\rightarrow \\alpha + {}^6Li$ reaction via a suitable 3-body reaction $\\rm ^9Be +{\\it d}\\rightarrow \\alpha + {}^6Li +\\it n$. The experimental neutron momentum distribution inside $\\rm ^9Be$ was reconstructed. The agreement between experimental and theoretical momentum distribution indicates that there should be a ($\\rm {}^8Be+\\it n$) cluster structure inside $\\rm ^9Be$. Therefor the experimental study of $\\rm ^8Be$ induced reactions, for ...

  14. Sigma-1 receptor mediates cocaine-induced transcriptional regulation by recruiting chromatin-remodeling factors at the nuclear envelope.

    Science.gov (United States)

    Tsai, Shang-Yi A; Chuang, Jian-Ying; Tsai, Meng-Shan; Wang, Xiao-Fei; Xi, Zheng-Xiong; Hung, Jan-Jong; Chang, Wen-Chang; Bonci, Antonello; Su, Tsung-Ping

    2015-11-24

    The sigma-1 receptor (Sig-1R) chaperone at the endoplasmic reticulum (ER) plays important roles in cellular regulation. Here we found a new function of Sig-1R, in that it translocates from the ER to the nuclear envelope (NE) to recruit chromatin-remodeling molecules and regulate the gene transcription thereof. Sig-1Rs mainly reside at the ER-mitochondrion interface. However, on stimulation by agonists such as cocaine, Sig-1Rs translocate from ER to the NE, where Sig-1Rs bind NE protein emerin and recruit chromatin-remodeling molecules, including lamin A/C, barrier-to-autointegration factor (BAF), and histone deacetylase (HDAC), to form a complex with the gene repressor specific protein 3 (Sp3). Knockdown of Sig-1Rs attenuates the complex formation. Cocaine was found to suppress the gene expression of monoamine oxidase B (MAOB) in the brain of wild-type but not Sig-1R knockout mouse. A single dose of cocaine (20 mg/kg) in rats suppresses the level of MAOB at nuclear accumbens without affecting the level of dopamine transporter. Daily injections of cocaine in rats caused behavioral sensitization. Withdrawal from cocaine in cocaine-sensitized rats induced an apparent time-dependent rebound of the MAOB protein level to about 200% over control on day 14 after withdrawal. Treatment of cocaine-withdrawn rats with the MAOB inhibitor deprenyl completely alleviated the behavioral sensitization to cocaine. Our results demonstrate a role of Sig-1R in transcriptional regulation and suggest cocaine may work through this newly discovered genomic action to achieve its addictive action. Results also suggest the MAOB inhibitor deprenyl as a therapeutic agent to block certain actions of cocaine during withdrawal.

  15. 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....... In conclusion, the Epo-R is present in the vasculature and myocytes in human skeletal muscle, suggesting a role in both cell types. In accordance, a single injection of Epo regulates myoglobin, MRF-4, and transferrin receptor mRNA levels. However, in contrast to our hypothesis, prolonged Epo administration had...

  16. Modeling of radiation-induced sink evolution in 6061 aluminum alloy in nuclear reactors

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Sang Il; Kim, Ji Hyun [Department of Nuclear Science and Engineering, School of Mechanical and Nuclear Engineering, Ulsan National Institute of Science and Technology (UNIST), Ulsan (Korea, Republic of); Lee, Gyeong-Geun; Kwon, Junhyun [Division of Nuclear Materials Research, Korea Atomic Energy Research Institute (KAERI), Daejeon (Korea, Republic of)

    2016-11-15

    The objective of this study is a detailed analysis of the radiation effects on sink generation and growth in order to understand the phenomenon of irradiation hardening of 6061 aluminum alloy in research reactor conditions. In order to have a fundamental understanding, various sink behavior characteristics such as size and number density of dislocation loop, void, and precipitation were calculated and examined. Thereafter, theoretical assessment of various sink effects on irradiation hardening was conducted based on the mean field rate theory (MFRT). Dislocation loop, void, and precipitation were examined by defect flux. For the quantitative analysis of radiation-induced degradation, change in sink size was calculated using number density. 6061 Alloy showed great dependence on precipitation generation and growth. However, dislocation loop and void did not have any significant effect on irradiation hardening. Finally, the behavior of sinks was compared with the experimental results for validation. (copyright 2016 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim)

  17. Production of medically useful bromine isotopes via alpha-particle induced nuclear reactions

    Science.gov (United States)

    Breunig, Katharina; Scholten, Bernhard; Spahn, Ingo; Hermanne, Alex; Spellerberg, Stefan; Coenen, Heinz H.; Neumaier, Bernd

    2017-09-01

    The cross sections of α-particle induced reactions on arsenic leading to the formation of 76,77,78Br were measured from their respective thresholds up to 37 MeV. Thin sediments of elemental arsenic powder were irradiated together with Al degrader and Cu monitor foils using the established stacked-foil technique. For determination of the effective α-particle energies and of the effective beam current through the stacks the cross-section ratios of the monitor nuclides 67Ga/66Ga were used. This should help resolve discrepancies in existing literature data. Comparison of the data with the available excitation functions shows some slight energy shifts as well as some differences in curve shapes. The calculated thick target yields indicate, that 77Br can be produced in the energy range Eα = 25 → 17 MeV free of isotopic impurities in quantities sufficient for medical application.

  18. Production of medically useful bromine isotopes via alpha-particle induced nuclear reactions

    Directory of Open Access Journals (Sweden)

    Breunig Katharina

    2017-01-01

    Full Text Available The cross sections of α-particle induced reactions on arsenic leading to the formation of 76,77,78Br were measured from their respective thresholds up to 37 MeV. Thin sediments of elemental arsenic powder were irradiated together with Al degrader and Cu monitor foils using the established stacked-foil technique. For determination of the effective α-particle energies and of the effective beam current through the stacks the cross-section ratios of the monitor nuclides 67Ga/66Ga were used. This should help resolve discrepancies in existing literature data. Comparison of the data with the available excitation functions shows some slight energy shifts as well as some differences in curve shapes. The calculated thick target yields indicate, that 77Br can be produced in the energy range Eα = 25 → 17 MeV free of isotopic impurities in quantities sufficient for medical application.

  19. The orphan nuclear receptor Rev-Erbalpha is a peroxisome proliferator-activated receptor (PPAR) gamma target gene and promotes PPARgamma-induced adipocyte differentiation

    DEFF Research Database (Denmark)

    Fontaine, Coralie; Dubois, Guillaume; Duguay, Yannick

    2003-01-01

    Rev-Erbalpha (NR1D1) is an orphan nuclear receptor encoded on the opposite strand of the thyroid receptor alpha gene. Rev-Erbalpha mRNA is induced during adipocyte differentiation of 3T3-L1 cells, and its expression is abundant in rat adipose tissue. Peroxisome proliferator-activated receptor gamma...... (PPARgamma) (NR1C3) is a nuclear receptor controlling adipocyte differentiation and insulin sensitivity. Here we show that Rev-Erbalpha expression is induced by PPARgamma activation with rosiglitazone in rat epididymal and perirenal adipose tissues in vivo as well as in 3T3-L1 adipocytes in vitro...... of functional PPARgamma response element. Finally, ectopic expression of Rev-Erbalpha in 3T3-L1 preadipocytes potentiated adipocyte differentiation induced by the PPARgamma ligand rosiglitazone. These results identify Rev-Erbalpha as a target gene of PPARgamma in adipose tissue and demonstrate a role...

  20. Management of anemia in patients undergoing curative radiotherapy. Erythropoietin, transfusions, or better nothing?

    Energy Technology Data Exchange (ETDEWEB)

    Dunst, J. [Dept. of Radiotherapy, Martin Luther Univ. Halle-Wittenberg, Halle (Germany)

    2004-11-01

    Background and results: anemia is a well-known risk factor for decreased local control and survival in patients undergoing curative radiotherapy. There is clear evidence from recent clinical investigations that anemia is an independent risk factor and hemoglobin (Hb) levels during radiotherapy are important (and not pretreatment Hb levels). The most likely explanation for the prognostic impact is the association with tumor hypoxia. An ''optimal'' Hb range with regard to tumor oxygenation seems to exist, and Hb levels < 11 g/dl and > {proportional_to}15 g/dl impair tumor oxygenation but have (over a broader range) no significant impact on normal tissue oxygenation. There is some evidence from retrospective and prospective studies that the response to radiotherapy and the prognosis, especially in cervical cancers, might be improved if the Hb levels during radiotherapy can be maintained in the optimal range, either by transfusions or by erythropoietin. The effect of any antianemic therapy should be analyzed according to whether or not treatment was successful with regard to achieving optimal Hb levels during irradiation. Erythropoietin is probably more effective in steadily increasing and stabilizing Hb levels, but bears the risk of overcorrection of Hb levels. The clinical relevance of erythropoietin receptors on tumor cells remains questionable. Conclusions: treatment of anemia with the objective of improving local control and survival in radiotherapy patients is probably more difficult and sophisticated than coping with symptoms of anemia or improving quality of life. Nevertheless, the potential of antianemic treatment is high on the basis of experimental and clinical data, and further clinical trials are warranted. (orig.)

  1. 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...... study investigates the effects of Epo on the neural and cognitive response to emotional facial expressions in depressed patients.......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...

  2. Colocalization of vertebrate lamin B and lamin B receptor (LBR) in nuclear envelopes and in LBR-induced membrane stacks of the yeast Saccharomyces cerevisiae.

    Science.gov (United States)

    Smith, S; Blobel, G

    1994-10-11

    We have expressed human lamin B and the chicken lamin B receptor (LBR), either separately or together, in yeast and have monitored the subcellular location of the expressed proteins by immunofluorescence microscopy, immunoelectron microscopy, and cell fractionation. At the light microscopic level, the heterologous lamin B localized to the yeast nuclear rim and at electron microscopic resolution was found subjacent to the yeast inner nuclear membrane. These data indicate that vertebrate lamin B was correctly targeted in yeast. Expression of the heterologous LBR, either alone or together with the heterologous lamin B, resulted in the formation of membrane stacks primarily adjacent to the nuclear envelope, but also projecting from the nuclear envelope into the cytoplasm or under the plasma membrane. Double immunoelectron microscopy showed colocalization of the heterologous lamin B and LBR in the yeast nuclear envelope and in the LBR-induced membrane stacks. Cell fractionation showed the presence of the heterologous lamin B and LBR in a subnuclear fraction enriched in nuclear envelopes. The heterologous lamin B was extracted at 8 M urea, but not at 4 M urea, thus behaving as a peripheral membrane protein and indistinguishable from assembled lamins. The heterologous LBR was not extracted by 8 M urea, indicating that it was integrated into the membrane. The observed colocalization and cofractionation are consistent with previously reported in vitro binding data and suggest that heterologous lamin B and LBR interact with each other when coexpressed in yeast.

  3. Evaluation of the therapeutic effect of hyperbaric oxygenation and erythropoietin in the treatment of chronic heart failure using myocardial perfusion scintigraphy G-SPECT

    Directory of Open Access Journals (Sweden)

    Baškot Branislav

    2009-01-01

    Full Text Available Background. The most important predictors of longterm survival in patients with cardiac ischemic disease are left ventricular ejection fraction, left ventricular volumes, infarction size, presence and extent of residual myocardial ischemia. One of the most important recent developments in single photon emission computed tomography (SPECT myocardial perfusion imaging is the ability to acquire these studies in conjunction with electrocardiogram (ECG gating (G-SPECT. The ability to asses radionuclide myocardial perfusion and function with ECG G-SPECT imaging has revolutionized this field of nuclear cardiology. Study with G-SPECT development algorithms permits to quantify measures of left ventricular (LV volume, ejection fraction (LVEF and even regional myocardial wall motion and thickening. The American Society of Nuclear Cardiology (ASNC in its position paper from March 1999 recommends the routine incorporation of G-SPECT during cardiac perfusion scintigraphy. Case report. We presented a 70-year-old male with ischemic heart disease (dilatative, cardiomyopathy and absolute arrhythmia. He was few times hospitally treated by medicamentous therapy with no evidence of improvement. After hospital treatment, we included hyperbaric oxygenation (HBO and erythropoietin injections. Hyperbaric oxygenation was carried out in a monoplace hyperbaric chamber, BLK S-303, by a graduated protocol for patients with severe heart insufficiency, totally 15 treatments. Recombinant erythropoietin beta (RecormonR F. Hoffmann-La Roche was applied deeply subcutaneously, every second day from 2 000 IU to totally 16 000 IU. Before the therapy G-SPECT study was performed with 99m technetium-MIBI, and we obtained the functional parameters and perfusion of the left ventricle to follow-up the therapy effects. The study was performed by an ADAC-VERTEX PLUS-EPIC two-head gamma camera with dedicated quantitatively algorithm Auto-QUANT. The results of LVEF were 15%, with severity

  4. 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 9)/L had a complete...... response, as did 3/9 with a neutrophil count 9)/L.Compared to rHuEpo or amifostine used as single agents, their combination did not offer substantial advantages....

  5. 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.

  6. 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.

  7. Activation cross-sections of longer-lived products of proton induced nuclear reactions on dysprosium up to 36 MeV

    OpenAIRE

    Tárkányi, F.; Ditrói, F.; Takács, S.; Hermanne, A.; Ignatyuk, A. V.

    2013-01-01

    Activation cross-sections of longer-lived products of proton induced nuclear reactions on dysprosium were measured up to 36 MeV by using stacked foil irradiation technique and gamma-spectrometry. We report for the first time experimental cross-sections for the formation of the radionuclides 162mHo, 161Ho, 159Ho, 159Dy, 157Dy, 155Dy, 161Tb, 160Tb, 156Tb and 155Tb. The experimental data were compared with the results of cross-section calculations of the ALICE and EMPIRE nuclear model codes and ...

  8. Activation cross-sections of long lived products of deuteron induced nuclear reactions on dysprosium up to 50 MeV

    OpenAIRE

    Tárkányi, F.; Ditrói, F.; Takács, S.; Csikai, J.; Hermanne, A.; Ignatyuk, A. V.

    2014-01-01

    Activation cross-sections for production of 162m,161,155Ho,165,159,157,155Dy and 161,160,156,155Tb radionuclides in deuteron induced nuclear reactions on elemental dysprosium were measured up to 50 MeV for practical application and the test of the predictive power of nuclear reaction model codes. A stacked-foil irradiation technique and off-line gamma-ray spectrometry were used to determine the activities. No earlier cross-section data were found in the literature. The experimental data are c...

  9. Improvement of traditional local rice varieties through induced mutations using nuclear techniques

    Energy Technology Data Exchange (ETDEWEB)

    Pham Van Ro; Do Huu At [Cuu Long Delta Rice Research Institute (Viet Nam)

    2001-03-01

    'Improvement of local rice varieties for high yield, resistance to disease and insect pests (brown plant hopper and rice blast) and export quality through induced mutations for the Mekong Delta' started in 1993. After six years, it showed effecting on the field in the MD as well as at the south of Vietnam. TNDB-100 manifest very wide adaptation and yield stable variety. THDB is suitable for deepwater rice region, coastal area, where rice cultivation effected by acid sulphate and salinity conditions. Both varieties are good example for the method. Thank to good Co-operation from extension center from provinces, hundred classes of extension were organized to recommend to the farmers. And thank to the strongly supporting from IAEA so that nearly 400,000 ha of TNDB-100 occupied at the south of Vietnam as well as nearly 15,000 ha of THDB grown in the coastal as well as rainfed lowland rice areas at the South of Vietnam. To continue the rice improvement by this technique, seeds of six traditional local varieties were exposed under different dose of gamma rays to create new mutants. At present day hundred improved breeding lines were selected, a dozen of uniform lines were isolated and entranced the yield trail as well as regional testing program. From these improved varieties would be selected to contribute to the rice cultivation at the south of Vietnam in the next years. (author)

  10. Cowden syndrome-associated germline SDHD variants alter PTEN nuclear translocation through SRC-induced PTEN oxidation

    Science.gov (United States)

    Yu, Wanfeng; He, Xin; Ni, Ying; Ngeow, Joanne; Eng, Charis

    2015-01-01

    Germline mutations in the PTEN tumor-suppressor gene and germline variations in succinate dehydrogenase subunit D gene (SDHD-G12S, SDHD-H50R) are associated with a subset of Cowden syndrome and Cowden syndrome-like individuals (CS/CSL) and confer high risk of breast, thyroid and other cancers. However, very little is known about the underlying crosstalk between SDHD and PTEN in CS-associated thyroid cancer. Here, we show SDHD-G12S and SDHD-H50R lead to impaired PTEN function through alteration of its subcellular localization accompanied by resistance to apoptosis and induction of migration in both papillary and follicular thyroid carcinoma cell lines. Other studies have shown elevated proto-oncogene tyrosine kinase (SRC) activity in invasive thyroid cancer cells; so, we explore bosutinib, a specific inhibitor for SRC, to explore SRC as a mediator of SDH-PTEN crosstalk in this context. We show that SRC inhibition could rescue SDHD dysfunction-induced cellular phenotype and tumorigenesis only when wild-type PTEN is expressed, in thyroid cancer lines. Patient lymphoblast cells carrying either SDHD-G12S or SDHD-H50R also show increased nuclear PTEN and more oxidized PTEN after hydrogen peroxide treatment. Like in thyroid cells, bosutinib decreases oxidative PTEN in patient lymphoblast cells carrying SDHD variants, but not in patients carrying both SDHD variants and PTEN truncating mutations. In summary, our data suggest a novel mechanism whereby SDHD germline variants SDHD-G12S or SDHD-H50R induce thyroid tumorigenesis mediated by PTEN accumulation in the nucleus and may shed light on potential treatment with SRC inhibitors like bosutinib in PTEN-wild-type SDHD-variant/mutation positive CS/CSL patients and sporadic thyroid neoplasias. PMID:25149476

  11. MicroRNA-194 Regulates Lipopolysaccharide-Induced Cell Viability by Inactivation of Nuclear Factor-κ B Pathway

    Directory of Open Access Journals (Sweden)

    Fei  Xie

    2017-10-01

    Full Text Available The present study explored the functional role of microRNA (miR-194 in lipopolysaccharide (LPS induced lung cell injury, along with the underlying mechanisms and to reveal the potential role in infantile pneumonia. Human fibroblasts WI38 cells were transfected with miR-194 mimic or miR-194 inhibitor, and the transfection efficiency was confirmed by quantitative real-time polymerase chain reaction (qRT-PCR. Thereafter, the cells were treated with or without LPS, and then cell viability, cell apoptosis and mRNA and protein expressions of key proteins of nuclear factor kappa B (NF-κB pathway including inhibitor of NF-κB (IκB α, p-65, and B-cell CLL/lymphoma (Bcl 3 were analyzed. Results showed that overexpression and suppression of miR-194 was effective. Administration of LPS significantly decreased the cell viability and statistically promoted the percentages of apoptotic cells and increased the mRNA and protein expressions of p-65 and Bcl-3 but downregulated IκBα compared to the control group (P < 0.05 or P < 0.01. LPS in combination with miR-194 suppression further enhanced the effects of LPS on cell viability and cell apoptosis compared to the LPS group (P < 0.05. In contrast, LPS in combination with miR-194 overexpression observably reversed the effects of LPS on cell viability, cell apoptosis and mRNA and protein expressions of the key proteins (P < 0.05 or P < 0.01. In conclusion, miR-194 increases the LPS-induced the inhibition of cell viability and increasing of the cell apoptosis by inhibition of NF-κB pathway in WI38 cells. MiR-194 might be a potential targeted therapy for treatment of infantile pneumonia.

  12. Satellite cell response to erythropoietin treatment and endurance training in healthy young men.

    Science.gov (United States)

    Hoedt, Andrea; Christensen, Britt; Nellemann, Birgitte; Mikkelsen, Ulla Ramer; Hansen, Mette; Schjerling, Peter; Farup, Jean

    2016-02-01

    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-receptor interaction. Moreover, endurance training, but not Epo treatment, increases the SC content in type II myofibres, as well as the content of MyoD(+) SCs. Collectively, our results suggest that Epo treatment can regulate human SCs in vivo, supported by Epo receptor mRNA expression in human SCs. In effect, long-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 to investigate the effects of prolonged erythropoiesis-stimulating agent (ESA; darbepoetin-α) treatment and endurance training, separately and combined, on SC quantity and commitment in human skeletal muscle. Thirty-five healthy, untrained men were randomized into four groups: sedentary-placebo (SP, n = 9), sedentary-ESA (SE, n = 9), training-placebo (TP, n = 9) or training-ESA (TE, n = 8). ESA/placebo was injected once weekly and training consisted of ergometer cycling three times a week for 10 weeks. Prior to and following the intervention period, blood samples and muscle biopsies were obtained and maximal oxygen uptake (V̇O2, max) was measured. Immunohistochemical analyses were used to quantify fibre type specific SCs (Pax7(+)), myonuclei and active SCs (Pax7(+)/MyoD(+)). ESA

  13. Thermal annihilation of photo-induced radicals following dynamic nuclear polarization to produce transportable frozen hyperpolarized 13C-substrates

    Science.gov (United States)

    Capozzi, Andrea; Cheng, Tian; Boero, Giovanni; Roussel, Christophe; Comment, Arnaud

    2017-06-01

    Hyperpolarization via dynamic nuclear polarization (DNP) is pivotal for boosting magnetic resonance imaging (MRI) sensitivity and dissolution DNP can be used to perform in vivo real-time 13C MRI. The type of applications is however limited by the relatively fast decay time of the hyperpolarized spin state together with the constraint of having to polarize the 13C spins in a dedicated apparatus nearby but separated from the MRI magnet. We herein demonstrate that by polarizing 13C with photo-induced radicals, which can be subsequently annihilated using a thermalization process that maintains the sample temperature below its melting point, hyperpolarized 13C-substrates can be extracted from the DNP apparatus in the solid form, while maintaining the enhanced 13C polarization. The melting procedure necessary to transform the frozen solid into an injectable solution containing the hyperpolarized 13C-substrates can therefore be performed ex situ, up to several hours after extraction and storage of the polarized solid.

  14. Novel Nuclear Factor-KappaB Targeting Peptide Suppresses β-Amyloid Induced Inflammatory and Apoptotic Responses in Neuronal Cells

    Science.gov (United States)

    Srinivasan, Mythily; Bayon, Baindu; Chopra, Nipun; Lahiri, Debomoy K.

    2016-01-01

    In the central nervous system (CNS), activation of the transcription factor nuclear factor-kappa B (NF-κβ) is associated with both neuronal survival and increased vulnerability to apoptosis. The mechanisms underlying these dichotomous effects are attributed to the composition of NF-κΒ dimers. In Alzheimer’s disease (AD), β-amyloid (Aβ) and other aggregates upregulate activation of p65:p50 dimers in CNS cells and enhance transactivation of pathological mediators that cause neuroinflammation and neurodegeneration. Hence selective targeting of activated p65 is an attractive therapeutic strategy for AD. Here we report the design, structural and functional characterization of peptide analogs of a p65 interacting protein, the glucocorticoid induced leucine zipper (GILZ). By virtue of binding the transactivation domain of p65 exposed after release from the inhibitory IκΒ proteins in activated cells, the GILZ analogs can act as highly selective inhibitors of activated p65 with minimal potential for off-target effects. PMID:27764084

  15. Cross section measurements of deuteron induced nuclear reactions on natural titanium up to 34 MeV.

    Science.gov (United States)

    Duchemin, C; Guertin, A; Haddad, F; Michel, N; Métivier, V

    2015-09-01

    Experimental cross sections for deuteron induced nuclear reactions on natural titanium were measured, using the stacked-foil technique and gamma spectrometry, up to 34 MeV with beams provided by the ARRONAX cyclotron. The experimental cross section values were monitored using the (nat)Ti(d,x)(48)V reaction, recommended by the IAEA. The excitation functions for (nat)Ti(d,x)(44m,46,47,48)Sc are presented and compared with the existing ones and with the TALYS 1.6 code calculations using default models. Our experimental values are in good agreement with data found in the literature. TALYS 1.6 is not able to give a good estimation of the production cross sections investigated in this work. These production cross sections of scandium isotopes fit with the new Coordinated Research Project (CRP) launched by the International Atomic Energy Agency (IAEA) to expand the database of monitor reactions. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Astrophysics Unearthed: Measuring the Beam-Induced 13C(d,n) Background in Underground Nuclear Astrophysics Experiments

    Science.gov (United States)

    Ummel, C. C.; Walter, D.; Corrado, F.; Cizewski, J. A.; Febbraro, M.; Pain, S. D.; Bannister, M. E.; Havener, C. C.; Chipps, K. A.; Temanson, E.; Peters, W. A.

    2017-09-01

    The slow neutron capture process (s-process) is a series of nuclear reactions responsible for the synthesis of approximately half the atomic nuclei heavier than iron. The s-process proceeds via a series of neutron capture and beta decay reactions in the low neutron flux environment of AGB stars. The primary source of neutrons for the s-process is the 13C(α,n)16O reaction. Extrapolation of the 13C(α,n) S-factor into the Gamow window is complicated by the unknown influence of a 1/2+ resonance in 17O near the alpha capture threshold, prompting an international effort to directly measure the cross section at low energies. Measurement of the 13C(α,n) cross section is made difficult by beam-induced background, such as deuterium contamination in the alpha particle beams of most accelerators. At astrophysically relevant energies, the 13C(d,n) cross section is many orders of magnitude higher than that of 13C(α,n). Accordingly, the 13C(d,n) cross section was measured at laboratory energies below 250 keV (corresponding to alpha beam energies of 500 keV and below) at Oak Ridge National Laboratory's Multicharged Ion Research Facility. Preliminary results and the implications of this work are discussed. This work is supported in part by the U.S. Department of Energy and the National Science Foundation.

  17. Programmed Cell Death, Proliferating Cell Nuclear Antigen and p53 Expression in Mouse Colon Mucosa during Diet-Induced Tumorigenesis

    Directory of Open Access Journals (Sweden)

    Mauro Risio

    2000-01-01

    Full Text Available Western‐style diets (WDs trigger and sustain the early phases of tumorigenesis in mouse colon, and when continued throughout the life span lead to the development of dysplastic crypts. In order to evaluate the roles both of cell proliferation and programmed cell death (PCD in WD‐induced tumorigenesis, immunohistochemical detection of proliferating nuclear antigen (PCNA, in situ end labeling (TUNEL of DNA breaks, and p53 protein were carried out in mouse colonic mucosa during prolonged feeding of two WDs. PCNA Labeling Index of colonic crypts was significantly higher in WD‐treated animals than in controls only at the beginning of the nutritional study, the gap rapidly bridged by increased cell proliferation spontaneously occurring in the colonic mucosa during aging. A transient early homeostatic activation of PCD at the base of the crypt also was observed in WD groups. No changes in PCD were seen in the upper third of the crypt or in surface epithelium throughout the study, indicating that PCD in that colonic crypt segment produces a constant flux of cell loss, uninfluenced by homeostatic fluctuations. A major finding was an irreversible, progressive, age‐related decline of PCD at the crypt base in both control and treated animals that occurred during the second half of the rodents  life span. p53 protein was not immunohistochemically detected, suggesting that neither overexpression of wild‐type nor mutated forms of the protein are involved in the above mentioned changes.

  18. Impact of anemia prevention by recombinant human erythropoietin on the sensitivity of xenografted glioblastomas to fractionated irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Stueben, G.; Poettgen, C.; Knuehmann, K.; Sack, H.; Stuschke, M. [West German Tumor Center, Dept. of Radiotherapy, Univ. Hospital Essen (Germany); Thews, O.; Vaupel, P. [Inst. of Physiology and Pathophysiology, Univ. of Mainz (Germany)

    2003-09-01

    Background: Pronounced oxygen deficiency in tumors which might be caused by a diminished oxygen transport capacity of the blood (e.g., in anemia) reduces the efficacy of ionizing radiation. The aim of this study was to analyze whether anemia prevention by recombinant human erythropoietin (rHuEPO) affects the radiosensitivity of human glioblastoma xenografts during fractionated irradiation. Material and Methods: Anemia was induced by total body irradiation (TBI, 2 x 4 Gy) of mice prior to tumor implantation into the subcutis of the hind leg. In one experimental group, the development of anemia was prevented by rHuEPO (750 U/kg s.c.) given three times weekly starting 10 days prior to TBI. 13 days after tumor implantation (tumor volume approx. 40 mm{sup 3}), fractionated irradiation (4 x 7 Gy, one daily fraction) of the glioblastomas was performed resulting in a growth delay with subsequent regrowth of the tumors. Results: Compared to nonanemic control animals (hemoglobin concentration cHb = 14.7 g/dl), the growth delay in anemic mice (cHb = 9.9 g/dl) was significantly shorter (49 {+-} 5 days vs. 79 {+-} 4 days to reach four times the initial tumor volume) upon fractionated radiation. The prevention of anemia by rHuEPO treatment (cHb = 13.3 g/dl) resulted in a significantly prolonged growth delay (61 {+-} 5 days) compared to the anemia group, even though the growth inhibition found in control animals was not completely achieved. Conclusions: These data indicate that moderate anemia significantly reduces the efficacy of radiotherapy. Prevention of anemia with rHuEPO partially restores the radiosensitivity of xenografted glioblastomas to fractionated irradiation. (orig.)

  19. Differential short-term regional effects of early high dose erythropoietin on white matter in preterm lambs after mechanical ventilation.

    Science.gov (United States)

    Barton, Samantha K; McDougall, Annie R A; Melville, Jacqueline M; Moss, Timothy J M; Zahra, Valerie A; Lim, Tammy; Crossley, Kelly J; Polglase, Graeme R; Tolcos, Mary

    2016-03-01

    Inadvertently injurious ventilation of preterm neonates in the delivery room can cause cerebral white matter (WM) inflammation and injury. We investigated the impact of an early high dose of recombinant human erythropoietin (EPO) on ventilation-induced WM changes in preterm lambs. Injurious ventilation, targeting a V(T) of 15 ml kg(-1) with no positive end-expiratory pressure, was initiated for 15 min in preterm lambs (0.85 gestation). Conventional ventilation was continued for a further 105 min. Lambs received either 5000 IU kg(-1) of EPO (EPREX®; Vent+EPO; n = 6) or vehicle (Vent; n = 8) via an umbilical vein at 4 ± 2 min. Markers of WM injury and inflammation were assessed using quantitative real-time PCR (qPCR) and immunohistochemistry and compared to a group of unventilated controls (UVC; n = 4). In Vent+EPO lambs compared to Vent lambs: (i) interleukin (IL)-1β and IL-6 mRNA levels in the periventricular WM and IL-8 mRNA levels in the subcortical WM were higher (P < 0.05 for all); (ii) the density of microglia within the aggregations was not different in the periventricular WM and was lower in the subcortical WM (P = 0.001); (iii) the density of astrocytes was lower in the subcortical WM (P = 0.002); (iv) occludin and claudin-1 mRNA levels were higher in the periventricular WM (P < 0.02 for all) and (vi) the number of blood vessels with protein extravasation was lower (P < 0.05). Recombinant human EPO had variable regional effects within the WM when administered during injurious ventilation. The adverse short-term outcomes discourage the use of early high dose EPO administration in preterm ventilated babies. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

  20. Nuclear envelope breakdown induced by herpes simplex virus type 1 involves the activity of viral fusion proteins.

    Science.gov (United States)

    Maric, Martina; Haugo, Alison C; Dauer, William; Johnson, David; Roller, Richard J

    2014-07-01

    Herpesvirus infection reorganizes components of the nuclear lamina usually without loss of integrity of the nuclear membranes. We report that wild-type HSV infection can cause dissolution of the nuclear envelope in transformed mouse embryonic fibroblasts that do not express torsinA. Nuclear envelope breakdown is accompanied by an eight-fold inhibition of virus replication. Breakdown of the membrane is much more limited during infection with viruses that lack the gB and gH genes, suggesting that breakdown involves factors that promote fusion at the nuclear membrane. Nuclear envelope breakdown is also inhibited during infection with virus that does not express UL34, but is enhanced when the US3 gene is deleted, suggesting that envelope breakdown may be enhanced by nuclear lamina disruption. Nuclear envelope breakdown cannot compensate for deletion of the UL34 gene suggesting that mixing of nuclear and cytoplasmic contents is insufficient to bypass loss of the normal nuclear egress pathway. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. Nuclear astrophysics

    Science.gov (United States)

    Penionzhkevich, Yu. E.

    2010-08-01

    The International Year of Astronomy 2009 (IYA2009) was declared by the 62nd General Assembly of the United Nations and was also endorsed by UNESCO. Investigations in the realms of particle and nuclear physicsmake a large contribution in the development of our ideas of the properties of the Universe. The present article discusses some problems of the evolution of the Universe, nucleosyntheses, and cosmochronology from the point of view of nuclear and particle physics. Processes occurring in the Universe are compared with the mechanisms of the production and decay of nuclei, as well as with the mechanisms of their interaction at high energies. Examples that demonstrate the potential of nuclearphysics methods for studying cosmic objects and the properties of the Universe are given. The results that come from investigations into nuclear reactions induced by beams of radioactive nuclei and which make it possible to take a fresh look at the nucleosynthesis scenario in the range at light nuclei are presented.

  2. 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.

  3. 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.

  4. Electric-Field-Induced Nuclear Spin Resonance Mediated by Oscillating Electron Spin Domains in GaAs-Based Semiconductors

    OpenAIRE

    Kumada, N.; Kamada, T.; Miyashita, S.; Hirayama, Y.; Fujisawa, T.

    2008-01-01

    We demonstrate an alternative nuclear spin resonance using radio frequency (RF) electric field (nuclear electric resonance: NER) instead of magnetic field. The NER is based on the electronic control of electron spins forming a domain structure. The RF electric field applied to a gate excites spatial oscillations of the domain walls and thus temporal oscillations of the hyperfine field to nuclear spins. The RF power and burst duration dependence of the NER spectrum provides insight into the in...

  5. Electric field induced nuclear spin resonance mediated by oscillating electron spin domains in GaAs-based semiconductors.

    Science.gov (United States)

    Kumada, N; Kamada, T; Miyashita, S; Hirayama, Y; Fujisawa, T

    2008-09-26

    We demonstrate an alternative nuclear spin resonance using a radio frequency (rf) electric field [nuclear electric resonance (NER)] instead of a magnetic field. The NER is based on the electronic control of electron spins forming a domain structure. The rf electric field applied to a gate excites spatial oscillations of the domain walls and thus temporal oscillations of the hyperfine field to nuclear spins. The rf power and burst duration dependence of the NER spectrum provides insight into the interplay between nuclear spins and the oscillating domain walls.

  6. 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...

  7. 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 Epo...

  8. Interactions of erythropoietin, granulocyte colony-stimulating factor, stem cell factor, and interleukin-11 on murine hematopoiesis during simultaneous administration

    NARCIS (Netherlands)

    Roeder, [No Value; de Haan, G; Engel, C; Nijhof, W; Dontje, B; Loeffler, M

    1998-01-01

    We investigated how in vivo effects of single hematopoietic cytokines change if given in combination for a prolonged time. Mice were treated with every combination of recombinant human (rh) erythropoietin (EPO), rh granulocyte colony-stimulating factor (G-CSF), recombinant rat (rr) stem cell factor

  9. Impact of hepcidin, interleukin 6, and other inflammatory markers with respect to erythropoietin on anemia in chronic hemodialysis patients

    Directory of Open Access Journals (Sweden)

    Ihab A. Ibrahim

    2014-01-01

    Conclusion Serum hepcidin levels were associated with iron status and inflammation in maintenance hemodialysis patients, and the high hepcidin serum levels, found in hemodialysis (HD patients, are dependent on the magnitude of the inflammatory process and on recombinant human erythropoietin doses. Hepcidin and its regulatory pathways are potential therapeutic targets, which could lead to effective treatment of anemia in chronic hemodialysis.

  10. 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; Helbo, Signe

    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...

  11. 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.

    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,

  12. Chemically Induced Dynamic Nuclear Polarization during the Thermolysis of Alkoxyamines: A New Approach to Detect the Occurrence of H-Transfer Reactions

    Directory of Open Access Journals (Sweden)

    Elena Bagryanskaya

    2010-09-01

    Full Text Available Thermal decomposition of alkoxyamines in the presence of scavengers was found to proceed with the formation of chemically induced nuclear polarization detected by 1H NMR. The distinctive Chemically Induced Dynamic Nuclear Polarization (CIDNP features were studied using the example of three alkoxyamines: 4-nitrophenyl 2-(2,2,6,6-tetramethylpiperidin-1-yloxy-2-methylpropanoate (1a, 4-nitrophenyl 2-(2,2-diphenyl-3-phenylimino-2,3-dihydroindol-1-yloxy-2-methylpropanoate (2a and 4-nitrophenyl 2-(2,2,5,5-tetramethyl-4-phenyl-2H-imidazol-1-oxy-2-methylpropanoate (3a in the presence of PhSH. The analysis of CIDNP signs of methacrylate protons allows us to conclude on the occurrence of hydrogen atom transfer reaction in geminate radical pair formed in alkoxyamine thermolysis. Thus, CIDNP is a fast and sensitive method to detect the occurrence of intra/intermolecular hydrogen transfer in alkoxyamine thermolysis.

  13. Importin β1 protein-mediated nuclear localization of death receptor 5 (DR5) limits DR5/tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced cell death of human tumor cells.

    Science.gov (United States)

    Kojima, Yuko; Nakayama, Masafumi; Nishina, Takashi; Nakano, Hiroyasu; Koyanagi, Makoto; Takeda, Kazuyoshi; Okumura, Ko; Yagita, Hideo

    2011-12-16

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/death receptor 5 (DR5)-mediated cell death plays an important role in the elimination of tumor cells and transformed cells. Recently, recombinant TRAIL and agonistic anti-DR5 monoclonal antibodies have been developed and applied to cancer therapy. However, depending on the type of cancer, the sensitivity to TRAIL has been reportedly different, and some tumor cells are resistant to TRAIL-mediated apoptosis. Using confocal microscopy, we found that large amounts of DR5 were localized in the nucleus in HeLa and HepG2 cells. Moreover, these tumor cells were resistant to TRAIL, whereas DU145 cells, which do not have nuclear DR5, were highly sensitive to TRAIL. By means of immunoprecipitation and Western blot analysis, we found that DR5 and importin β1 were physically associated, suggesting that the nuclear DR5 was transported through the nuclear import pathway mediated by importin β1. Two functional nuclear localization signals were identified in DR5, the mutation of which abrogated the nuclear localization of DR5 in HeLa cells. Moreover, the nuclear transport of DR5 was also prevented by the knockdown of importin β1 using siRNA, resulting in the up-regulation of DR5 expression on the cell surface and an increased sensitivity of HeLa and HepG2 cells to TRAIL. Taken together, our findings suggest that the importin β1-mediated nuclear localization of DR5 limits the DR5/TRAIL-induced cell death of human tumor cells and thus can be a novel target to improve cancer therapy with recombinant TRAIL and anti-DR5 antibodies.

  14. Placotylene A, an Inhibitor of the Receptor Activator of Nuclear Factor-κB Ligand-Induced Osteoclast Differentiation, from a Korean Sponge Placospongia sp.

    Directory of Open Access Journals (Sweden)

    Hiyoung Kim

    2014-04-01

    Full Text Available A new inhibitor, placotylene A (1, of the receptor activator of nuclear factor-κB ligand (RANKL-induced osteoclast differentiation, and a regioisomer of placotylene A, placotylene B (2, were isolated from a Korean marine sponge Placospongia sp. The chemical structures of placotylenes A and B were elucidated on the basis of 1D and 2D NMR, along with MS spectral analysis and revealed as an iodinated polyacetylene class of natural products. Placotylene A (1 displayed inhibitory activity against RANKL-induced osteoclast differentiation at 10 μM while placotylene B (2 did not show any significant activity up to 100 μM, respectively.

  15. Effects of intratracheal administration of nuclear factor-kappaB decoy oligodeoxynucleotides on long-term cigarette smoke-induced lung inflammation and pathology in mice

    OpenAIRE

    Li, Yu-Tao; He, Bei; Wang, Yu-Zhu; Wang, Jing

    2009-01-01

    Abstract To determine if nuclear factor-κB (NF-κB) activation may be a key factor in lung inflammation and respiratory dysfunction, we investigated whether NF-κB can be blocked by intratracheal administration of NF-κB decoy oligodeoxynucleotides (ODNs), and whether decoy ODN-mediated NF-κB inhibition can prevent smoke-induced lung inflammation, respiratory dysfunction, and improve pathological alteration in the small airways and lung parenchyma in the long-term smoke-induced mouse model syste...

  16. Recombinant human erythropoietin pretreatment attenuates acute renal tubular injury against ischemia-reperfusion by restoring transient receptor potential channel-6 expression and function in collecting ducts.

    Science.gov (United States)

    Shen, Sai'e; Jin, Yi; Li, Weiyan; Liu, Xiaoming; Zhang, Tingting; Xia, Weiliang; Wang, Yingwei; Ma, Ke

    2014-10-01

    Acute renal tubular injury is a serious complication in the postoperative period, which is associated with high mortality and increased ICU stay. We aimed to demonstrate the protective effect of rhEPO against acute tubular injury induced by ischemia-reperfusion and to explore the mechanism of canonical transient receptor potential channel-6. Randomized laboratory animal study. Animal research laboratory. Male Sprague-Dawley rats were randomly divided into three groups: the sham group, the control group, and the rhEPO group. Experimental acute tubular injury was established in rats by bilateral renal arterial occlusion for 30 minutes followed by reperfusion. Blood samples were obtained for cystatin-C and neutrophil gelatinase-associated lipocalin measurements by enzyme-linked immunosorbance assays. Seventy-two hours after reperfusion, urine samples were collected for osmolality and fractional excretion of sodium (%) assays on a chemistry analyzer. Kidneys were harvested at 24, 48, and 72 hours after reperfusion. Transient receptor potential channel-6, aquaporin-2, and Na,K-ATPase expression in collecting ducts were studied by immunofluorescence and Western blot. Coimmunoprecipitations were also performed to identify the possible signalplex relation between transient receptor potential channel-6 and aquaporin-2 or Na,K-ATPase channels. RhEPO pretreatment significantly inhibited serum cystatin-C (2 hr: 453 ± 64 μg/L vs 337 ± 28 μg/L, p human erythropoietin greatly improved the ischemia-reperfusion-induced attenuation of transient receptor potential channel-6 expression (48 hr: 42% ± 2% vs 67% ± 2% and 72 hr: 55% ± 2% vs 66% ± 2%), as well as aquaporin-2 and Na,K-ATPase expression in collecting ducts. Transient receptor potential channel-6 functionally interacted with Na,K-ATPase but not aquaporin-2. Recombinant human erythropoietin pretreatment at the dose of 5,000 IU/kg potently prevented ischemia-reperfusion-induced acute tubular injury, which might be

  17. Productive and Penicillin-StressedChlamydia pecorumInfection Induces Nuclear Factor Kappa B Activation and Interleukin-6 SecretionIn Vitro.

    Science.gov (United States)

    Leonard, Cory A; Schoborg, Robert V; Borel, Nicole

    2017-01-01

    Nuclear factor kappa B (NFκB) is an inflammatory transcription factor that plays an important role in the host immune response to infection. The potential for chlamydiae to activate NFκB has been an area of interest, however most work has focused on chlamydiae impacting human health. Given that inflammation characteristic of chlamydial infection may be associated with severe disease outcomes or contribute to poor overall fitness in farmed animals, we evaluated the ability of porcine chlamydiae to induce NFκB activation in vitro . C. pecorum infection induced both NFκB nuclear translocation and activation at 2 hours post infection (hpi), an effect strongly enhanced by suppression of host de novo protein synthesis. C. suis and C. trachomatis showed less capacity for NFκB activation compared to C. pecorum , suggesting a species-specific variation in NFκB activation. At 24 hpi, C. pecorum induced significant NFκB activation, an effect not abolished by penicillin (beta lactam)-induced chlamydial stress. C. pecorum -dependent secretion of interleukin 6 was also detected in the culture supernatant of infected cells at 24 hpi, and this effect, too, was unchanged by penicillin-induced chlamydial stress. Taken together, these results suggest that NFκB participates in the early inflammatory response to C. pecorum and that stressed chlamydiae can promote inflammation.

  18. Nuclear Medicine

    Science.gov (United States)

    ... Parents/Teachers Resource Links for Students Glossary Nuclear Medicine What is nuclear medicine? What are radioactive tracers? ... funded researchers advancing nuclear medicine? What is nuclear medicine? Nuclear medicine is a medical specialty that uses ...

  19. Effects of ganglioside G(M1 and erythropoietin on spinal cord lesions in rats: functional and histological evaluations

    Directory of Open Access Journals (Sweden)

    Raphael Martus Marcon

    Full Text Available OBJECTIVE: To evaluate the functional and histological effects of ganglioside G(M1 and erythropoietin after experimental spinal cord contusion injury. METHODS: Fifty male Wistar rats underwent experimental spinal cord lesioning using an NYU-Impactor device and were randomly divided into the following groups, which received treatment intraperitoneally. The G(M1 group received ganglioside G(M1 (30 mg/kg; the erythropoietin group received erythropoietin (1000 IU/kg; the combined group received both drugs; and the saline group received saline (0.9% as a control. A fifth group was the laminectomy group, in which the animals were subjected to laminectomy alone, without spinal lesioning or treatment. The animals were evaluated according to the Basso, Beattie and Bresnahan (BBB scale, motor evoked potential recordings and, after euthanasia, histological analysis of spinal cord tissue. RESULTS: The erythropoietin group had higher BBB scores than the G(M1 group. The combined group had the highest BBB scores, and the saline group had the lowest BBB scores. No significant difference in latency was observed between the three groups that underwent spinal cord lesioning and intervention. However, the combined group showed a significantly higher signal amplitude than the other treatment groups or the saline group (p<0.01. Histological tissue analysis showed no significant difference between the groups. Axonal index was significantly enhanced in the combined group than any other intervention (p<0.01. CONCLUSION: G(M1 and erythropoietin exert therapeutic effects on axonal regeneration and electrophysiological and motor functions in rats subjected to experimental spinal cord lesioning and administering these two substances in combination potentiates their effects.

  20. Quantification of Petrophysical Properties and Their Correlations with Nuclear Magnetic Resonance and Spectral Induced Polarization Responses in Carbonate

    Science.gov (United States)

    Zhang, F.; Zhang, C.

    2016-12-01

    Carbonate rocks are well known for their highly complex petrophysical behaviors due to their intrinsically heterogeneous pore geometry. This laboratory study focuses on integrating two geophysical methods: nuclear magnetic resonance (NMR) and spectral induced polarization (SIP) to determine porosity, pore size distribution, and permeability of various carbonate rock samples. Carbonate samples from Pennsylvanian and Mississippian reservoir are selected from four classes (mudstones, packstones, wackstones and grainstones), with distinct depositional fabrics and pore system. NMR measures the relaxation of hydrogen nuclei at pore scale, and SIP determines dielectric property of a sample and is sensitive to the interfacial properties at mineral-fluid. Samples were fully saturated for T2 relaxation and complex conductivity measurements. The permeability and porosity were also obtained from Klinkenberg K-air tests. Additionally, the results from thin section, mercury intrusion, and gas adsorption will be used to calibrate NMR and SIP datasets and further analyze the control of porosity, pore size distribution, and specific surface on NMR and SIP signals. Comparing T2 relaxation and complex conductivity with petrographic and analytical data on pore attributes, our results elucidate how porosity, pore size distribution, and permeability correlate in carbonate pore system. Porosity (phi)-permeability (K)-T2,ML plots illustrate the general distribution of samples' petrophysical properties. Clusters of four rock classes, as well as linear correlations between phi-K, and phi-T2 can be identified from these plots. Furthermore, variations of peak frequencies of phase changes in samples indicate that pore size distribution has the critical impact on SIP responses. As the first attempt to characterize carbonates with integrated NMR and SIP method, these results would help establish correlations among pore attributes, permeability and NMR/SIP responses, and provide reasonable

  1. Inducibility of nuclear Rad51 foci after DNA damage distinguishes all Fanconi anemia complementation groups from D1/BRCA2

    Energy Technology Data Exchange (ETDEWEB)

    Godthelp, Barbara C. [Department of Toxicogenetics, Leiden University Medical Center, Wassenaarseweg 72, NL-2333 AL Leiden (Netherlands); Wiegant, Wouter W. [Department of Toxicogenetics, Leiden University Medical Center, Wassenaarseweg 72, NL-2333 AL Leiden (Netherlands); Waisfisz, Quinten [Department of Clinical Genetics and Human Genetics, Free University Medical Center, Van der Boechorststraat 7, NL-1081 BT Amsterdam (Netherlands); Medhurst, Annette L. [Department of Clinical Genetics and Human Genetics, Free University Medical Center, Van der Boechorststraat 7, NL-1081 BT Amsterdam (Netherlands); Arwert, Fre [Department of Clinical Genetics and Human Genetics, Free University Medical Center, Van der Boechorststraat 7, NL-1081 BT Amsterdam (Netherlands); Joenje, Hans [Department of Clinical Genetics and Human Genetics, Free University Medical Center, Van der Boechorststraat 7, NL-1081 BT Amsterdam (Netherlands); Zdzienicka, Malgorzata Z. [Department of Toxicogenetics, Leiden University Medical Center, Wassenaarseweg 72, NL-2333 AL Leiden (Netherlands) and Department of Molecular Cell Genetics, Collegium Medicum, N. Copernicus University, Bydgoszcz (Poland)]. E-mail: m.z.zdzienicka@lumc.nl

    2006-02-22

    Fanconi anemia (FA) is a cancer susceptibility disorder characterized by chromosomal instability and hypersensitivity to DNA cross-linking agents. So far 11 complementation groups have been identified, from which only FA-D1/BRCA2 and FA-J are defective downstream of the central FANCD2 protein as cells from these groups are capable of monoubiquitinating FANCD2. In this study we show that cells derived from patients from the new complementation groups, FA-I, FA-J and FA-L are all proficient in DNA damage induced Rad51 foci formation, making the cells from FA-D1/BRCA2 patients that are defective in this process the sole exception. Although FA-B patient HSC230 was previously reported to also have biallelic BRCA2 mutations, we found normal Rad51 foci formation in cells from this patient, consistent with the recent identification of an X-linked gene being mutated in four unrelated FA-B patients. Thus, our data show that none of the FA proteins, except BRCA2, are required to sequester Rad51 into nuclear foci. Since cells from the FA-D1 and FA-J patient groups are both able to monoubiquitinate FANCD2, the 'Rad51 foci phenotype' provides a convenient assay to distinguish between these two groups. Our results suggest that FANCJ and FANCD1/BRCA2 are part of the integrated FANC/BRCA DNA damage response pathway or, alternatively, that they represent sub-pathways in which only FANCD1/BRCA2 is directly connected to the process of homologous recombination.

  2. Niacin and Selenium Attenuate Sepsis-Induced Lung Injury by Up-Regulating Nuclear Factor Erythroid 2-Related Factor 2 Signaling.

    Science.gov (United States)

    Kwon, Woon Yong; Suh, Gil Joon; Kim, Kyung Su; Jung, Yoon Sun; Kim, Sung Hee; Kim, Jae Seong; You, Kyoung Min

    2016-06-01

    To determine whether the combination therapy of niacin and selenium attenuates lung injury and improves survival during sepsis in rats and whether its benefits are associated with the activation of the glutathione redox cycle and up-regulation of nuclear factor erythroid 2-related factor 2. Prospective laboratory study. University laboratory. Human lung microvascular endothelial cells and male Sprague-Dawley rats (n = 291). In lipopolysaccharide-exposed cells, the dose-related effects of niacin and selenium were assessed, and the therapeutic effects of the combination therapy of niacin (0.9 mM) and selenium (1.5 μM) were evaluated. The role of nuclear factor erythroid 2-related factor 2 was determined using nuclear factor erythroid 2-related factor 2 knockdown cells. In endotoxemic and cecal ligation and puncture with antibiotics rats, the therapeutic effects of the posttreatments of clinically relevant doses of niacin (360 mg/kg) and selenium (60 μg/kg) were evaluated. Combination therapy reduced the hydrogen peroxide level via the synergistic activation of the glutathione redox cycle, which involves niacin-induced increases in glutathione reductase activity, and reduced the glutathione level and a selenium-induced increase in glutathione peroxidase activity. Combination therapy contributed to the up-regulation of nuclear factor erythroid 2-related factor 2, enhancement of glutathione synthesis, and down-regulation of nuclear factor κB signaling, but nuclear factor erythroid 2-related factor 2 knockdown inhibited the enhancement of glutathione synthesis and down-regulation of the nuclear factor κB pathway. The therapeutic effects of combination therapy on endotoxemic rats were consistent with those on lipopolysaccharide-exposed cells. In addition, the posttreatment of combination therapy attenuated lung injury and improved survival in endotoxemic and cecal ligation and puncture with antibiotics rats. However, individual therapies of niacin or selenium

  3. MicroRNA-1301-Mediated RanGAP1 Downregulation Induces BCR-ABL Nuclear Entrapment to Enhance Imatinib Efficacy in Chronic Myeloid Leukemia Cells.

    Science.gov (United States)

    Lin, Tsung-Yao; Chen, Ku-Chung; Liu, Hsing-Jin Eugene; Liu, Ann-Jeng; Wang, Kun-Li; Shih, Chwen-Ming

    2016-01-01

    Chronic myeloid leukemia (CML) is a myeloproliferative disease. Imatinib (IM), the first line treatment for CML, is excessively expensive and induces various side effects in CML patients. Therefore, it is essential to investigate a new strategy for improving CML therapy. Our immunoblot data revealed that RanGTPase activating protein 1 (RanGAP1) protein levels increased by approximately 30-fold in K562 cells compared with those in normal cells. RanGAP1 is one of the important components of RanGTPase system, which regulates the export of nuclear protein. However, whether RanGAP1 level variation influences BCR-ABL nuclear export is still unknown. In this report, using shRNA to downregulate RanGAP1 expression level augmented K562 cell apoptosis by approximately 40% after treatment with 250 nM IM. Immunofluorescence assay also indicated that three-fold of nuclear BCR-ABL was detected. These data suggest that BCR-ABL nuclear entrapment induced by RanGAP1 downregulation can be used to improve IM efficacy. Moreover, our qRT-PCR data indicated a trend of inverse correlation between the RanGAP1 and microRNA (miR)-1301 levels in CML patients. MiR-1301, targeting the RanGAP1 3' untranslated region, decreased by approximately 100-fold in K562 cells compared with that in normal cells. RanGAP1 downregulation by miR-1301 transfection impairs BCR-ABL nuclear export to increase approximately 60% of cell death after treatment of 250 nM IM. This result was almost the same as treatment with 1000 nM IM alone. Furthermore, immunofluorescence assay demonstrated that Tyr-99 of nuclear P73 was phosphorylated accompanied with nuclear entrapment of BCR-ABL after transfection with RanGAP1 shRNA or miR-1301 in IM-treated K562 cells. Altogether, we demonstrated that RanGAP1 downregulation can mediate BCR-ABL nuclear entrapment to activate P73-dependent apoptosis pathway which is a novel strategy for improving current IM treatment for CML.

  4. Cross-talk between constitutive androstane receptor and hypoxia-inducible factor in the regulation of gene expression.

    Science.gov (United States)

    Shizu, Ryota; Shindo, Sawako; Yoshida, Takemi; Numazawa, Satoshi

    2013-05-23

    Hypoxia inducible factor (HIF) and 5'-AMP-activated protein kinase are often activated under similar physiological conditions. Constitutive androstane receptor (CAR) translocates into the nucleus in accordance with 5'-AMP-activated protein kinase and thus confers transactivation. The aim of the present study was to investigate a possible link between CAR and HIFα. Phenobarbital (PB), a typical CAR activator, increased the gene expression of HIF-target genes in the livers of mice, including erythropoietin, heme oxygenase-1 and vascular endothelial growth factor-a. PB induced an accumulation of nuclear HIF-1α and an increase in the HIF-responsive element-mediated transactivation in HepG2 cells. Cobalt chloride, a typical HIF activator, induced the gene expression of CAR-target genes, including cyp2b9 and cyp2b10, an accumulation of nuclear CAR and an increase in the PB-responsive enhancer module-mediated transactivation in the mouse liver. Immunoprecipitation-immunoblot and chromatin immunoprecipitation analyses suggest that CAR binds to the PB-responsive enhancer module with HIF-1α in the liver of untreated mice and that the complex dissociates upon PB treatment. Taken together these results suggest that CAR and HIF-α interact and reciprocally modulate the functions of each other. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  5. Nuclear factor-κB is involved in oxyhemoglobin-induced endothelin-1 expression in cerebrovascular muscle cells of the rabbit basilar artery.

    Science.gov (United States)

    Cheng, Gao; Yu, Wei H; Yan, Cong; Liu, Yao; Li, Wei J; Zhang, Dong D; Liu, Nan

    2016-08-17

    The present research was designed to investigate whether endothelin-1 (ET-1) secretion can be induced by oxyhemoglobin and whether nuclear factor κB (NF-κB) is involved in the regulation of ET-1 transcription in cerebrovascular muscle cells. Cerebrovascular muscle cells isolated from a rabbit basilar artery were stimulated by oxyhemoglobin (OxyHb) and ET-1 production was increased significantly in the supernatant. Inhibition of NF-κB with pyrrolidine dithiocarbamate and small interfering RNA decreased the expression of ET-1. Nuclear translocation of NF-κB and the degradation of IkB-α was observed with the stimulation of OxyHb. The supernatant obtained from cerebrovascular muscle cells stimulated by OxyHb produced contractions in arterial rings and was blocked by the ET-1 receptor antagonist (BQ-123). The time course of the OxyHb-induced contractions of the basilar artery rings correlated with the time course of the OxyHb-induced ET-1 secretion. The contraction of the basilar artery rings induced by OxyHb was attenuated when the artery rings were preincubated with pyrrolidine dithiocarbamate and SN50 (20 and 10 µM, respectively). These results indicate that cerebrovascular muscle cells may be an important source of ET-1 production after subarachnoid hemorrhage. NF-κB was involved in the expression of ET-1 and the inhibition of the NF-κB pathway may be beneficial for the treatment of cerebral vasospasm.

  6. Buddleja officinalis suppresses high glucose-induced vascular smooth muscle cell proliferation: role of mitogen-activated protein kinases, nuclear factor-kappaB and matrix metalloproteinases.

    Science.gov (United States)

    Lee, Yun Jung; Kim, Jin Sook; Kang, Dae Gill; Lee, Ho Sub

    2010-02-01

    Diabetes mellitus is a well-established risk factor for vascular diseases caused by atherosclerosis. In the development of diabetic atherogenesis, vascular smooth muscle cell proliferation is recognized as a key event. Thus, we aimed to investigate whether an ethanol extract of Buddleja officinalis (EBO) suppresses high glucose-induced proliferation in primary cultured human aortic smooth muscle cells (HASMC). [(3)H]-thymidine incorporation revealed that incubation of HASMC with a high concentration of glucose (25 mmol/L) increased cell proliferation. The expression levels of cell cycle protein were also increased by treatment with high glucose concentration. Pretreatment of HASMC with EBO significantly attenuated the increase of high glucose-induced cell proliferation as well as p38 mitogen-activated protein kinases (MAPK) and JNK phosphorylation. EBO suppressed high glucose-induced matrix metalloproteinase (MMP)-9 activity in a dose-dependent manner. In addition, EBO suppressed nuclear factor-kappaB (NF-kappaB) nuclear translocation and transcriptional activity in high glucose conditions. Taken together, the present data suggest that EBO could suppress high glucose-induced atherosclerotic processes through inhibition of p38, JNK, NF-kappaB and MMP signal pathways in HASMC.

  7. Protective effect of alpha glucosyl hesperidin (G-hesperidin) on chronic vanadium induced testicular toxicity and sperm nuclear DNA damage in male Sprague Dawley rats.

    Science.gov (United States)

    Vijaya Bharathi, B; Jaya Prakash, G; Krishna, K M; Ravi Krishna, C H; Sivanarayana, T; Madan, K; Rama Raju, G A; Annapurna, A

    2015-06-01

    The study was conducted to evaluate the vanadium-induced testicular toxicity and its effect on sperm parameters, sperm nuclear DNA damage and histological alterations in Sprague Dawley rats and to assess the protective effect of G-hesperidin against this damage. Treatment of rats with vanadium at a dose of 1 mg kg bw(-1) for 90 days resulted in significant reduction in serum testosterone levels, sperm count and motility. Further, a parallel increase in abnormal sperm morphology and adverse histopathological changes in testis was also associated with vanadium administration when compared to normal control. Moreover, sperm chromatin dispersion assay revealed that vanadium induces sperm nuclear DNA fragmentation. A marked increase in testicular malondialdehyde levels and decreased activity of antioxidant enzymes such as superoxide dismutase and catalase indicates vanadium-induced oxidative stress. Co-administration of G-hesperidin at a dose of 25 and 50 mg kg bw(-1) significantly attenuated the sperm parameters and histological changes by restoring the antioxidant levels in rat testis. These results suggested that vanadium exposure caused reduced bioavailability of androgens to the tissue and increased free radical formation, thereby causing structural and functional changes in spermatozoa. G-hesperidin exhibited antioxidant effect by protecting the rat testis against vanadium-induced oxidative damage, further ensures antioxidant potential of bioflavonoids. © 2014 Blackwell Verlag GmbH.

  8. Influence of erythropoietin on microvesicles derived from mesenchymal stem cells protecting renal function of chronic kidney disease.

    Science.gov (United States)

    Wang, Yan; Lu, Xingyan; He, Juan; Zhao, Weihong

    2015-05-22

    Mesenchymal stem cells (MSCs) play a central role in the remediation of cell and tissue damage. Erythropoietin (EPO) may enhance the beneficial influence of MSCs during recovery from tissue and organ injuries. Microvesicles (MVs) released from MSCs contribute to the restoration of kidney damage. We studied the influence of EPO on MVs derived from MSCs, and the protective effects of these factors in subjects with chronic kidney disease (CKD). The MVs derived from untreated MSCs (MSC-MVs) or from MSCs incubated in different concentrations of EPO (1, 10, 100, and 500 IU/ml EPO-MVs) were used to treat renal injury of unilateral ureteral obstruction (UUO) in vivo, and transforming growth factor-β1 (TGF-β1)-induced fibrosis in a human renal proximal tubular epithelial (HK2) cell line in vitro. Western blot and reverse transcription polymerase chain reaction (RT-PCR) analyses were used to evaluate the expression of epithelial and mesenchymal markers in the renal tissue and HK2 cells. Flow cytometry was used to assess apoptosis within the HK2 cells, and microRNA (miRNA) microarray assays were used to determine the expression profiles of miRNA in the MSC-MVs and EPO-MVs. Compared to MSC-MVs (untreated), there was a significant increase in the number of EPO-MVs derived from MSCs treated with 1-100 IU/ml EPO, and these EPO-MVs had a greater benefit in UUO mice on days 7 and 14. Moreover, the EPO-MVs had a better restorative effect following TGF-β1-induced fibrosis in HK2 cells at 24 h and 48 h. The flow cytometry results revealed that both types of MVs, especially EPO-MVs, play an important anti-apoptotic role in HK2 cells treated with TGF-β1. The miRNA profiles of the MVs revealed that EPO-MVs changed 212 miRNAs (fold-change ≥ 1.5), including miR-299, miR-499, miR-302, and miRNA-200, and that 70.28 % of these changes involved upregulation. The changed miRNA in EPO-MVs may have contributed to their enhanced protective effects following renal injury compared to MSC

  9. 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

  10. Novel small molecule XPO1/CRM1 inhibitors induce nuclear accumulation of TP53, phosphorylated MAPK and apoptosis in human melanoma cells.

    Directory of Open Access Journals (Sweden)

    Jennifer Yang

    Full Text Available XPO1/CRM1 is a key nuclear exporter protein that mediates translocation of numerous cellular regulatory proteins. We investigated whether XPO1 is a potential therapeutic target in melanoma using novel selective inhibitors of nuclear export (SINE. In vitro effects of SINE on cell growth and apoptosis were measured by MTS assay and flow cytometry [Annexin V/propidium iodide (PI], respectively in human metastatic melanoma cell lines. Immunoblot analysis was used to measure nuclear localization of key cellular proteins. The in vivo activity of oral SINE was evaluated in NOD/SCID mice bearing A375 or CHL-1 human melanoma xenografts. SINE compounds induced cytostatic and pro-apoptotic effects in both BRAF wild type and mutant (V600E cell lines at nanomolar concentrations. The cytostatic and pro-apoptotic effects of XPO1 inhibition were associated with nuclear accumulation of TP53, and CDKN1A induction in the A375 cell line with wild type TP53, while pMAPK accumulated in the nucleus regardless of TP53 status. The orally bioavailable KPT-276 and KPT-330 compounds significantly inhibited growth of A375 (p<0.0001 and CHL-1 (p = 0.0087 human melanoma cell lines in vivo at well tolerated doses. Inhibition of XPO1 using SINE represents a potential therapeutic approach for melanoma across cells with diverse molecular phenotypes by promoting growth inhibition and apoptosis.

  11. Patient Blood Management in Major Orthopedic Surgery: Less Erythropoietin and More Iron?

    Science.gov (United States)

    Rineau, Emmanuel; Stoyanov, Alexandra; Samson, Emmanuel; Hubert, Laurent; Lasocki, Sigismond

    2017-11-01

    Erythropoietin (EPO) is proposed preoperatively to reduce blood transfusion in anemic patients (hemoglobin < 13 g/dL) scheduled for a major orthopedic surgery. New intravenous iron formulations allow infusion of higher doses, increasing EPO response. In that context, we evaluated in a before-after study (n = 62 and 65 patients for each period) a new EPO administration protocol (2 injections 4 and 3 weeks before surgery, and a third if hemoglobin <13 g/dL instead of <15 g/dL 2 weeks before surgery). After this protocol implementation, the mean (standard deviation) number of EPO injections decreased from 2.8 (0.5) to 2.2 (0.4)/patient (P < .0001) without changing transfusion rates (3% in the 2 periods).

  12. 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....

  13. Effects of erythropoietin on depressive symptoms and neurocognitive deficits in depression and bipolar disorder

    DEFF Research Database (Denmark)

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

    2010-01-01

    BACKGROUND: Depression and bipolar disorder are associated with reduced neural plasticity and deficits in memory, attention and executive function. Drug treatments for these affective disorders have insufficient clinical effects in a large group and fail to reverse cognitive deficits. There is thus...... a need for more effective treatments which aid cognitive function. Erythropoietin (Epo) is involved in neuroplasticity and is a candidate for future treatment of affective disorders. The investigators have demonstrated that a single dose of Epo improves cognitive function and reduces neurocognitive...... processing of negative emotional information in healthy and depressed individuals similar to effects seen with conventional antidepressants. The current study adds to the previous findings by investigating whether repeated Epo administration has antidepressant effects in patients with treatment resistant...

  14. 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......HuEpo treatment VO2max increased (PVO2max) was increased by 54.0 and 54.3% (P... week 11), TTE was decreased by 26.8% as compared to pre rHuEpo administration. In conclusion, in healthy non-athlete subjects rHuEpo administration prolongs submaximal exercise performance by about 54% independently of the approximately 12% increase in VO2max....

  15. PRELIMINARY MODELING OF AN INDUSTRIAL RECOMBINANT HUMAN ERYTHROPOIETIN PURIFICATION PROCESS BY ARTIFICIAL NEURAL NETWORKS

    Directory of Open Access Journals (Sweden)

    R. H. R. Garcel1

    2015-09-01

    Full Text Available AbstractIn the present study a preliminary neural network modelling to improve our understanding of Recombinant Human Erythropoietin purification process in a plant was explored. A three layer feed-forward back propagation neural network was constructed for predicting the efficiency of the purification section comprising four chromatographic steps as a function of eleven operational variables. The neural network model performed very well in the training and validation phases. Using the connection weight method the predictor variables were ranked based on their estimated explanatory importance in the neural network and five input variables were found to be predominant over the others. These results provided useful information showing that the first chromatographic step and the third chromatographic step are decisive to achieve high efficiencies in the purification section, thus enriching the control strategy of the plant.

  16. 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

    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....... These findings demonstrate cerebral hypoxia in malaria, strongly associated with cerebral dysfunction and a possible target for adjunctive therapy....

  17. 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......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...... 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....

  18. 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...... of EPO (40 000 IU) (N = 30) or saline (N = 26) in a double-blind, parallel-group design. Patients underwent fMRI, mood ratings and blood tests at baseline and week 14. During fMRI patients performed an n-back WM task. RESULTS: EPO improved WM accuracy compared with saline (p = 0.045). Whole......, baseline to follow-up changes in WM performance correlated positively with changes in WM-related SFG activity and negatively with hippocampal response (r = 0.28-0.30, p mood or red blood cells (p ⩾0.08). CONCLUSIONS: The present findings...

  19. Erythropoietin deficiency in acute crescentic glomerulonephritis and in total bilateral renal cortical necrosis

    DEFF Research Database (Denmark)

    Thaysen, J H; Nielsen, O J; Brandi, L

    1991-01-01

    Six patients with acute renal failure, in five cases due to acute crescentic glomerulonephritis and in one case due to total bilateral renal cortical necrosis, were studied. All had serum erythropoietin (EPO) concentrations in the normal range, despite a relatively severe anaemia. Half...... treated with rhEPO (Eprex). In marked contrast to untreated controls, both patients responded with vigorous reticulocytosis and normalization of haemoglobin levels while they were still in severe renal failure. These results are similar to our previous findings in patients with acute renal failure due...... of EPO is not only a permanent and irreversible feature of severe chronic renal failure, but that it is also present, usually in a transient and reversible form, in different types of acute renal failure....

  20. 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

    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......-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...

  1. Erythropoietin levels in patients with sleep apnea: a meta-analysis.

    Science.gov (United States)

    Zhang, Xiao-Bin; Zeng, Yi-Ming; Zeng, Hui-Qing; Zhang, Hua-Ping; Wang, Hui-Ling

    2017-06-01

    Currently available data regarding the blood levels of erythropoietin (EPO) in sleep apnea (SA) patients are contradictory. The aim of the present meta-analysis was to evaluate the EPO levels in SA patients via quantitative analysis. A systematic search of Pubmed, Embase, and Web of Science were performed. EPO levels in SA group and control group were extracted from each eligible study. Weight mean difference (WMD) or Standard mean difference (SMD) with 95% confidence interval (CI) was calculated by using fixed-effects or random effect model analysis according to the degree of heterogeneity between studies. A total of 9 studies involving 407 participants were enrolled. The results indicated that EPO levels in SA group were significantly higher than that in control group (SMD 0.61, 95% CI 0.11-1.11, p = 0.016). Significantly higher EPO levels were found in patients with body mass index analysis (both p analysis.

  2. Herpesvirus Genome Recognition Induced Acetylation of Nuclear IFI16 Is Essential for Its Cytoplasmic Translocation, Inflammasome and IFN-β Responses.

    Directory of Open Access Journals (Sweden)

    Mairaj Ahmed Ansari

    2015-07-01

    Full Text Available The IL-1β and type I interferon-β (IFN-β molecules are important inflammatory cytokines elicited by the eukaryotic host as innate immune responses against invading pathogens and danger signals. Recently, a predominantly nuclear gamma-interferon-inducible protein 16 (IFI16 involved in transcriptional regulation has emerged as an innate DNA sensor which induced IL-1β and IFN-β production through inflammasome and STING activation, respectively. Herpesvirus (KSHV, EBV, and HSV-1 episomal dsDNA genome recognition by IFI16 leads to IFI16-ASC-procaspase-1 inflammasome association, cytoplasmic translocation and IL-1β production. Independent of ASC, HSV-1 genome recognition results in IFI16 interaction with STING in the cytoplasm to induce interferon-β production. However, the mechanisms of IFI16-inflammasome formation, cytoplasmic redistribution and STING activation are not known. Our studies here demonstrate that recognition of herpesvirus genomes in the nucleus by IFI16 leads into its interaction with histone acetyltransferase p300 and IFI16 acetylation resulting in IFI16-ASC interaction, inflammasome assembly, increased interaction with Ran-GTPase, cytoplasmic redistribution, caspase-1 activation, IL-1β production, and interaction with STING which results in IRF-3 phosphorylation, nuclear pIRF-3 localization and interferon-β production. ASC and STING knockdowns did not affect IFI16 acetylation indicating that this modification is upstream of inflammasome-assembly and STING-activation. Vaccinia virus replicating in the cytoplasm did not induce nuclear IFI16 acetylation and cytoplasmic translocation. IFI16 physically associates with KSHV and HSV-1 genomes as revealed by proximity ligation microscopy and chromatin-immunoprecipitation studies which is not hampered by the inhibition of acetylation, thus suggesting that acetylation of IFI16 is not required for its innate sensing of nuclear viral genomes. Collectively, these studies identify the

  3. Erythropoietin treatment alleviates ultrastructural myelin changes induced by murine cerebral malaria

    DEFF Research Database (Denmark)

    Hempel, Casper; Hyttel, Poul; Staalso, Trine

    2012-01-01

    BACKGROUND: Cerebral malaria (CM) is a severe complication of malaria with considerable mortality. In addition to acute encephalopathy, survivors frequently suffer from neurological sequelae. The pathogenesis is incompletely understood, hampering the development of an effective, adjunctive therapy...... microscopy. Myelin sheaths in the corpus callosum were analysed with transmission electron microscopy and stereology. RESULTS: The infection caused clinical CM, which was counteracted by EPO. The total number of myelinated axons was identical in the four groups and mice with CM did not have reduced mean...

  4. Assessing the instability of the isoelectric focusing patterns of erythropoietin in urine.

    Science.gov (United States)

    Belalcazar, Viviana; Gutiérrez Gallego, Ricardo; Llop, Esther; Segura, Jordi; Pascual, José Antonio

    2006-11-01

    IEF can be used to differentiate human urinary erythropoietin (uEPO), recombinant human erythropoietin or epoetin (rEPO) and darbepoetin (novel erythropoiesis stimulating protein (NESP)). This is the basis of the method currently used to detect misuse of rEPO and NESP by elite athletes. Recently, an unknown activity has been attributed to some urine samples (denominated 'unstable' urine by the World Anti-Doping Agency; WADA). This activity has shown to give rise to artefactual profiles for both rEPO and NESP when incubated with such urine and, thus, raised concerns with respect to doping control. We have evaluated which charges produce the characteristic IEF profiles of uEPO, rEPO and NESP and how these profiles respond to distinct enzymatic reactions. From sialidase digestions it became evident that only uEPO contains charges different from sialic acid, and a comparison of all substances after complete de-N-glycosylation localized these charges in the carbohydrate moiety. Partial desialylation, or digestion with arylsulfatase from Helix pomatia yielded profiles for recombinants species similar to those observed for unstable urine samples. The contributions from our studies to the anti-doping problem include: (i) protocols that may corroborate the potential misuse of rEPO or NESP based on the particular enzymatic activity of an arylsulfatase preparation, or a broad-specificity sialidase; (ii) assurance that the instability observed in some urine samples may only result from false-negatives, but not from false-positive testing; and (iii) a simple remedy to prevent an unstable urine from altering the IEF profile by adding selective competitive substrates.

  5. 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, a