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Sample records for revealing severe hypoxia

  1. Chest computed tomography of a patient revealing severe hypoxia due to amniotic fluid embolism: a case report

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    Inui Daisuke

    2010-02-01

    Full Text Available Abstract Introduction Amniotic fluid embolism is one of the most severe complications in the peripartum period. Because its onset is abrupt and fulminant, it is unlikely that there will be time to examine the condition using thoracic computed tomography (CT. We report a case of life-threatening amniotic fluid embolism, where chest CT in the acute phase was obtained. Case presentation A 22-year-old Asian Japanese primiparous woman was suspected of having an amniotic fluid embolism. After a Cesarean section for cephalopelvic disproportion, her respiratory condition deteriorated. Her chest CT images were examined. CT findings revealed diffuse homogeneous ground-glass shadow in her bilateral peripheral lung fields. She was therefore transferred to our hospital. On admission to our hospital's intensive care unit, she was found to have severe hypoxemia, with SpO2 of 50% with a reservoir mask of 15 L/min oxygen. She was intubated with the support of noninvasive positive pressure ventilation. She was successfully extubated on the sixth day, and discharged from the hospital on the twentieth day. Conclusion This is the first case report describing amniotic fluid embolism in which CT revealed an acute respiratory distress syndrome-like shadow.

  2. Determinants of maximal oxygen uptake in severe acute hypoxia

    DEFF Research Database (Denmark)

    Calbet, J A L; Boushel, Robert Christopher; Rådegran, G

    2003-01-01

    To unravel the mechanisms by which maximal oxygen uptake (VO2 max) is reduced with severe acute hypoxia in humans, nine Danish lowlanders performed incremental cycle ergometer exercise to exhaustion, while breathing room air (normoxia) or 10.5% O2 in N2 (hypoxia, approximately 5,300 m above sea......: 1) reduction of PiO2, 2) impairment of pulmonary gas exchange, and 3) reduction of maximal cardiac output and peak leg blood flow, each explaining about one-third of the loss in VO2 max....

  3. Influence of moderate and severe hypoxia on the diurnal activity pattern of lesser sandeel Ammodytes tobianus

    DEFF Research Database (Denmark)

    Behrens, Jane; Petersen, Jens Kjerulf; Ærtebjerg, G.

    2010-01-01

    , but the behaviour of the fish was also changed. The summed activity (emerging plus burying events) was lower in severe hypoxia compared to normoxia except during hours of dim light. All fish were buried during night-time, regardless of treatment, with the exception of some in severe hypoxia during the first couple...

  4. RNA Sequencing Reveals that Kaposi Sarcoma-Associated Herpesvirus Infection Mimics Hypoxia Gene Expression Signature

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    Viollet, Coralie; Davis, David A.; Tekeste, Shewit S.; Reczko, Martin; Pezzella, Francesco; Ragoussis, Jiannis

    2017-01-01

    Kaposi sarcoma-associated herpesvirus (KSHV) causes several tumors and hyperproliferative disorders. Hypoxia and hypoxia-inducible factors (HIFs) activate latent and lytic KSHV genes, and several KSHV proteins increase the cellular levels of HIF. Here, we used RNA sequencing, qRT-PCR, Taqman assays, and pathway analysis to explore the miRNA and mRNA response of uninfected and KSHV-infected cells to hypoxia, to compare this with the genetic changes seen in chronic latent KSHV infection, and to explore the degree to which hypoxia and KSHV infection interact in modulating mRNA and miRNA expression. We found that the gene expression signatures for KSHV infection and hypoxia have a 34% overlap. Moreover, there were considerable similarities between the genes up-regulated by hypoxia in uninfected (SLK) and in KSHV-infected (SLKK) cells. hsa-miR-210, a HIF-target known to have pro-angiogenic and anti-apoptotic properties, was significantly up-regulated by both KSHV infection and hypoxia using Taqman assays. Interestingly, expression of KSHV-encoded miRNAs was not affected by hypoxia. These results demonstrate that KSHV harnesses a part of the hypoxic cellular response and that a substantial portion of hypoxia-induced changes in cellular gene expression are induced by KSHV infection. Therefore, targeting hypoxic pathways may be a useful way to develop therapeutic strategies for KSHV-related diseases. PMID:28046107

  5. Hypoxic pretreatment protects against neuronal damage of the rat hippocampus induced by severe hypoxia.

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    Gorgias, N; Maidatsi, P; Tsolaki, M; Alvanou, A; Kiriazis, G; Kaidoglou, K; Giala, M

    1996-04-01

    The present study investigates whether under conditions of successive hypoxic exposures pretreatment with mild (15% O(2)) or moderate (10% O(2)) hypoxia, protects hippocampal neurones against damage induced by severe (3% O(2)) hypoxia. The ultrastructural findings were also correlated with regional superoxide dismutase (SOD) activity changes. In unpretreated rats severe hypoxia induced ultrastructural changes consistent with the aspects of delayed neuronal death (DND). However, in preexposed animals hippocampal damage was attenuated in an inversely proportional way with the severity of the hypoxic pretreatment. The ultrastructural hypoxic tolerance findings were also closely related to increased regional SOD activity levels. Thus the activation of the endogenous antioxidant defense by hypoxic preconditioning, protects against hippocampal damage induced by severe hypoxia. The eventual contribution of increased endogenous adenosine and/or reduced excitotoxicity to induce hypoxic tolerance is discussed.

  6. Restraint stress intensifies interstitial K+ accumulation during severe hypoxia

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    Christian eSchnell

    2012-03-01

    Full Text Available Chronic stress affects neuronal networks by inducing dendritic retraction, modifying neuronal excitability and plasticity, and modulating glial cells. To elucidate the functional consequences of chronic stress for the hippocampal network, we submitted adult rats to daily restraint stress for three weeks (6 h/day. In acute hippocampal tissue slices of stressed rats, basal synaptic function and short-term plasticity at Schaffer collateral/CA1 neuron synapses were unchanged while long-term potentiation was markedly impaired. The spatiotemporal propagation pattern of hypoxia-induced spreading depression episodes was indistinguishable among control and stress slices. However, the duration of the extracellular direct current (DC potential shift was shortened after stress. Moreover, K+ fluxes early during hypoxia were more intense, and the postsynaptic recoveries of interstitial K+ levels and synaptic function were slower. Morphometric analysis of immunohistochemically stained sections suggested hippocampal shrinkage in stressed rats, and the number of cells that are immunoreactive for GFAP (glial fibrillary acidic protein was increased in the CA1 subfield indicating activation of astrocytes. Western blots showed a marked downregulation of the inwardly rectifying K+ channel Kir4.1 in stressed rats. Yet, resting membrane potentials, input resistance and K+-induced inward currents in CA1 astrocytes were indistinguishable from controls. These data indicate an intensified interstitial K+ accumulation during hypoxia in the hippocampus of chronically stressed rats which seems to arise from a reduced interstitial volume fraction rather than impaired glial K+ buffering. One may speculate that chronic stress aggravates hypoxia-induced pathophysiological processes in the hippocampal network and that this has implications for the ischemic brain.

  7. Gene expression profiling in equine polysaccharide storage myopathy revealed inflammation, glycogenesis inhibition, hypoxia and mitochondrial dysfunctions

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    Benech Philippe

    2009-08-01

    Full Text Available Abstract Background Several cases of myopathies have been observed in the horse Norman Cob breed. Muscle histology examinations revealed that some families suffer from a polysaccharide storage myopathy (PSSM. It is assumed that a gene expression signature related to PSSM should be observed at the transcriptional level because the glycogen storage disease could also be linked to other dysfunctions in gene regulation. Thus, the functional genomic approach could be conducted in order to provide new knowledge about the metabolic disorders related to PSSM. We propose exploring the PSSM muscle fiber metabolic disorders by measuring gene expression in relationship with the histological phenotype. Results Genotypying analysis of GYS1 mutation revealed 2 homozygous (AA and 5 heterozygous (GA PSSM horses. In the PSSM muscles, histological data revealed PAS positive amylase resistant abnormal polysaccharides, inflammation, necrosis, and lipomatosis and active regeneration of fibers. Ultrastructural evaluation revealed a decrease of mitochondrial number and structural disorders. Extensive accumulation of an abnormal polysaccharide displaced and partially replaced mitochondria and myofibrils. The severity of the disease was higher in the two homozygous PSSM horses. Gene expression analysis revealed 129 genes significantly modulated (p Conclusion The main disorders observed in PSSM muscles could be related to mitochondrial dysfunctions, glycogenesis inhibition and the chronic hypoxia of the PSSM muscles.

  8. Severe hypoxia induces chemo-resistance in clinical cervical tumors through MVP over-expression.

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    Lara, Pedro C; Lloret, Marta; Clavo, Bernardino; Apolinario, Rosa M; Henríquez-Hernández, Luis Alberto; Bordón, Elisa; Fontes, Fausto; Rey, Agustín

    2009-08-06

    Oxygen molecule modulates tumour response to radiotherapy. Higher radiation doses are required under hypoxic conditions to induce cell death. Hypoxia may inhibit the non-homologous end-joining DNA repair through down regulating Ku70/80 expression. Hypoxia induces drug resistance in clinical tumours, although the mechanism is not clearly elucidated. Vaults are ribonucleoprotein particles with a hollow barrel-like structure composed of three proteins: major vault protein (MVP), vault poly(ADP-ribose) polymerase, and telomerase associated protein-1 and small untranslated RNA. Over-expression of MVP has been associated with chemotherapy resistance. Also, it has been related to poor outcome in patients treated with radiotherapy alone. The aim of the present study was to assess the relation of Major Vault Protein expression and tumor hypoxia in clinical cervical tumors. MVP, p53 and angiogenesis, together with tumor oxygenation, were determined in forty-three consecutive patients suffering from localized cervix carcinoma. High MVP expression was related to severe hypoxia compared to low MVP expressing tumors (p = 0.022). Tumors over-expressing MVP also showed increased angiogenesis (p = 0.003). Besides it, in this study we show for the first time that severe tumor hypoxia is associated with high MVP expression in clinical cervical tumors. Up-regulation of MVP by hypoxia is of critical relevance as chemotherapy is currently a standard treatment for those patients. From our results it could be suggested that hypoxia not only induces increased genetic instability, oncogenic properties and metastatization, but through the correlation observed with MVP expression, another pathway of chemo and radiation resistance could be developed.

  9. Severe hypoxia induces chemo-resistance in clinical cervical tumors through MVP over-expression

    International Nuclear Information System (INIS)

    Lara, Pedro C; Lloret, Marta; Clavo, Bernardino; Apolinario, Rosa M; Henríquez-Hernández, Luis Alberto; Bordón, Elisa; Fontes, Fausto; Rey, Agustín

    2009-01-01

    Oxygen molecule modulates tumour response to radiotherapy. Higher radiation doses are required under hypoxic conditions to induce cell death. Hypoxia may inhibit the non-homologous end-joining DNA repair through down regulating Ku70/80 expression. Hypoxia induces drug resistance in clinical tumours, although the mechanism is not clearly elucidated. Vaults are ribonucleoprotein particles with a hollow barrel-like structure composed of three proteins: major vault protein (MVP), vault poly(ADP-ribose) polymerase, and telomerase associated protein-1 and small untranslated RNA. Over-expression of MVP has been associated with chemotherapy resistance. Also, it has been related to poor outcome in patients treated with radiotherapy alone. The aim of the present study was to assess the relation of Major Vault Protein expression and tumor hypoxia in clinical cervical tumors. MVP, p53 and angiogenesis, together with tumor oxygenation, were determined in forty-three consecutive patients suffering from localized cervix carcinoma. High MVP expression was related to severe hypoxia compared to low MVP expressing tumors (p = 0.022). Tumors over-expressing MVP also showed increased angiogenesis (p = 0.003). Besides it, in this study we show for the first time that severe tumor hypoxia is associated with high MVP expression in clinical cervical tumors. Up-regulation of MVP by hypoxia is of critical relevance as chemotherapy is currently a standard treatment for those patients. From our results it could be suggested that hypoxia not only induces increased genetic instability, oncogenic properties and metastatization, but through the correlation observed with MVP expression, another pathway of chemo and radiation resistance could be developed

  10. Air exposure behavior of the semiterrestrial crab Neohelice granulata allows tolerance to severe hypoxia but not prevent oxidative damage due to hypoxia-reoxygenation cycle.

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    de Lima, Tábata Martins; Geihs, Márcio Alberto; Nery, Luiz Eduardo Maia; Maciel, Fábio Everton

    2015-11-01

    The air exposure behavior of the semi-terrestrial crab Neohelice granulata during severe hypoxia was studied. This study also verified whether this behavior mitigates possible oxidative damage, namely lipoperoxidation, caused by hypoxia and reoxygenation cycles. The lethal time for 50% of the crabs subjected to severe hypoxia (0.5 mgO2 · L(-1)) with free access to air was compared to that of crabs subjected to severe hypoxia without access to air. Crabs were placed in aquaria divided into three zones: water (when the animal was fully submersed), land (when the animal was completely emerged) and intermediate (when the animal was in contact with both environments) zones. Then the crabs were held in this condition for 270 min, and the time spent in each zone was recorded. Lipid peroxidation (LPO) damage to the walking leg muscles was determined for the following four experimental conditions: a--normoxic water with free access to air; b--hypoxic water without access to air; c--hypoxic water followed by normoxic water without air access; and d--hypoxic water with free access to air. When exposed to hypoxic water, N. granulata spent significantly more time on land, 135.3 ± 17.7 min, whereas control animals (exposed to normoxic water) spent more time submerged, 187.4 ± 20.2 min. By this behavior, N. granulata was able to maintain a 100% survival rate when exposed to severe hypoxia. However, N. granulata must still return to water after periods of air exposure (~ 14 min), causing a sequence of hypoxia/reoxygenation events. Despite increasing the survival rate, hypoxia with air access does not decrease the lipid peroxidation damage caused by the hypoxia and reoxygenation cycle experienced by these crabs.

  11. Investigating the complexity of respiratory patterns during recovery from severe hypoxia

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    Akay, Metin; Sekine, Noriko

    2004-03-01

    Progressive hypoxemia in anesthetized, peripherally chemodenervated piglets results in initial depression of the phrenic neurogram (PN) culminating in phrenic silence and, eventually, gasping. These changes reverse after the 30 min reoxygenation (recovery) period. To determine if changes in the PN patterns correspond to changes in temporal patterning, we have used the approximate entropy (ApEn) method to examine the effects of maturation on the complexity of breathing patterns in chemodenervated, vagotomized and decerebrated piglets during severe hypoxia and reoxygenation. The phrenic neurogram in piglets was recorded during eupnea (normal breathing), severe hypoxia (gasping) and recovery from severe hypoxia in 31 piglets (2 35 days). Nonlinear dynamical analysis of the phrenic neurogram was performed using the ApEn method. The mean ApEn values for a recording of five consecutive breaths during eupnea, a few phrenic neurogram signals during gasping, the beginning of the recovery period, and five consecutive breaths at every 5 min interval for the 30 min recovery period were calculated. Our data suggest that gasping resulted in reduced duration of the phrenic neurogram, and the gasp-like patterns exist at the beginning of the recovery. But, the durations of phrenic neurograms during recovery were increased after 10 min postreoxygenation, but were restored 30 min post recovery. The ApEn (complexity) values of the phrenic neurogram during eupnea were higher than those of gasping and the early (the onset of) recovery from severe hypoxia (p < 0.01), but were not statistically different than 5 min post recovery regardless of the maturation stages. These results suggest that hypoxia results in a reversible reconfiguration of the central respiratory pattern generator.

  12. Telomere elongation protects heart and lung tissue cells from fatal damage in rats exposed to severe hypoxia.

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    Wang, Yaping; Zhao, Zhen; Zhu, Zhiyong; Li, Pingying; Li, Xiaolin; Xue, Xiaohong; Duo, Jie; Ma, Yingcai

    2018-02-17

    The effects of acute hypoxia at high altitude on the telomere length of the cells in the heart and lung tissues remain unclear. This study aimed to investigate the change in telomere length of rat heart and lung tissue cells in response to acute exposure to severe hypoxia and its role in hypoxia-induced damage to heart and lung tissues. Forty male Wistar rats (6-week old) were randomized into control group (n = 10) and hypoxia group (n = 30). Rats in control group were kept at an altitude of 1500 m, while rats in hypoxia group were exposed to simulated hypoxia with an altitude of 5000 m in a low-pressure oxygen chamber for 1, 3, and 7 days (n = 10). The left ventricular and right middle lobe tissues of each rat were collected for measurement of telomere length and reactive oxygen species (ROS) content, and the mRNA and protein levels of telomerase reverse transcriptase (TERT), hypoxia-inducible factor1α (HIF-1α), and hypoxia-inducible factor1α (HIF-2α). Increased exposure to hypoxia damaged rat heart and lung tissue cells and increased ROS production and telomere length. The mRNA and protein levels of TERT and HIF-1α were significantly higher in rats exposed to hypoxia and increased with prolonged exposure; mRNA and protein levels of HIF-2α increased only in rats exposed to hypoxia for 7 days. TERT was positively correlated with telomere length and the levels of HIF-1α but not HIF-2α. Acute exposure to severe hypoxia causes damage to heart and lung tissues due to the production of ROS but promotes telomere length and adaptive response by upregulating TERT and HIF-1α, which protect heart and lung tissue cells from fatal damage.

  13. Increased MCP-1 gene expression in monocytes of severe OSA patients and under intermittent hypoxia.

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    Chuang, Li-Pang; Chen, Ning-Hung; Lin, Yuling; Ko, Wen-Shan; Pang, Jong-Hwei S

    2016-03-01

    Obstructive sleep apnea (OSA) is known to be a risk factor of coronary artery disease. Monocyte chemoattractant protein-1 (MCP-1), as a critical factor for monocyte infiltration, is known to play a role in the development of atherosclerosis. This study aimed to investigate the effect of intermittent hypoxia, the hallmark of OSA, on the MCP-1 expression of monocytes. Peripheral blood was sampled from 61 adults enrolled for suspected OSA. RNA was prepared from the isolated monocytes for the analysis of MCP-1. The effect of in vitro intermittent hypoxia on the regulation and function of MCP-1 was investigated on THP-1 monocytic cells and human monocytes. The mRNA and secreted protein levels were investigated by RT/real-time PCR and enzyme-linked immunosorbent assay, respectively. Monocytic MCP-1 gene expression was found to be increased significantly in severe OSA patients. In vitro intermittent hypoxia was demonstrated to increase the mRNA and protein expression levels of MCP-1 dose- and time-dependently in THP-1 monocytic cells. The MCP-1 mRNA expression in monocytes isolated from OSA patient was induced to a much higher level compared to that from normal control. Pre-treatment with inhibitor for p42/44 MAPK or p38 MAPK suppressed the activation of MCP-1 expression by intermittent hypoxia. This is the first study to demonstrate the increase of MCP-1 gene expression in monocytes of severe OSA patients. In addition, monocytic MCP-1 gene expression can be induced under intermittent hypoxia.

  14. Comparative proteomics and codon substitution analysis reveal mechanisms of differential resistance to hypoxia in congeneric snails

    KAUST Repository

    Mu, Huawei; Sun, Jin; Cheung, Siu Gin; Fang, Ling; Zhou, Haiyun; Luan, Tiangang; Zhang, Huoming; Wong, Chris K.C.; Qiu, Jian-Wen

    2017-01-01

    Although high-throughput proteomics has been widely applied to study mechanisms of environmental adaptation, the conclusions from studies that are based on one species can be confounded by phylogeny. We compare the freshwater snail Pomacea canaliculata (a notorious invasive species) and its congener Pomacea diffusa (a non-invasive species) to understand the molecular mechanisms of their differential resistance to hypoxia. A 72-h acute exposure experiment showed that P. canaliculata is more tolerant to hypoxia than P. diffusa. The two species were then exposed to three levels of dissolved oxygen (6.7, 2.0 and 1.0mgL−1) for 8h, and their gill proteins were analyzed using iTRAQ-coupled LC-MS/MS. The two species showed striking differences in protein expression profiles, with the more hypoxia tolerant P. canaliculata having more up-regulated proteins in signal transduction and down-regulated proteins in glycolysis and the tricarboxylic acid cycle. Evolutionary analysis revealed five orthologous genes encoding differentially expressed proteins having clear signal of positive selection, indicating selection has acted on some of the hypoxia responsive genes. Our case study has highlighted the potential of integrated proteomics and comparative evolutionary analysis for understanding the genetic basis of adaptation to global environmental change in non-model species. SignificanceRapid globalization in recent decades has greatly facilitated species introduction around the world. Successfully established introduced species, so-called invasive species, have threatened the invaded ecosystems. There has been substantial interest in studying how invasive species respond to extreme environmental conditions because the results can help not only predict their range of expansion and manage their impact, but also may reveal the adaptive mechanisms underlying their invasiveness. Our study has adopted a comparative approach to study the differential physiological and proteomic

  15. Comparative proteomics and codon substitution analysis reveal mechanisms of differential resistance to hypoxia in congeneric snails

    KAUST Repository

    Mu, Huawei

    2017-11-06

    Although high-throughput proteomics has been widely applied to study mechanisms of environmental adaptation, the conclusions from studies that are based on one species can be confounded by phylogeny. We compare the freshwater snail Pomacea canaliculata (a notorious invasive species) and its congener Pomacea diffusa (a non-invasive species) to understand the molecular mechanisms of their differential resistance to hypoxia. A 72-h acute exposure experiment showed that P. canaliculata is more tolerant to hypoxia than P. diffusa. The two species were then exposed to three levels of dissolved oxygen (6.7, 2.0 and 1.0mgL−1) for 8h, and their gill proteins were analyzed using iTRAQ-coupled LC-MS/MS. The two species showed striking differences in protein expression profiles, with the more hypoxia tolerant P. canaliculata having more up-regulated proteins in signal transduction and down-regulated proteins in glycolysis and the tricarboxylic acid cycle. Evolutionary analysis revealed five orthologous genes encoding differentially expressed proteins having clear signal of positive selection, indicating selection has acted on some of the hypoxia responsive genes. Our case study has highlighted the potential of integrated proteomics and comparative evolutionary analysis for understanding the genetic basis of adaptation to global environmental change in non-model species. SignificanceRapid globalization in recent decades has greatly facilitated species introduction around the world. Successfully established introduced species, so-called invasive species, have threatened the invaded ecosystems. There has been substantial interest in studying how invasive species respond to extreme environmental conditions because the results can help not only predict their range of expansion and manage their impact, but also may reveal the adaptive mechanisms underlying their invasiveness. Our study has adopted a comparative approach to study the differential physiological and proteomic

  16. [Severe pulmonary embolism revealed by status epilepticus].

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    Allou, N; Coolen-Allou, N; Delmas, B; Cordier, C; Allyn, J

    2016-12-01

    High-risk pulmonary embolism (PE) is associated with high mortality rate (>50%). In some cases, diagnosis of PE remains a challenge with atypical presentations like in this case report with a PE revealed by status epilepticus. We report the case of a 40-year-old man without prior disease, hospitalized in ICU for status epilepticus. All paraclinical examinations at admission did not show any significant abnormalities (laboratory tests, cardiologic and neurological investigations). On day 1, he presented a sudden circulatory collapse and echocardiography showed right intra-auricular thrombus. He was treated by thrombolysis and arteriovenous extracorporeal membrane oxygenation. After stabilization, computed tomography showed severe bilateral PE. He developed multi-organ failure and died 4days after admission. Pulmonary embolism revealed by status epilepticus has rarely been reported and is associated with poor prognosis. Physicians should be aware and think of the possibility of PE in patients with status epilepticus without any history or risk factors of seizure and normal neurological investigations. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  17. Severe hypoxia affects exercise performance independently of afferent feedback and peripheral fatigue.

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    Millet, Guillaume Y; Muthalib, Makii; Jubeau, Marc; Laursen, Paul B; Nosaka, Kazunori

    2012-04-01

    To test the hypothesis that hypoxia centrally affects performance independently of afferent feedback and peripheral fatigue, we conducted two experiments under complete vascular occlusion of the exercising muscle under different systemic O(2) environmental conditions. In experiment 1, 12 subjects performed repeated submaximal isometric contractions of the elbow flexor to exhaustion (RCTE) with inspired O(2) fraction fixed at 9% (severe hypoxia, SevHyp), 14% (moderate hypoxia, ModHyp), 21% (normoxia, Norm), or 30% (hyperoxia, Hyper). The number of contractions (performance), muscle (biceps brachii), and prefrontal near-infrared spectroscopy (NIRS) parameters and high-frequency paired-pulse (PS100) evoked responses to electrical muscle stimulation were monitored. In experiment 2, 10 subjects performed another RCTE in SevHyp and Norm conditions in which the number of contractions, biceps brachii electromyography responses to electrical nerve stimulation (M wave), and transcranial magnetic stimulation responses (motor-evoked potentials, MEP, and cortical silent period, CSP) were recorded. Performance during RCTE was significantly reduced by 10-15% in SevHyp (arterial O(2) saturation, SpO(2) = ∼75%) compared with ModHyp (SpO(2) = ∼90%) or Norm/Hyper (SpO(2) > 97%). Performance reduction in SevHyp occurred despite similar 1) metabolic (muscle NIRS parameters) and functional (changes in PS100 and M wave) muscle states and 2) MEP and CSP responses, suggesting comparable corticospinal excitability and spinal and cortical inhibition between SevHyp and Norm. It is concluded that, in SevHyp, performance and central drive can be altered independently of afferent feedback and peripheral fatigue. It is concluded that submaximal performance in SevHyp is partly reduced by a mechanism related directly to brain oxygenation.

  18. Limited effects of exogenous glucose during severe hypoxia and a lack of hypoxia-stimulated glucose uptake in isolated rainbow trout cardiac muscle

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    Becker, Tracy A.; DellaValle, Brian; Gesser, Hans; Rodnick, Kenneth J.

    2013-01-01

    SUMMARY We examined whether exogenous glucose affects contractile performance of electrically paced ventricle strips from rainbow trout under conditions known to alter cardiomyocyte performance, ion regulation and energy demands. Physiological levels of d-glucose did not influence twitch force development for aerobic preparations (1) paced at 0.5 or 1.1 Hz, (2) at 15 or 23°C, (3) receiving adrenergic stimulation or (4) during reoxygenation with or without adrenaline after severe hypoxia. Contractile responses to ryanodine, an inhibitor of Ca2+ release from the sarcoplasmic reticulum, were also not affected by exogenous glucose. However, glucose did attenuate the fall in twitch force during severe hypoxia. Glucose uptake was assayed in non-contracting ventricle strips using 2-[3H] deoxy-d-glucose (2-DG) under aerobic and hypoxic conditions, at different incubation temperatures and with different inhibitors. Based upon a lack of saturation of 2-DG uptake and incomplete inhibition of uptake by cytochalasin B and d-glucose, 2-DG uptake was mediated by a combination of facilitated transport and simple diffusion. Hypoxia stimulated lactate efflux sixfold to sevenfold with glucose present, but did not increase 2-DG uptake or reduce lactate efflux in the presence of cytochalasin B. Increasing temperature (14 to 24°C) also did not increase 2-DG uptake, but decreasing temperature (14 to 4°C) reduced 2-DG uptake by 45%. In conclusion, exogenous glucose improves mechanical performance under hypoxia but not under any of the aerobic conditions applied. The extracellular concentration of glucose and cold temperature appear to determine and limit cardiomyocyte glucose uptake, respectively, and together may help define a metabolic strategy that relies predominantly on intracellular energy stores. PMID:23685969

  19. Intermittent Hypoxia Increases the Severity of Bleomycin-Induced Lung Injury in Mice

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    Thomas Gille

    2018-01-01

    Full Text Available Background. Severe obstructive sleep apnea (OSA with chronic intermittent hypoxia (IH is common in idiopathic pulmonary fibrosis (IPF. Here, we evaluated the impact of IH on bleomycin- (BLM- induced pulmonary fibrosis in mice. Methods. C57BL/6J mice received intratracheal BLM or saline and were exposed to IH (40 cycles/hour; FiO2 nadir: 6%; 8 hours/day or intermittent air (IA. In the four experimental groups, we evaluated (i survival; (ii alveolar inflammation, pulmonary edema, lung oxidative stress, and antioxidant enzymes; (iii lung cell apoptosis; and (iv pulmonary fibrosis. Results. Survival at day 21 was lower in the BLM-IH group (p<0.05. Pulmonary fibrosis was more severe at day 21 in BLM-IH mice, as assessed by lung collagen content (p=0.02 and histology. At day 4, BLM-IH mice developed a more severe neutrophilic alveolitis, (p<0.001. Lung oxidative stress was observed, and superoxide dismutase and glutathione peroxidase expression was decreased in BLM-IH mice (p<0.05 versus BLM-IA group. At day 8, pulmonary edema was observed and lung cell apoptosis was increased in the BLM-IH group. Conclusion. These results show that exposure to chronic IH increases mortality, lung inflammation, and lung fibrosis in BLM-treated mice. This study raises the question of the worsening impact of severe OSA in IPF patients.

  20. Increased oxidative stress and anaerobic energy release, but blunted Thr172-AMPKα phosphorylation, in response to sprint exercise in severe acute hypoxia in humans.

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    Morales-Alamo, David; Ponce-González, Jesús Gustavo; Guadalupe-Grau, Amelia; Rodríguez-García, Lorena; Santana, Alfredo; Cusso, Maria Roser; Guerrero, Mario; Guerra, Borja; Dorado, Cecilia; Calbet, José A L

    2012-09-01

    AMP-activated protein kinase (AMPK) is a major mediator of the exercise response and a molecular target to improve insulin sensitivity. To determine if the anaerobic component of the exercise response, which is exaggerated when sprint is performed in severe acute hypoxia, influences sprint exercise-elicited Thr(172)-AMPKα phosphorylation, 10 volunteers performed a single 30-s sprint (Wingate test) in normoxia and in severe acute hypoxia (inspired Po(2): 75 mmHg). Vastus lateralis muscle biopsies were obtained before and immediately after 30 and 120 min postsprint. Mean power output and O(2) consumption were 6% and 37%, respectively, lower in hypoxia than in normoxia. O(2) deficit and muscle lactate accumulation were greater in hypoxia than in normoxia. Carbonylated skeletal muscle and plasma proteins were increased after the sprint in hypoxia. Thr(172)-AMPKα phosphorylation was increased by 3.1-fold 30 min after the sprint in normoxia. This effect was prevented by hypoxia. The NAD(+)-to-NADH.H(+) ratio was reduced (by 24-fold) after the sprints, with a greater reduction in hypoxia than in normoxia (P exercise in human skeletal muscle is altered in severe acute hypoxia, which abrogated Thr(172)-AMPKα phosphorylation, likely due to lower LKB1 activation by SIRT1.

  1. Exposure to acute severe hypoxia leads to increased urea loss and disruptions in acid-base and ionoregulatory balance in dogfish sharks (Squalus acanthias).

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    Zimmer, Alex M; Wood, Chris M

    2014-01-01

    The effects of acute moderate (20% air O2 saturation; 6-h exposure) and severe (5% air O2 saturation; 4-h exposure) hypoxia on N-waste, acid-base, and ion balance in dogfish sharks (Squalus acanthias suckleyi) were evaluated. We predicted that the synthesis and/or retention of urea, which are active processes, would be inhibited by hypoxia. Exposure to moderate hypoxia had negligible effects on N-waste fluxes or systemic physiology, except for a modest rise in plasma lactate. Exposure to severe hypoxia led to a significant increase in urea excretion (Jurea), while plasma, liver, and muscle urea concentrations were unchanged, suggesting a loss of urea retention. Ammonia excretion (Jamm) was elevated during normoxic recovery. Moreover, severe hypoxia led to disruptions in acid-base balance, indicated by a large increase in plasma [lactate] and substantial decreases in arterial pHa and plasma [Formula: see text], as well as loss of ionic homeostasis, indicated by increases in plasma [Mg(2+)], [Ca(2+)], and [Na(+)]. We suggest that severe hypoxia in dogfish sharks leads to a reduction in active gill homeostatic processes, such as urea retention, acid-base regulation and ionoregulation, and/or an osmoregulatory compromise due to increased functional gill surface area. Overall, the results provide a comprehensive picture of the physiological responses to a severe degree of hypoxia in an ancient fish species.

  2. Metabolic profiling reveals potential metabolic markers associated with Hypoxia Inducible Factor-mediated signalling in hypoxic cancer cells.

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    Armitage, Emily G; Kotze, Helen L; Allwood, J William; Dunn, Warwick B; Goodacre, Royston; Williams, Kaye J

    2015-10-28

    Hypoxia inducible factors (HIFs) plays an important role in oxygen compromised environments and therefore in tumour survival. In this research, metabolomics has been applied to study HIFs metabolic function in two cell models: mouse hepatocellular carcinoma and human colon carcinoma, whereby the metabolism has been profiled for a range of oxygen potentials. Wild type cells have been compared to cells deficient in HIF signalling to reveal its effect on cellular metabolism under normal oxygen conditions as well as low oxygen, hypoxic and anoxic environments. Characteristic responses to hypoxia that were conserved across both cell models involved the anti-correlation between 2-hydroxyglutarate, 2-oxoglutarate, fructose, hexadecanoic acid, hypotaurine, pyruvate and octadecenoic acid with 4-hydroxyproline, aspartate, cysteine, glutamine, lysine, malate and pyroglutamate. Further to this, network-based correlation analysis revealed HIF specific pathway responses to each oxygen condition that were also conserved between cell models. From this, 4-hydroxyproline was revealed as a regulating hub in low oxygen survival of WT cells while fructose appeared to be in HIF deficient cells. Pathways surrounding these hubs were built from the direct connections of correlated metabolites that look beyond traditional pathways in order to understand the mechanism of HIF response to low oxygen environments.

  3. Effect of adjuvant low-molecular-weight heparin therapy on placental hypoxia and cell apoptosis in puerperae with severe preeclampsia

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    Miao Zhou1

    2017-04-01

    Full Text Available Objective: To study the effect of adjuvant low-molecular-weight heparin therapy on placental hypoxia and cell apoptosis in puerperae with severe preeclampsia. Methods: A total of 94 puerperae with severe preeclampsia who received treatment and safely gave birth in our hospital between May 2014 and May 2016 were selected as the research subjects and randomly divided into the LMWH group who received low-molecular-weight heparin combined with conventional symptomatic treatment and the control group who received conventional symptomatic treatment. Before and after treatment, serum was collected respectively to determine the levels of placental hypoxia-related cytokines, and after delivery, the placentas were collected to detect oxidative stress indexes and cell apoptosis indexes. Results: After treatment, serum PLGF and PAPP-A levels of both groups were significantly higher than those before treatment while sFlt-1 and sEng levels were significantly lower than those before treatment, and after treatment, serum PLGF and PAPP-A levels of LMWH group were significantly higher than those of control group while sFlt-1 and sEng levels were significantly lower than those of control group; ROS and RNS levels as well as Fas, FasL, caspase-3 and caspase-8 protein expression in placenta tissue of LMWH group were significantly lower than those of control group while GPx-1, SOD-1 and Trx levels as well as Survivin, XIAP and Bcl-2 protein expression were significantly higher than those of control group. Conclusion: Adjuvant low-molecular-weight heparin therapy can relieve the placental hypoxia, improve oxidative stress reaction and inhibit cell apoptosis in puerperae with severe preeclampsia.

  4. ERK1/2 and Akt phosphorylation were essential for MGF E peptide regulating cell morphology and mobility but not proangiogenic capacity of BMSCs under severe hypoxia.

    Science.gov (United States)

    Sha, Yongqiang; Yang, Li; Lv, Yonggang

    2018-04-01

    Severe hypoxia inhibits the adhesion and mobility of bone marrow-derived mesenchymal stem cells (BMSCs) and limits their application in bone tissue engineering. In this study, CoCl 2 was used to simulate severe hypoxia and the effects of mechano-growth factor (MGF) E peptide on the morphology, adhesion, migration, and proangiogenic capacity of BMSCs under hypoxia were measured. It was demonstrated that severe hypoxia (500-μM CoCl 2 ) significantly caused cell contraction and reduced cell area, roundness, adhesion, and migration of BMSCs. RhoA and ROCK1 expression levels were upregulated by severe hypoxia, but p-RhoA and mobility-relevant protein (integrin β1, p-FAK and fibronectin) expression levels in BMSCs were inhibited. Fortunately, MGF E peptide could restore all abovementioned indexes except RhoA expression. MEK-ERK1/2 pathway was involved in MGF E peptide regulating cell morphological changes, mobility, and relevant proteins (except p-FAK). PI3K-Akt pathway was involved in MGF E peptide regulating cell area, mobility, and relevant proteins. Besides, severe hypoxia upregulated vascular endothelial growth factor α expression but was harmful for proangiogenic capacity of BMSCs. Our study suggested that MGF E peptide might be helpful for the clinical application of tissue engineering strategy in bone defect repair. Sever hypoxia impairs bone defect repair with bone marrow-derived mesenchymal stem cells (BMSCs). This study proved that mechano-growth factor E (MGF E) peptide could improve the severe hypoxia-induced cell contraction and decline of cell adhesion and migration of BMSCs. Besides, MGF E peptide weakened the effects of severe hypoxia on the cytoskeleton arrangement- and mobility-relevant protein expression levels in BMSCs. The underlying molecular mechanism was also verified. Finally, it was confirmed that MGF E peptide showed an adverse effect on the expression level of vascular endothelial growth factor α in BMSCs under severe hypoxia but could

  5. Impact of repeated daily exposure to intermittent hypoxia and mild sustained hypercapnia on apnea severity.

    Science.gov (United States)

    Yokhana, Sanar S; Gerst, David G; Lee, Dorothy S; Badr, M Safwan; Qureshi, Tabarak; Mateika, Jason H

    2012-02-01

    We examined whether exposure to intermittent hypoxia (IH) during wakefulness impacted on the apnea/hypopnea index (AHI) during sleep in individuals with sleep apnea. Participants were exposed to twelve 4-min episodes of hypoxia in the presence of sustained mild hypercapnia each day for 10 days. A control group was exposed to sustained mild hypercapnia for a similar duration. The intermittent hypoxia protocol was completed in the evening on day 1 and 10 and was followed by a sleep study. During all sleep studies, the change in esophageal pressure (ΔPes) from the beginning to the end of an apnea and the tidal volume immediately following apneic events were used to measure respiratory drive. Following exposure to IH on day 1 and 10, the AHI increased above baseline measures (day 1: 1.95 ± 0.42 fraction of baseline, P ≤ 0.01, vs. day 10: 1.53 ± 0.24 fraction of baseline, P < 0.06). The indexes were correlated to the hypoxic ventilatory response (HVR) measured during the IH protocol but were not correlated to the magnitude of ventilatory long-term facilitation (vLTF). Likewise, ΔPes and tidal volume measures were greater on day 1 and 10 compared with baseline (ΔPes: -8.37 ± 0.84 vs. -5.90 ± 1.30 cmH(2)0, P ≤ 0.04; tidal volume: 1,193.36 ± 101.85 vs. 1,015.14 ± 119.83 ml, P ≤ 0.01). This was not the case in the control group. Interestingly, the AHI on day 10 (0.78 ± 0.13 fraction of baseline, P ≤ 0.01) was significantly less than measures obtained during baseline and day 1 in the mild hypercapnia control group. We conclude that enhancement of the HVR initiated by exposure to IH may lead to increases in the AHI during sleep and that initiation of vLTF did not appear to impact on breathing stability. Lastly, our results suggest that repeated daily exposure to mild sustained hypercapnia may lead to a decrease in breathing events.

  6. Skeletal Muscle Pyruvate Dehydrogenase Phosphorylation and Lactate Accumulation During Sprint Exercise in Normoxia and Severe Acute Hypoxia: Effects of Antioxidants

    Directory of Open Access Journals (Sweden)

    David Morales-Alamo

    2018-03-01

    Full Text Available Compared to normoxia, during sprint exercise in severe acute hypoxia the glycolytic rate is increased leading to greater lactate accumulation, acidification, and oxidative stress. To determine the role played by pyruvate dehydrogenase (PDH activation and reactive nitrogen and oxygen species (RNOS in muscle lactate accumulation, nine volunteers performed a single 30-s sprint (Wingate test on four occasions: two after the ingestion of placebo and another two following the intake of antioxidants, while breathing either hypoxic gas (PIO2 = 75 mmHg or room air (PIO2 = 143 mmHg. Vastus lateralis muscle biopsies were obtained before, immediately after, 30 and 120 min post-sprint. Antioxidants reduced the glycolytic rate without altering performance or VO2. Immediately after the sprints, Ser293- and Ser300-PDH-E1α phosphorylations were reduced to similar levels in all conditions (~66 and 91%, respectively. However, 30 min into recovery Ser293-PDH-E1α phosphorylation reached pre-exercise values while Ser300-PDH-E1α was still reduced by 44%. Thirty minutes after the sprint Ser293-PDH-E1α phosphorylation was greater with antioxidants, resulting in 74% higher muscle lactate concentration. Changes in Ser293 and Ser300-PDH-E1α phosphorylation from pre to immediately after the sprints were linearly related after placebo (r = 0.74, P < 0.001; n = 18, but not after antioxidants ingestion (r = 0.35, P = 0.15. In summary, lactate accumulation during sprint exercise in severe acute hypoxia is not caused by a reduced activation of the PDH. The ingestion of antioxidants is associated with increased PDH re-phosphorylation and slower elimination of muscle lactate during the recovery period. Ser293 re-phosphorylates at a faster rate than Ser300-PDH-E1α during the recovery period, suggesting slightly different regulatory mechanisms.

  7. Genomic Analysis Reveals Hypoxia Adaptation in the Tibetan Mastiff by Introgression of the Gray Wolf from the Tibetan Plateau.

    Science.gov (United States)

    Miao, Benpeng; Wang, Zhen; Li, Yixue

    2017-03-01

    The Tibetan Mastiff (TM), a native of the Tibetan Plateau, has quickly adapted to the extreme highland environment. Recently, the impact of positive selection on the TM genome was studied and potential hypoxia-adaptive genes were identified. However, the origin of the adaptive variants remains unknown. In this study, we investigated the signature of genetic introgression in the adaptation of TMs with dog and wolf genomic data from different altitudes in close geographic proximity. On a genome-wide scale, the TM was much more closely related to other dogs than wolves. However, using the 'ABBA/BABA' test, we identified genomic regions from the TM that possibly introgressed from Tibetan gray wolf. Several of the regions, including the EPAS1 and HBB loci, also showed the dominant signature of selective sweeps in the TM genome. We validated the introgression of the two loci by excluding the possibility of convergent evolution and ancestral polymorphisms and examined the haplotypes of all available canid genomes. The estimated time of introgression based on a non-coding region of the EPAS1 locus mostly overlapped with the Paleolithic era. Our results demonstrated that the introgression of hypoxia adaptive genes in wolves from the highland played an important role for dogs living in hypoxic environments, which indicated that domestic animals could acquire local adaptation quickly by secondary contact with their wild relatives. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  8. Supra- and Sub-Baseline Phosphocreatine Recovery in Developing Brain after Transient Hypoxia-Ischaemia: Relation to Baseline Energetics, Insult Severity and Outcome

    Science.gov (United States)

    Iwata, Osuke; Iwata, Sachiko; Bainbridge, Alan; De Vita, Enrico; Matsuishi, Toyojiro; Cady, Ernest B.; Robertson, Nicola J.

    2008-01-01

    Following hypoxia-ischaemia (HI), an early biomarker of insult severity is desirable to target neuroprotective therapies to patients most likely to benefit; currently there are no biomarkers within the "latent phase" period before the establishment of secondary energy failure. Brief transient phosphocreatine (PCr) recovery overshoot (measured…

  9. Severe acute intermittent hypoxia elicits phrenic long-term facilitation by a novel adenosine-dependent mechanism

    Science.gov (United States)

    Nichols, Nicole L.; Dale, Erica A.

    2012-01-01

    Acute intermittent hypoxia [AIH; 3, 5-min episodes; 35–45 mmHg arterial Po2 (PaO2)] elicits serotonin-dependent phrenic long-term facilitation (pLTF), a form of phrenic motor facilitation (pMF) initiated by Gq protein-coupled metabotropic 5-HT2 receptors. An alternate pathway to pMF is induced by Gs protein-coupled metabotropic receptors, including adenosine A2A receptors. AIH-induced pLTF is dominated by the serotonin-dependent pathway and is actually restrained via inhibition from the adenosine-dependent pathway. Here, we hypothesized that severe AIH shifts pLTF from a serotonin-dependent to an adenosine-dependent form of pMF. pLTF induced by severe (25–30 mmHg PaO2) and moderate (45–55 mmHg PaO2) AIH were compared in anesthetized rats, with and without intrathecal (C4) spinal A2A (MSX-3, 130 ng/kg, 12 μl) or 5-HT receptor antagonist (methysergide, 300 μg/kg, 15 μl) injections. During severe, but not moderate AIH, progressive augmentation of the phrenic response during hypoxic episodes was observed. Severe AIH (78% ± 8% 90 min post-AIH, n = 6) elicited greater pLTF vs. moderate AIH (41% ± 12%, n = 8; P MSX-3 (28% ± 6%; n = 6; P 0.05). Thus severe AIH shifts pLTF from a serotonin-dependent to an adenosine-dependent mechanism; the adenosinergic pathway inhibits the serotonergic pathway following moderate AIH. Here we demonstrate a novel adenosine-dependent pathway to pLTF following severe AIH. Shifts in the mechanisms of respiratory plasticity provide the ventilatory control system greater flexibility as challenges that differ in severity are confronted. PMID:22403346

  10. Increased C-C chemokine receptor 2 gene expression in monocytes of severe obstructive sleep apnea patients and under intermittent hypoxia.

    Science.gov (United States)

    Chuang, Li-Pang; Chen, Ning-Hung; Lin, Shih-Wei; Chang, Ying-Ling; Liao, Hsiang-Ruei; Lin, Yu-Sheng; Chao, I-Ju; Lin, Yuling; Pang, Jong-Hwei S

    2014-01-01

    Obstructive sleep apnea (OSA) is known to be a risk factor of coronary artery disease. The chemotaxis and adhesion of monocytes to the endothelium in the early atherosclerosis is important. This study aimed to investigate the effect of intermittent hypoxia, the hallmark of OSA, on the chemotaxis and adhesion of monocytes. Peripheral blood was sampled from 54 adults enrolled for suspected OSA. RNA was prepared from the isolated monocytes for the analysis of C-C chemokine receptor 2 (CCR2). The effect of intermittent hypoxia on the regulation and function of CCR2 was investigated on THP-1 monocytic cells and monocytes. The mRNA and protein expression levels were investigated by RT/real-time PCR and western blot analysis, respectively. Transwell filter migration assay and cell adhesion assay were performed to study the chemotaxis and adhesion of monocytes. Monocytic CCR2 gene expression was found to be increased in severe OSA patients and higher levels were detected after sleep. Intermittent hypoxia increased the CCR2 expression in THP-1 monocytic cells even in the presence of TNF-α and CRP. Intermittent hypoxia also promoted the MCP-1-mediated chemotaxis and adhesion of monocytes to endothelial cells. Furthermore, inhibitor for p42/44 MAPK or p38 MAPK suppressed the activation of monocytic CCR2 expression by intermittent hypoxia. This is the first study to demonstrate the increase of CCR2 gene expression in monocytes of severe OSA patients. Monocytic CCR2 gene expression can be induced under intermittent hypoxia which contributes to the chemotaxis and adhesion of monocytes.

  11. Impact of Chronic Neonatal Intermittent Hypoxia on Severity of Retinal Damage in a Rat Model of Oxygen-Induced Retinopathy.

    Science.gov (United States)

    Beharry, Kay D; Cai, Charles L; Ahmad, Taimur; Guzel, Sibel; Valencia, Gloria B; Aranda, Jacob V

    2018-01-01

    Neonatal intermittent hypoxia (IH) followed by re-oxygenation in normoxia or supplemental oxygen (IHR) increases the risk for severe retinopathy of prematurity (ROP). The exact timing for the onset of retinal damage which may guide strategic interventions during retinal development, is unknown. We tested the hypothesis that chronic exposure of the immature retina to neonatal IH induces early manifestations of retinal damage that can be utilized as key time points for strategic pharmacologic intervention. Newborn rats were exposed to IH within 2 hours of birth (P0) until P14, or allowed to recover in room air (RA) from P14 to P21 (IHR). Retinal integrity and angiogenesis biomarkers were progressively assessed before (P0), during IH, and post IH (recovery in RA), or IHR, and compared to normoxic age-matched controls. Retinal damage occurred as early as day 3 of neonatal IH, consistent with vascular abnormalities and disturbances in the astrocytic template. These abnormalities worsened during IHR. Pharmacologic and non-pharmacologic interventions to identify, prevent, or minimize neonatal IH should be implemented shortly after birth in high risk preterm newborns. This strategy may lead to a reduction in the outcome of severe ROP requiring later invasive treatments.

  12. Hypoxia symptoms during altitude training in professional Iranian fighter pilots.

    Science.gov (United States)

    Alagha, Babak; AhmadBeygi, Shervin; Ahmadbeigy, Shervin; Moosavi, Seyed Ali Javad; Jalali, Seyed Mahmood

    2012-01-01

    Susceptibility to hypoxia is influenced by a multitude of factors, including fatigue, physical activity, illnesses, ambient temperature, rate of ascent, destination altitude, medications, and alcohol. Anecdotally, several reports have been made regarding changes in the form of hypoxia presentation in Iranian fighter pilots in the absence of these factors. This study focused specifically on the effect of pilot age on susceptibility to hypoxia and its initial presentation. We assumed that a pilot's age may increase his susceptibility to hypoxia and consequently reduce the amount of time it takes for hypoxia to present. Because our literature review did not reveal any previous study addressing the possible relationship between age and susceptibility to hypoxia, the purpose of this study is to address and clarify this relationship. In this retrospective study, we collected information from Iranian fighter pilots (n = 30) through an anonymous questionnaire in 2000. The form of hypoxia presentation of each subject was evaluated during five altitude chamber training (ACT) sessions that were conducted routinely from 1972 to 1984. To enhance the accuracy of the study's results, confounding factors such as prior hypoxia experience in an ACT session have been taken into consideration. The results revealed a statistically significant relationship between age and a change in the form of hypoxia presentation in our subjects. Increased age reduced the amount of time before the first individual hypoxia symptom appeared (P < .000002). Although having previous hypoxia experience may help pilots to recognize their symptoms earlier, its effect was not statistically significant (P < .18). A few changes in the nature of individual symptoms were observed; however, we did not find a meaningful statistical correlation between pilot age and change in the nature of symptoms. Susceptibility ot hypoxia increases with pilot age. Copyright © 2012 Air Medical Journal Associates. Published by

  13. Mammalian target of rapamycin is required for phrenic long-term facilitation following severe but not moderate acute intermittent hypoxia.

    Science.gov (United States)

    Dougherty, Brendan J; Fields, Daryl P; Mitchell, Gordon S

    2015-09-01

    Phrenic long-term facilitation (pLTF) is a persistent increase in phrenic nerve activity after acute intermittent hypoxia (AIH). Distinct cell-signaling cascades give rise to pLTF depending on the severity of hypoxemia within hypoxic episodes. Moderate AIH (mAIH; three 5-min episodes, PaO2 ∼35-55 mmHG) elicits pLTF by a serotonin (5-HT)-dependent mechanism that requires new synthesis of brain-derived neurotrophic factor (BDNF), activation of its high-affinity receptor (TrkB), and ERK MAPK signaling. In contrast, severe AIH (sAIH; three 5-min episodes, PaO2 ∼25-30 mmHG) elicits pLTF by an adenosine-dependent mechanism that requires new TrkB synthesis and Akt signaling. Although both mechanisms require spinal protein synthesis, the newly synthesized proteins are distinct, as are the neurochemicals inducing plasticity (serotonin vs. adenosine). In many forms of neuroplasticity, new protein synthesis requires translational regulation via mammalian target of rapamycin (mTOR) signaling. Since Akt regulates mTOR activity, we hypothesized that mTOR activity is necessary for sAIH- but not mAIH-induced pLTF. Phrenic nerve activity in anesthetized, paralyzed, and ventilated rats was recorded before, during, and 60 min after mAIH or sAIH. Rats were pretreated with intrathecal injections of 20% DMSO (vehicle controls) or rapamycin (0.1 mM, 12 μl), a selective mTOR complex 1 inhibitor. Consistent with our hypothesis, rapamycin blocked sAIH- but not mAIH-induced pLTF. Thus spinal mTOR activity is required for adenosine-dependent (sAIH) but not serotonin-dependent (mAIH) pLTF, suggesting that distinct mechanisms regulate new protein synthesis in these forms of spinal neuroplasticity. Copyright © 2015 the American Physiological Society.

  14. ChIP-seq and in vivo transcriptome analyses of the Aspergillus fumigatus SREBP SrbA reveals a new regulator of the fungal hypoxia response and virulence.

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    Dawoon Chung

    2014-11-01

    Full Text Available The Aspergillus fumigatus sterol regulatory element binding protein (SREBP SrbA belongs to the basic Helix-Loop-Helix (bHLH family of transcription factors and is crucial for antifungal drug resistance and virulence. The latter phenotype is especially striking, as loss of SrbA results in complete loss of virulence in murine models of invasive pulmonary aspergillosis (IPA. How fungal SREBPs mediate fungal virulence is unknown, though it has been suggested that lack of growth in hypoxic conditions accounts for the attenuated virulence. To further understand the role of SrbA in fungal infection site pathobiology, chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-seq was used to identify genes under direct SrbA transcriptional regulation in hypoxia. These results confirmed the direct regulation of ergosterol biosynthesis and iron uptake by SrbA in hypoxia and revealed new roles for SrbA in nitrate assimilation and heme biosynthesis. Moreover, functional characterization of an SrbA target gene with sequence similarity to SrbA identified a new transcriptional regulator of the fungal hypoxia response and virulence, SrbB. SrbB co-regulates genes involved in heme biosynthesis and demethylation of C4-sterols with SrbA in hypoxic conditions. However, SrbB also has regulatory functions independent of SrbA including regulation of carbohydrate metabolism. Loss of SrbB markedly attenuates A. fumigatus virulence, and loss of both SREBPs further reduces in vivo fungal growth. These data suggest that both A. fumigatus SREBPs are critical for hypoxia adaptation and virulence and reveal new insights into SREBPs' complex role in infection site adaptation and fungal virulence.

  15. Hypoxia Room

    Data.gov (United States)

    Federal Laboratory Consortium — The Hypoxia Room is a 8x8x8 ft. clear vinyl plastic and aluminum frame construction enclosure located within USAREIM laboratory 028. The Hypoxia Room (manufactured...

  16. [Severe neonatal hyperthyroidism which reveals a maternal Graves' disease].

    Science.gov (United States)

    Guérin, B; Vautier, V; Boin-Gay, V; Estrade, G; Choulot, J-J; Doireau, V

    2004-04-01

    Two of every thousand pregnancies are complicated by Graves' disease. Diagnosis is suggested by maternal disorders (tachycardia, exophthalmia, weight loss.) or fetal disorders (tachycardia, intra-uterine growth retardation, preterm birth.). Due to transfer into the fetal compartment of maternal antibodies which stimulate the fetal thyroid by binding to the thyroid thyrotropin (TSH) receptor, only 1% of children born to these mothers are described as having hyperthyroidism. Neonatal thyrotoxicosis disappears with clearance of the maternal antibodies; clinical signs usually disappear during the first four Months of life. The most frequent neonatal clinical signs of thyrotoxicosis are tachycardia, goiter, hyperexcitability, poor weight gain, hepatosplenomegaly, stare and eyelid retraction. Diagnosis is based on determination of the blood level of triiodothyronine (T3), thyroxine (T4) and TSH. To confirm the nature of hyperthyroidism, thyroid-stimulating immunoglobulins (TSI) should be assayed. The kinetics of TSI provides a guide for therapeutic adaptation and disappearance of TSI is a sign of recovery. Rare cases of familial non-autoimmune hyperthyroidism have been shown to be caused by germline mutation of the thyrotropin receptor. We report a case of severe neonatal hyperthyroidism which led to the diagnosis of maternal Graves' disease.

  17. Sestrin2 induced by hypoxia inducible factor1 alpha protects the blood-brain barrier via inhibiting VEGF after severe hypoxic-ischemic injury in neonatal rats.

    Science.gov (United States)

    Shi, Xudan; Doycheva, Desislava Met; Xu, Liang; Tang, Jiping; Yan, Min; Zhang, John H

    2016-11-01

    Hypoxic ischemic (HI) encephalopathy remains the leading cause of perinatal brain injury resulting in long term disabilities. Stabilization of blood brain barrier (BBB) after HI is an important target, therefore, in this study we aim to determine the role of sestrin2, a stress inducible protein which is elevated after various insults, on BBB stabilization after moderate and severe HI injuries. Rat pups underwent common carotid artery ligation followed by either 150min (severe model) or 100min (moderate model) of hypoxia. 1h post HI, rats were intranasally administered with recombinant human sestrin2 (rh-sestrin2) and sacrificed for infarct area, brain water content, righting reflex and geotaxis reflex. Sestrin2 was silenced using siRNA and an activator/inhibitor of hypoxia inducible factor1α (HIF1α) was used to examine their roles on BBB permeability. Rats subjected to severe HI exhibited larger infarct area and higher sestrin2 expression compared to rats in the moderate HI group. rh-sestrin2 attenuated brain infarct and edema, while silencing sestrin2 reversed these protective effects after severe HI. HIF1α induced sestrin2 activation in severe HI but not in moderate HI groups. A HIF1a agonist was shown to increase permeability of the BBB via vascular endothelial growth factor (VEGF) after moderate HI. However, after severe HI, HIF1α activated both VEGF and sestrin2. But HIF1α dependent sestrin2 activation was the predominant pathway after severe HI which inhibited VEGF and attenuated BBB permeability. rh-sestrin2 attenuated BBB permeability via upregulation of endogenous sestrin2 which was induced by HIF1α after severe HI. However, HIF1α's effects as a prodeath or prosurvival signal were influenced by the severity of HI injury. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. TST, as a polysomnographic variable, is superior to the apnea hypopnea index for evaluating intermittent hypoxia in severe obstructive sleep apnea.

    Science.gov (United States)

    Zhang, Xiao-Bin; Zen, Hui-Qing; Lin, Qi-Chang; Chen, Gong-Ping; Chen, Li-Da; Chen, Hua

    2014-10-01

    The polysomnography (PSG) index of the apnea hypopnea index (AHI) is considered the 'gold standard' for stratifying the severity of obstructive sleep apnea (OSA). However, AHI cannot reflect the true characteristic of chronic intermittent hypoxia (CIH), which may trigger systemic inflammation in some OSA patients. High-sensitivity C-reactive protein (hsCRP) is considered a biomarker of systemic inflammation in OSA patients. The aim of the present study was to evaluate the relationship between PSG variables and hsCRP in men with severe OSA. Men with severe OSA (AHI ≥ 30 events/h) diagnosed by PSG were enrolled. AHI and body mass index were matched between a high hsCRP group (hsCRP ≥ 3.0 mg/L) and a low hsCRP group. A blood sample was taken for serum hsCRP analysis. Multiple regression analysis was performed to assess independent predictors of high hsCRP. One hundred and fifty-two subjects were enrolled in the study (76 in each group). Mean serum hsCRP was 3.76 ± 2.13 mg/L. The mean percentage of total sleep time spent with SaO2 hypoxia variables.

  19. Synthesis of ent-BE-43547A1 reveals a potent hypoxia-selective anticancer agent and uncovers the biosynthetic origin of the APD-CLD natural products

    Science.gov (United States)

    Villadsen, Nikolaj L.; Jacobsen, Kristian M.; Keiding, Ulrik B.; Weibel, Esben T.; Christiansen, Bjørn; Vosegaard, Thomas; Bjerring, Morten; Jensen, Frank; Johannsen, Mogens; Tørring, Thomas; Poulsen, Thomas B.

    2017-03-01

    Tumour hypoxia is speculated to be a key driver of therapeutic resistance and metastatic dissemination. Consequently, the discovery of new potent agents that selectively target the hypoxic cell population may reveal new and untapped antitumour mechanisms. Here we demonstrate that the BE-43547 subclass of the APD-CLD (amidopentadienoate-containing cyclolipodepsipeptides) natural products possesses highly hypoxia-selective growth-inhibitory activity against pancreatic cancer cells. To enable this discovery, we have developed the first synthesis of the BE-43547-macrocyclic scaffold in 16 steps (longest linear sequence), which also allowed access to the full panel of relative stereoisomers and ultimately to the assignment of stereochemical configuration. Discrepancies between the spectroscopic signatures of the synthetic compounds with that originally reported for the BE-43547 members stimulated us to re-isolate the natural product from a BE-43547-producing microorganism during which we elucidated the biosynthetic gene clusters for the BE-43547 family as well as for all other known APD-CLDs. Our studies underline the exciting possibilities for the further development of the anticancer activities of these natural products.

  20. Gene Expression Correlated with Severe Asthma Characteristics Reveals Heterogeneous Mechanisms of Severe Disease.

    Science.gov (United States)

    Modena, Brian D; Bleecker, Eugene R; Busse, William W; Erzurum, Serpil C; Gaston, Benjamin M; Jarjour, Nizar N; Meyers, Deborah A; Milosevic, Jadranka; Tedrow, John R; Wu, Wei; Kaminski, Naftali; Wenzel, Sally E

    2017-06-01

    Severe asthma (SA) is a heterogeneous disease with multiple molecular mechanisms. Gene expression studies of bronchial epithelial cells in individuals with asthma have provided biological insight and underscored possible mechanistic differences between individuals. Identify networks of genes reflective of underlying biological processes that define SA. Airway epithelial cell gene expression from 155 subjects with asthma and healthy control subjects in the Severe Asthma Research Program was analyzed by weighted gene coexpression network analysis to identify gene networks and profiles associated with SA and its specific characteristics (i.e., pulmonary function tests, quality of life scores, urgent healthcare use, and steroid use), which potentially identified underlying biological processes. A linear model analysis confirmed these findings while adjusting for potential confounders. Weighted gene coexpression network analysis constructed 64 gene network modules, including modules corresponding to T1 and T2 inflammation, neuronal function, cilia, epithelial growth, and repair mechanisms. Although no network selectively identified SA, genes in modules linked to epithelial growth and repair and neuronal function were markedly decreased in SA. Several hub genes of the epithelial growth and repair module were found located at the 17q12-21 locus, near a well-known asthma susceptibility locus. T2 genes increased with severity in those treated with corticosteroids but were also elevated in untreated, mild-to-moderate disease compared with healthy control subjects. T1 inflammation, especially when associated with increased T2 gene expression, was elevated in a subgroup of younger patients with SA. In this hypothesis-generating analysis, gene expression networks in relation to asthma severity provided potentially new insight into biological mechanisms associated with the development of SA and its phenotypes.

  1. Cell-Based Phenotyping Reveals QTL for Membrane Potential Maintenance Associated with Hypoxia and Salinity Stress Tolerance in Barley

    Directory of Open Access Journals (Sweden)

    Muhammad B. Gill

    2017-11-01

    Full Text Available Waterlogging and salinity are two major abiotic stresses that hamper crop production world-wide resulting in multibillion losses. Plant abiotic stress tolerance is conferred by many interrelated mechanisms. Amongst these, the cell’s ability to maintain membrane potential (MP is considered to be amongst the most crucial traits, a positive relationship between the ability of plants to maintain highly negative MP and its tolerance to both salinity and waterlogging stress. However, no attempts have been made to identify quantitative trait loci (QTL conferring this trait. In this study, the microelectrode MIFE technique was used to measure the plasma membrane potential of epidermal root cells of 150 double haploid (DH lines of barley (Hordeum vulgare L. from a cross between a Chinese landrace TX9425 and Japanese malting cultivar Naso Nijo under hypoxic conditions. A major QTL for the MP in the epidermal root cells in hypoxia-exposed plants was identified. This QTL was located on 2H, at a similar position to the QTL for waterlogging and salinity tolerance reported in previous studies. Further analysis confirmed that MP showed a significant contribution to both waterlogging and salinity tolerance. The fact that the QTL for MP was controlled by a single major QTL illustrates the power of the single-cell phenotyping approach and opens prospects for fine mapping this QTL and thus being more effective in marker assisted selection.

  2. Imaging Mass Spectrometry Revealed the Accumulation Characteristics of the 2-Nitroimidazole-Based Agent "Pimonidazole" in Hypoxia.

    Directory of Open Access Journals (Sweden)

    Yukiko Masaki

    Full Text Available Hypoxia, or low oxygen concentration, is a key factor promoting tumor progression and angiogenesis and resistance of cancer to radiotherapy and chemotherapy. 2-Nitroimidazole-based agents have been widely used in pathological and nuclear medicine examinations to detect hypoxic regions in tumors; in particular, pimonidazole is used for histochemical staining of hypoxic regions. It is considered to accumulate in hypoxic cells via covalent binding with macromolecules or by forming reductive metabolites after reduction of its nitro group. However, the detailed mechanism of its accumulation remains unknown. In this study, we investigated the accumulation mechanism of pimonidazole in hypoxic tumor tissues in a mouse model by mass spectrometric analyses including imaging mass spectrometry (IMS. Pimonidazole and its reductive metabolites were observed in the tumor tissues. However, their locations in the tumor sections were not similar to the positively stained areas in pimonidazole-immunohistochemistry, an area considered hypoxic. The glutathione conjugate of reduced pimonidazole, a low-molecular-weight metabolite of pimonidazole, was found in tumor tissues by LC-MS analysis, and our IMS study determined that the intratumor localization of the glutathione conjugate was consistent with the area positively immunostained for pimonidazole. We also found complementary localization of the glutathione conjugate and reduced glutathione (GSH, implying that formation of the glutathione conjugate occurred in the tumor tissue. These results suggest that in hypoxic tumor cells, pimonidazole is reduced at its nitro group, followed by conjugation with GSH.

  3. Teleosts in hypoxia : Aspects of anaerobic metabolism

    NARCIS (Netherlands)

    Van den Thillart, G.; van Waarde, Aren

    1985-01-01

    Moderate hypoxia can be tolerated by many fish species, while only some species survive severe hypoxia or anoxia. Hypoxia usually activates anaerobic glycolysis, which may be temporary when the animals are able to improve their oxygen extraction capacity. Switching over to aerobic metabolism allows

  4. Transcriptome sequencing revealed differences in the response of renal cancer cells to hypoxia and CoCl2 treatment [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Nadezhda Zhigalova

    2015-12-01

    Full Text Available Human cancer cells are subjected to hypoxic conditions in many tumours. Hypoxia causes alterations in the glycolytic pathway activation through stabilization of hypoxia-inducible factor 1. Currently, two approaches are commonly used to model hypoxia: an alternative to generating low-oxygen conditions in an incubator, cells can be treated with CoCl2. We performed RNA-seq experiments to study transcriptomes of human Caki-1 cells under real hypoxia and after CoCl2 treatment. Despite causing transcriptional changes of a much higher order of magnitude for the genes in the hypoxia regulation pathway, CoCl2 treatment fails to induce alterations in the glycolysis / gluconeogenesis pathway. Moreover, CoCl2 caused aberrant activation of other oxidoreductases in glycine, serine and threonine metabolism pathways.

  5. Radiation-induced hypoxia may perpetuate late normal tissue injury

    International Nuclear Information System (INIS)

    Vujaskovic, Zeljko; Anscher, Mitchell S.; Feng, Q.-F.; Rabbani, Zahid N.; Amin, Khalid; Samulski, Thaddeus S.; Dewhirst, Mark W.; Haroon, Zishan A.

    2001-01-01

    Purpose: The purpose of this study was to determine whether or not hypoxia develops in rat lung tissue after radiation. Methods and Materials: Fisher-344 rats were irradiated to the right hemithorax using a single dose of 28 Gy. Pulmonary function was assessed by measuring the changes in respiratory rate every 2 weeks, for 6 months after irradiation. The hypoxia marker was administered 3 h before euthanasia. The tissues were harvested at 6 weeks and 6 months after irradiation and processed for immunohistochemistry. Results: A moderate hypoxia was detected in the rat lungs at 6 weeks after irradiation, before the onset of functional or histopathologic changes. The more severe hypoxia, that developed at the later time points (6 months) after irradiation, was associated with a significant increase in macrophage activity, collagen deposition, lung fibrosis, and elevation in the respiratory rate. Immunohistochemistry studies revealed an increase in TGF-β, VEGF, and CD-31 endothelial cell marker, suggesting a hypoxia-mediated activation of the profibrinogenic and proangiogenic pathways. Conclusion: A new paradigm of radiation-induced lung injury should consider postradiation hypoxia to be an important contributing factor mediating a continuous production of a number of inflammatory and fibrogenic cytokines

  6. The impact of intermittent or sustained carbon dioxide on intermittent hypoxia initiated respiratory plasticity. What is the effect of these combined stimuli on apnea severity?

    Science.gov (United States)

    Mateika, Jason H; Panza, Gino; Alex, Raichel; El-Chami, Mohamad

    2017-10-31

    The following review explores the effect that intermittent or sustained hypercapnia coupled to intermittent hypoxia has on respiratory plasticity. The review explores published work which suggests that intermittent hypercapnia leads to long-term depression of respiration when administered in isolation and prevents the initiation of long-term facilitation when administered in combination with intermittent hypoxia. The review also explores the impact that sustained hypercapnia alone and in combination with intermittent hypoxia has on the magnitude of long-term facilitation. After exploring the outcomes linked to intermittent hypoxia/hypercapnia and intermittent hypoxia/sustained hypercapnia the translational relevance of the outcomes as it relates to breathing stability during sleep is addressed. The likelihood that naturally induced cycles of intermittent hypoxia, coupled to oscillations in carbon dioxide that range between hypocapnia and hypercapnia, do not initiate long-term facilitation is addressed. Moreover, the conditions under which intermittent hypoxia/sustained hypercapnia could serve to improve breathing stability and mitigate co-morbidities associated with sleep apnea are considered. Published by Elsevier B.V.

  7. The role of hypoxia inducible factor 1 (HIF-1) in hypoxia induced apoptosis

    NARCIS (Netherlands)

    Greijer, A.E.; Wall, E. van der

    2004-01-01

    Apoptosis can be induced in response to hypoxia. The severity of hypoxia determines whether cells become apoptotic or adapt to hypoxia and survive. A hypoxic environment devoid of nutrients prevents the cell undergoing energy dependent apoptosis and cells become necrotic. Apoptosis regulatory

  8. Meta-analysis using a novel database, miRStress, reveals miRNAs that are frequently associated with the radiation and hypoxia stress-responses.

    Directory of Open Access Journals (Sweden)

    Laura Ann Jacobs

    Full Text Available Organisms are often exposed to environmental pressures that affect homeostasis, so it is important to understand the biological basis of stress-response. Various biological mechanisms have evolved to help cells cope with potentially cytotoxic changes in their environment. miRNAs are small non-coding RNAs which are able to regulate mRNA stability. It has been suggested that miRNAs may tip the balance between continued cytorepair and induction of apoptosis in response to stress. There is a wealth of data in the literature showing the effect of environmental stress on miRNAs, but it is scattered in a large number of disparate publications. Meta-analyses of this data would produce added insight into the molecular mechanisms of stress-response. To facilitate this we created and manually curated the miRStress database, which describes the changes in miRNA levels following an array of stress types in eukaryotic cells. Here we describe this database and validate the miRStress tool for analysing miRNAs that are regulated by stress. To validate the database we performed a cross-species analysis to identify miRNAs that respond to radiation. The analysis tool confirms miR-21 and miR-34a as frequently deregulated in response to radiation, but also identifies novel candidates as potentially important players in this stress response, including miR-15b, miR-19b, and miR-106a. Similarly, we used the miRStress tool to analyse hypoxia-responsive miRNAs. The most frequently deregulated miRNAs were miR-210 and miR-21, as expected. Several other miRNAs were also found to be associated with hypoxia, including miR-181b, miR-26a/b, miR-106a, miR-213 and miR-192. Therefore the miRStress tool has identified miRNAs with hitherto unknown or under-appreciated roles in the response to specific stress types. The miRStress tool, which can be used to uncover new insight into the biological roles of miRNAs, and also has the potential to unearth potential biomarkers for

  9. Analysis of the Aspergillus fumigatus proteome reveals metabolic changes and the activation of the pseurotin A biosynthesis gene cluster in response to hypoxia.

    Science.gov (United States)

    Vödisch, Martin; Scherlach, Kirstin; Winkler, Robert; Hertweck, Christian; Braun, Hans-Peter; Roth, Martin; Haas, Hubertus; Werner, Ernst R; Brakhage, Axel A; Kniemeyer, Olaf

    2011-05-06

    The mold Aspergillus fumigatus is the most important airborne fungal pathogen. Adaptation to hypoxia represents an important virulence attribute for A. fumigatus. Therefore, we aimed at obtaining a comprehensive overview about this process on the proteome level. To ensure highly reproducible growth conditions, an oxygen-controlled, glucose-limited chemostat cultivation was established. Two-dimensional gel electrophoresis analysis of mycelial and mitochondrial proteins as well as two-dimensional Blue Native/SDS-gel separation of mitochondrial membrane proteins led to the identification of 117 proteins with an altered abundance under hypoxic in comparison to normoxic conditions. Hypoxia induced an increased activity of glycolysis, the TCA-cycle, respiration, and amino acid metabolism. Consistently, the cellular contents in heme, iron, copper, and zinc increased. Furthermore, hypoxia induced biosynthesis of the secondary metabolite pseurotin A as demonstrated at proteomic, transcriptional, and metabolite levels. The observed and so far not reported stimulation of the biosynthesis of a secondary metabolite by oxygen depletion may also affect the survival of A. fumigatus in hypoxic niches of the human host. Among the proteins so far not implicated in hypoxia adaptation, an NO-detoxifying flavohemoprotein was one of the most highly up-regulated proteins which indicates a link between hypoxia and the generation of nitrosative stress in A. fumigatus.

  10. Coastal hypoxia and sediment biogeochemistry

    Directory of Open Access Journals (Sweden)

    J. J. Middelburg

    2009-07-01

    Full Text Available The intensity, duration and frequency of coastal hypoxia (oxygen concentration <63 μM are increasing due to human alteration of coastal ecosystems and changes in oceanographic conditions due to global warming. Here we provide a concise review of the consequences of coastal hypoxia for sediment biogeochemistry. Changes in bottom-water oxygen levels have consequences for early diagenetic pathways (more anaerobic at expense of aerobic pathways, the efficiency of re-oxidation of reduced metabolites and the nature, direction and magnitude of sediment-water exchange fluxes. Hypoxia may also lead to more organic matter accumulation and burial and the organic matter eventually buried is also of higher quality, i.e. less degraded. Bottom-water oxygen levels also affect the organisms involved in organic matter processing with the contribution of metazoans decreasing as oxygen levels drop. Hypoxia has a significant effect on benthic animals with the consequences that ecosystem functions related to macrofauna such as bio-irrigation and bioturbation are significantly affected by hypoxia as well. Since many microbes and microbial-mediated biogeochemical processes depend on animal-induced transport processes (e.g. re-oxidation of particulate reduced sulphur and denitrification, there are indirect hypoxia effects on biogeochemistry via the benthos. Severe long-lasting hypoxia and anoxia may result in the accumulation of reduced compounds in sediments and elimination of macrobenthic communities with the consequences that biogeochemical properties during trajectories of decreasing and increasing oxygen may be different (hysteresis with consequences for coastal ecosystem dynamics.

  11. Prolonged Exposures to Intermittent Hypoxia Promote Visceral White Adipose Tissue Inflammation in a Murine Model of Severe Sleep Apnea: Effect of Normoxic Recovery.

    Science.gov (United States)

    Gileles-Hillel, Alex; Almendros, Isaac; Khalyfa, Abdelnaby; Nigdelioglu, Recep; Qiao, Zhuanhong; Hamanaka, Robert B; Mutlu, Gökhan M; Akbarpour, Mahzad; Gozal, David

    2017-03-01

    Increased visceral white adipose tissue (vWAT) mass results in infiltration of inflammatory macrophages that drive inflammation and insulin resistance. Patients with obstructive sleep apnea (OSA) suffer from increased prevalence of obesity, insulin resistance, and metabolic syndrome. Murine models of intermittent hypoxia (IH) mimicking moderate-severe OSA manifest insulin resistance following short-term IH. We examined in mice the effect of long-term IH on the inflammatory cellular changes within vWAT and the potential effect of normoxic recovery (IH-R). Male C57BL/6J mice were subjected to IH for 20 weeks, and a subset was allowed to recover in room air (RA) for 6 or 12 weeks (IH-R). Stromal vascular fraction was isolated from epididymal vWAT and mesenteric vWAT depots, and single-cell suspensions were prepared for flow cytometry analyses, reactive oxygen species (ROS), and metabolic assays. IH reduced body weight and vWAT mass and IH-R resulted in catch-up weight and vWAT mass. IH-exposed vWAT exhibited increased macrophage counts (ATMs) that were only partially improved in IH-R. IH also caused a proinflammatory shift in ATMs (increased Ly6c(hi)(+) and CD36(+) ATMs). These changes were accompanied by increased vWAT insulin resistance with only partial improvements in IH-R. In addition, ATMs exhibited increased ROS production, altered metabolism, and changes in electron transport chain, which were only partially improved in IH-R. Prolonged exposures to IH during the sleep period induce pronounced vWAT inflammation and insulin resistance despite concomitant vWAT mass reductions. These changes are only partially reversible after 3 months of normoxic recovery. Thus, long-lasting OSA may preclude complete reversibility of metabolic changes. © Sleep Research Society (SRS) 2016. All rights reserved. For permissions, please email: journals.permissions@oup.com

  12. Dynamic changes in glucose metabolism of living rat brain slices induced by hypoxia and neurotoxic chemical-loading revealed by positron autoradiography

    International Nuclear Information System (INIS)

    Omata, N.; Fujibayashi, Y.; Waki, A.; Sadato, N.; Yano, R.; Yoshimoto, M.; Yonekura, Y.; Murata, T.; Yoshida, S.

    1999-01-01

    Fresh rat brain slices were incubated with 2-deoxy-2-[ 18 F]-fluoro-D-glucose ([ 18 F]FDG) in oxygenated Krebs-Ringer solution at 36 degree C, and serial two-dimensional time-resolved images of [ 18 F]FDG uptake were obtained from these specimens on imaging plates. The fractional rate constant (= k3*) of [ 18 F]FDG proportional to the cerebral glucose metabolic rate (CMRglc) was evaluated by applying the Gjedde-Patlak graphical method to the image data. With hypoxia loading (oxygen deprivation) or glucose metabolism inhibitors acting on oxidative phosphorylation, the k3* value increased dramatically suggesting enhanced glycolysis. After relieving hypoxia ≤10-min, the k3* value returned to the pre-loading level. In contrast, with ≥20-min hypoxia only partial or no recovery was observed, indicating that irreversible neuronal damage had been induced. However, after loading with tetrodotoxin (TTX), the k3* value also decreased but returned to the pre-loading level even after 70-min TTX-loading, reflecting a transient inhibition of neuronal activity. This technique provides a new means of quantifying dynamic changes in the regional CMRglc in living brain slices in response to various interventions such as hypoxia and neurotoxic chemical-loading as well as determining the viability and prognosis of brain tissues. (author)

  13. Normobaric Hypoxia as a Cognitive Stress Test for Mild Traumatic Brain Injury: Oculometrics, Pulse Oximetry, and the Self Report of Symptom Severity

    Science.gov (United States)

    2011-06-20

    fitness for duty of personnel. Hypoxia and Mild Traumatic Brain Injury The present research was motivated in part by a serendipitous observation made...athletic departments, bicycle shops, fitness and health centers as well as such clubs and organizations as roller derby teams, rodeo clubs, rugby teams

  14. Neuroglobin-deficiency exacerbates Hif1A and c-FOS response, but does not affect neuronal survival during severe hypoxia in vivo

    DEFF Research Database (Denmark)

    Hundahl, Christian Ansgar; Luuk, Hendrik; Ilmjärv, Sten

    2011-01-01

    Neuroglobin (Ngb), a neuron-specific globin that binds oxygen in vitro, has been proposed to play a key role in neuronal survival following hypoxic and ischemic insults in the brain. Here we address whether Ngb is required for neuronal survival following acute and prolonged hypoxia in mice...

  15. Ageing and cardiorespiratory response to hypoxia.

    Science.gov (United States)

    Lhuissier, François J; Canouï-Poitrine, Florence; Richalet, Jean-Paul

    2012-11-01

    The risk of severe altitude-induced diseases is related to ventilatory and cardiac responses to hypoxia and is dependent on sex, age and exercise training status. However, it remains unclear how ageing modifies these physiological adaptations to hypoxia. We assessed the physiological responses to hypoxia with ageing through a cross-sectional 20 year study including 4675 subjects (2789 men, 1886 women; 14-85 years old) and a longitudinal study including 30 subjects explored at a mean 10.4 year interval. The influence of sex, training status and menopause was evaluated. The hypoxia-induced desaturation and the ventilatory and cardiac responses to hypoxia at rest and exercise were measured. In men, ventilatory response to hypoxia increased (P ageing. Cardiac response to hypoxia was blunted with ageing in both sexes (P ageing. These adaptive responses were less pronounced or absent in post-menopausal women (P ageing in men while cardiac response is blunted with ageing in both sexes. Training aggravates desaturation at exercise in hypoxia, improves the ventilatory response and limits the ageing-induced blunting of cardiac response to hypoxia. Training limits the negative effects of menopause in cardiorespiratory adaptations to hypoxia.

  16. Post-Traumatic Hypoxia Is Associated with Prolonged Cerebral Cytokine Production, Higher Serum Biomarker Levels, and Poor Outcome in Patients with Severe Traumatic Brain Injury

    Science.gov (United States)

    Yan, Edwin B.; Satgunaseelan, Laveniya; Paul, Eldho; Bye, Nicole; Nguyen, Phuong; Agyapomaa, Doreen; Kossmann, Thomas; Rosenfeld, Jeffrey V.

    2014-01-01

    Abstract Secondary hypoxia is a known contributor to adverse outcomes in patients with traumatic brain injury (TBI). Based on the evidence that hypoxia and TBI in isolation induce neuroinflammation, we investigated whether TBI combined with hypoxia enhances cerebral cytokine production. We also explored whether increased concentrations of injury biomarkers discriminate between hypoxic (Hx) and normoxic (Nx) patients, correlate to worse outcome, and depend on blood–brain barrier (BBB) dysfunction. Forty-two TBI patients with Glasgow Coma Scale ≤8 were recruited. Cerebrospinal fluid (CSF) and serum were collected over 6 days. Patients were divided into Hx (n=22) and Nx (n=20) groups. Eight cytokines were measured in the CSF; albumin, S100, myelin basic protein (MBP) and neuronal specific enolase (NSE) were quantified in serum. CSF/serum albumin quotient was calculated for BBB function. Glasgow Outcome Scale Extended (GOSE) was assessed at 6 months post-TBI. Production of granulocye macrophage-colony stimulating factor (GM-CSF) was higher, and profiles of GM-CSF, interferon (IFN)-γ and, to a lesser extent, tumor necrosis factor (TNF), were prolonged in the CSF of Hx but not Nx patients at 4–5 days post-TBI. Interleukin (IL)-2, IL-4, IL-6, and IL-10 increased similarly in both Hx and Nx groups. S100, MBP, and NSE were significantly higher in Hx patients with unfavorable outcome. Among these three biomarkers, S100 showed the strongest correlations to GOSE after TBI-Hx. Elevated CSF/serum albumin quotients lasted for 5 days post-TBI and displayed similar profiles in Hx and Nx patients. We demonstrate for the first time that post-TBI hypoxia is associated with prolonged neuroinflammation, amplified extravasation of biomarkers, and poor outcome. S100 and MBP could be implemented to track the occurrence of post-TBI hypoxia, and prompt adequate treatment. PMID:24279428

  17. Modification of bacterial cell survival by postirradiation hypoxia

    Energy Technology Data Exchange (ETDEWEB)

    Vexler, F B; Eidus, L Kh

    1986-01-27

    It is shown that postirradiation hypoxia affects the survival of E.coli. Hypoxic conditions immediately after a single-dose irradiation diminish cell survival in nutrient medium. Increasing time intervals between irradiation and hypoxia decrease the efficiency of the latter, while 1 h after irradiation hypoxia does not modify the survival of irradiated cells. These findings reveal that the mechanisms of action of postirradiation hypoxia on eu- and prokaryotic cells are similar.

  18. Ecosystem impacts of hypoxia: thresholds of hypoxia and pathways to recovery

    International Nuclear Information System (INIS)

    Steckbauer, A; Duarte, C M; Vaquer-Sunyer, R; Carstensen, J; Conley, D J

    2011-01-01

    Coastal hypoxia is increasing in the global coastal zone, where it is recognized as a major threat to biota. Managerial efforts to prevent hypoxia and achieve recovery of ecosystems already affected by hypoxia are largely based on nutrient reduction plans. However, these managerial efforts need to be informed by predictions on the thresholds of hypoxia (i.e. the oxygen levels required to conserve biodiversity) as well as the timescales for the recovery of ecosystems already affected by hypoxia. The thresholds for hypoxia in coastal ecosystems are higher than previously thought and are not static, but regulated by local and global processes, being particularly sensitive to warming. The examination of recovery processes in a number of coastal areas managed for reducing nutrient inputs and, thus, hypoxia (Northern Adriatic; Black Sea; Baltic Sea; Delaware Bay; and Danish Coastal Areas) reveals that recovery timescales following the return to normal oxygen conditions are much longer than those of loss following the onset of hypoxia, and typically involve decadal timescales. The extended lag time for ecosystem recovery from hypoxia results in non-linear pathways of recovery due to hysteresis and the shift in baselines, affecting the oxygen thresholds for hypoxia through time.

  19. Whole-exome sequencing reveals GPIHBP1 mutations in infantile colitis with severe hypertriglyceridemia.

    Science.gov (United States)

    Gonzaga-Jauregui, Claudia; Mir, Sabina; Penney, Samantha; Jhangiani, Shalini; Midgen, Craig; Finegold, Milton; Muzny, Donna M; Wang, Min; Bacino, Carlos A; Gibbs, Richard A; Lupski, James R; Kellermayer, Richard; Hanchard, Neil A

    2014-07-01

    Severe congenital hypertriglyceridemia (HTG) is a rare disorder caused by mutations in genes affecting lipoprotein lipase (LPL) activity. Here we report a 5-week-old Hispanic girl with severe HTG (12,031 mg/dL, normal limit 150 mg/dL) who presented with the unusual combination of lower gastrointestinal bleeding and milky plasma. Initial colonoscopy was consistent with colitis, which resolved with reduction of triglycerides. After negative sequencing of the LPL gene, whole-exome sequencing revealed novel compound heterozygous mutations in GPIHBP1. Our study broadens the phenotype of GPIHBP1-associated HTG, reinforces the effectiveness of whole-exome sequencing in Mendelian diagnoses, and implicates triglycerides in gastrointestinal mucosal injury.

  20. Hypoxia training: symptom replication in experienced military aircrew.

    Science.gov (United States)

    Johnston, Ben J; Iremonger, Gareth S; Hunt, Sheena; Beattie, Elizabeth

    2012-10-01

    Military aircrew are trained to recognize the signs and symptoms of hypoxia in a safe environment using a variety of methods to simulate altitude. In order to investigate the effectiveness of hypoxia training, this study compared the recall of hypoxia symptoms in military aircrew between two consecutive hypobaric chamber hypoxia training sessions conducted, on average, 4.5 yr apart. Previously trained subjects completed a questionnaire immediately before and after they underwent refresher hypoxia training and recorded the occurrence, order, and severity of symptoms experienced. Responses from refresher training were compared with their recall of symptoms experienced during previous training. There was no difference in the recall of most hypoxia symptoms between training sessions. Slurred speech was recalled more frequently from previous training compared to refresher training (14 vs. 4 subjects), whereas hot/cold flushes were recalled less frequently from previous training compared to refresher training (5 vs. 17 subjects). There was a statistically significant difference in overall hypoxia score (10.3 vs. 8.3), suggesting that from memory subjects may underestimate the level of hypoxia experienced in previous training. A high level of similarity between the recall of previously experienced hypoxia symptoms and recent experience supports the effectiveness of hypoxia training. These results replicate the finding of a 'hypoxia signature' reported by a previous study. Small differences in the recall of some symptoms and in overall hypoxia score highlight the importance of drawing attention to the more subtle symptoms of early hypoxia, and of using training techniques which optimize aircrew recall.

  1. Time-dependent effect of severe hypoxia/reoxygenation on oxidative stress level, antioxidant capacity and p53 accumulation in mitochondria of rat heart

    Directory of Open Access Journals (Sweden)

    O. A. Gonchar

    2017-12-01

    Full Text Available The intensity of oxidative stress, protein expression of antiapoptotic Bcl-2 as well as antioxidant enzymes manganese superoxide dismutase (MnSOD and glutathione peroxidase (GPx and their regulator p53 were studied in the mitochondria of rat heart. Sessions of repeated hypoxia/reoxygenation ((H/R, 5 cycles of 10 min hypoxia (5.5% O2 in N2 alternated with 10 min normoxia, daily were performed in our study. It was shown that short-term sessions of H/R (during 1-3 days caused a significant increase in the oxidative stress markers (ROS formation and lipid peroxidation, mitochondrial p53 translocation, a decrease in MnSOD­ protein expression/activity and Bcl-2 protein content, but up-regulated GPx. We have demonstrated that prolonged H/R (7-14 days induced myocardial tolerance to fluctuation in oxygen levels that was associa­ted with the reduction in mitochondrial p53 protein content, elevation of mitochondrial Bcl-2 protein level, and increase in antioxidant capacity. A close correlation between the mitochondrial p53 accumulation and ROS formation as well as the activity and protein content of MnSOD and GPx allowed us to assume that p53 took an active part in the regulation of prooxidant/antioxidant balance in mitochondria of rat heart during repeated H/R.

  2. In Vivo Imaging Reveals Significant Tumor Vascular Dysfunction and Increased Tumor Hypoxia-Inducible Factor-1α Expression Induced by High Single-Dose Irradiation in a Pancreatic Tumor Model

    Energy Technology Data Exchange (ETDEWEB)

    Maeda, Azusa [Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario (Canada); Department of Medical Biophysics, University of Toronto, Toronto, Ontario (Canada); Chen, Yonghong; Bu, Jiachuan; Mujcic, Hilda [Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario (Canada); Wouters, Bradly G. [Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario (Canada); Department of Medical Biophysics, University of Toronto, Toronto, Ontario (Canada); Department of Radiation Oncology, University of Toronto, Toronto, Ontario (Canada); DaCosta, Ralph S., E-mail: rdacosta@uhnres.utoronto.ca [Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario (Canada); Department of Medical Biophysics, University of Toronto, Toronto, Ontario (Canada); Techna Institute, University Health Network, Toronto, Ontario (Canada)

    2017-01-01

    Purpose: To investigate the effect of high-dose irradiation on pancreatic tumor vasculature and microenvironment using in vivo imaging techniques. Methods and Materials: A BxPC3 pancreatic tumor xenograft was established in a dorsal skinfold window chamber model and a subcutaneous hind leg model. Tumors were irradiated with a single dose of 4, 12, or 24 Gy. The dorsal skinfold window chamber model was used to assess tumor response, vascular function and permeability, platelet and leukocyte adhesion to the vascular endothelium, and tumor hypoxia for up to 14 days after 24-Gy irradiation. The hind leg model was used to monitor tumor size, hypoxia, and vascularity for up to 65 days after 24-Gy irradiation. Tumors were assessed histologically to validate in vivo observations. Results: In vivo fluorescence imaging revealed temporary vascular dysfunction in tumors irradiated with a single dose of 4 to 24 Gy, but most significantly with a single dose of 24 Gy. Vascular functional recovery was observed by 14 days after irradiation in a dose-dependent manner. Furthermore, irradiation with 24 Gy caused platelet and leukocyte adhesion to the vascular endothelium within hours to days after irradiation. Vascular permeability was significantly higher in irradiated tumors compared with nonirradiated controls 14 days after irradiation. This observation corresponded with increased expression of hypoxia-inducible factor-1α in irradiated tumors. In the hind leg model, irradiation with a single dose of 24 Gy led to tumor growth delay, followed by tumor regrowth. Conclusions: Irradiation of the BxPC3 tumors with a single dose of 24 Gy caused transient vascular dysfunction and increased expression of hypoxia-inducible factor-1α. Such biological changes may impact tumor response to high single-dose and hypofractionated irradiation, and further investigations are needed to better understand the clinical outcomes of stereotactic body radiation therapy.

  3. Progressive hypoxia decouples activity and aerobic performance of skate embryos.

    Science.gov (United States)

    Di Santo, Valentina; Tran, Anna H; Svendsen, Jon C

    2016-01-01

    Although fish population size is strongly affected by survival during embryonic stages, our understanding of physiological responses to environmental stressors is based primarily on studies of post-hatch fishes. Embryonic responses to acute exposure to changes in abiotic conditions, including increase in hypoxia, could be particularly important in species exhibiting long developmental time, as embryos are unable to select a different environment behaviourally. Given that oxygen is key to metabolic processes in fishes and aquatic hypoxia is becoming more severe and frequent worldwide, organisms are expected to reduce their aerobic performance. Here, we examined the metabolic and behavioural responses of embryos of a benthic elasmobranch fish, the little skate (Leucoraja erinacea), to acute progressive hypoxia, by measuring oxygen consumption and movement (tail-beat) rates inside the egg case. Oxygen consumption rates were not significantly affected by ambient oxygen levels until reaching 45% air saturation (critical oxygen saturation, S crit). Below S crit, oxygen consumption rates declined rapidly, revealing an oxygen conformity response. Surprisingly, we observed a decoupling of aerobic performance and activity, as tail-beat rates increased, rather than matching the declining metabolic rates, at air saturation levels of 55% and below. These results suggest a significantly divergent response at the physiological and behavioural levels. While skate embryos depressed their metabolic rates in response to progressive hypoxia, they increased water circulation inside the egg case, presumably to restore normoxic conditions, until activity ceased abruptly around 9.8% air saturation.

  4. Urinary uric acid excretion as an indicator of severe hypoxia and mortality in patients with obstructive sleep apnea and chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    E. Ozanturk

    2016-01-01

    Full Text Available Objective: Uric acid (UA is the end product of adenosine triphosphate degradation, and could increase due to hypoxia. We investigated the association of UA metabolites with nocturnal hypoxemia, apnea-hypopnea index (AHI, noninvasive mechanical ventilation (NIMV usage and five-year mortality. Materials/subjects and methods: We obtained urinary specimen before and after the night polysomnography in order to measure UA excretion and overnight change in urinary UA/creatinine ratio (ΔUA/Cr in 75 subjects (14 controls, 15 chronic obstructive pulmonary disease (COPD without nocturnal hypoxemia (NH, 15 COPD with NH, 16 obstructive sleep apnea syndrome (OSAS without NH, 15 OSAS with NH. Percentage of time spent below SaO2 of 90% (T90% for >10% of sleep time was considered as nocturnal hypoxemia. Patients were contacted after 5 years with a questionnaire including information on the use of NIMV treatment (n: 58 and urinary specimen analysis (n: 35. Results: T90% was found to be significantly correlated with UA excretion (coefficient: 0.005, 95%CI: 0.003–0.007 and ΔUA/Cr (coefficient: 0.8, 95%CI: 0.3–1.2 after adjustments for age, gender, body mass index and apnea-hypopnea index. Median and IQR (interquartile range of baseline UA excretion were 0.79 (0.51–0.89 and 0.41 (0.31–0.55 in 10 deceased and 58 surviving patients, respectively (p = 0.001. UA excretion median and IQR of baseline and 5 years of NIMV treatment were 0.41 (0.36–0.57 and 0.29 (0.23–0.37, respectively (p = 0.01. Conclusion: UA excretion, as a marker of tissue hypoxia, may be useful in the management of OSA and COPD patients. Keywords: Uric acid, Hypoxia, Obstructive sleep apnea, COPD

  5. Differential Expression of miRNAs in the Respiratory Tree of the Sea Cucumber Apostichopus japonicus Under Hypoxia Stress.

    Science.gov (United States)

    Huo, Da; Sun, Lina; Li, Xiaoni; Ru, Xiaoshang; Liu, Shilin; Zhang, Libin; Xing, Lili; Yang, Hongsheng

    2017-11-06

    The sea cucumber, an important economic species, has encountered high mortality since 2013 in northern China because of seasonal environmental stress such as hypoxia, high temperature, and low salinity. MicroRNAs (miRNAs) are important in regulating gene expression in marine organisms in response to environmental change. In this study, high-throughput sequencing was used to investigate alterations in miRNA expression in the sea cucumber under different levels of dissolved oxygen (DO). Nine small RNA libraries were constructed from the sea cucumber respiratory trees. A total of 26 differentially expressed miRNAs, including 12 upregulated and 14 downregulated miRNAs, were observed in severe hypoxia (DO 2 mg/L) compared with mild hypoxia (DO 4 mg/L) and normoxic conditions (DO 8 mg/L). Twelve differentially expressed miRNAs were clustered in severe hypoxia. In addition, real-time PCR revealed that 14 randomly selected differentially expressed miRNAs showed significantly increased expressions in severe hypoxia and the expressions of nine miRNAs, including key miRNAs such as Aja-miR-1, Aja-miR-2008, and Aja-miR-184, were consistent with the sequencing results. Moreover, gene ontology and pathway analyses of putative target genes suggest that these miRNAs are important in redox, transport, transcription, and hydrolysis under hypoxia stress. Notably, novel-miR-1, novel-miR-2, and novel-miR-3 were specifically clustered and upregulated in severe hypoxia, which may provide new insights into novel "hypoxamiR" identification. These results will provide a basis for future studies of miRNA regulation and molecular adaptive mechanisms in sea cucumbers under hypoxia stress. Copyright © 2017 Huo et al.

  6. Medieval Irish chronicles reveal persistent volcanic forcing of severe winter cold events, 431–1649 CE

    International Nuclear Information System (INIS)

    Ludlow, Francis; Stine, Alexander R; Leahy, Paul; Kiely, Gerard; Murphy, Enda; Mayewski, Paul A; Taylor, David; Killen, James; Hennessy, Mark; Baillie, Michael G L

    2013-01-01

    Explosive volcanism resulting in stratospheric injection of sulfate aerosol is a major driver of regional to global climatic variability on interannual and longer timescales. However, much of our knowledge of the climatic impact of volcanism derives from the limited number of eruptions that have occurred in the modern period during which meteorological instrumental records are available. We present a uniquely long historical record of severe short-term cold events from Irish chronicles, 431–1649 CE, and test the association between cold event occurrence and explosive volcanism. Thirty eight (79%) of 48 volcanic events identified in the sulfate deposition record of the Greenland Ice Sheet Project 2 ice-core correspond to 37 (54%) of 69 cold events in this 1219 year period. We show this association to be statistically significant at the 99.7% confidence level, revealing both the consistency of response to explosive volcanism for Ireland’s climatically sensitive Northeast Atlantic location and the large proportional contribution of volcanism to historic cold event frequencies here. Our results expose, moreover, the extent to which volcanism has impacted winter-season climate for the region, and can help to further resolve the complex spatial patterns of Northern Hemisphere winter-season cooling versus warming after major eruptions. (letter)

  7. Hypoxia independent drivers of melanoma angiogenesis

    Directory of Open Access Journals (Sweden)

    Svenja eMeierjohann

    2015-05-01

    Full Text Available Tumor angiogenesis is a process which is traditionally regarded as the tumor`s response to low nutrient supply occurring under hypoxic conditions. However, hypoxia is not a prerequisite for angiogenesis. The fact that even single tumor cells or small tumor cell aggregates are capable of attracting blood vessels reveals the early metastatic capability of tumor cells. This review sheds light on the hypoxia independent mechanisms of tumor angiogenesis in melanoma.

  8. Kinetic modeling in PET imaging of hypoxia

    DEFF Research Database (Denmark)

    Li, Fan; Jørgensen, Jesper Tranekjær; Hansen, Anders E

    2014-01-01

    be used for non-invasive mapping of tissue oxygenation in vivo and several hypoxia specific PET tracers have been developed. Evaluation of PET data in the clinic is commonly based on visual assessment together with semiquantitative measurements e.g. standard uptake value (SUV). However, dynamic PET......Tumor hypoxia is associated with increased therapeutic resistance leading to poor treatment outcome. Therefore the ability to detect and quantify intratumoral oxygenation could play an important role in future individual personalized treatment strategies. Positron Emission Tomography (PET) can...... analysis for PET imaging of hypoxia....

  9. Hypoxia and hypoxia inducible factor-1α are required for normal endometrial repair during menstruation.

    Science.gov (United States)

    Maybin, Jacqueline A; Murray, Alison A; Saunders, Philippa T K; Hirani, Nikhil; Carmeliet, Peter; Critchley, Hilary O D

    2018-01-23

    Heavy menstrual bleeding (HMB) is common and debilitating, and often requires surgery due to hormonal side effects from medical therapies. Here we show that transient, physiological hypoxia occurs in the menstrual endometrium to stabilise hypoxia inducible factor 1 (HIF-1) and drive repair of the denuded surface. We report that women with HMB have decreased endometrial HIF-1α during menstruation and prolonged menstrual bleeding. In a mouse model of simulated menses, physiological endometrial hypoxia occurs during bleeding. Maintenance of mice under hyperoxia during menses decreases HIF-1α induction and delays endometrial repair. The same effects are observed upon genetic or pharmacological reduction of endometrial HIF-1α. Conversely, artificial induction of hypoxia by pharmacological stabilisation of HIF-1α rescues the delayed endometrial repair in hypoxia-deficient mice. These data reveal a role for HIF-1 in the endometrium and suggest its pharmacological stabilisation during menses offers an effective, non-hormonal treatment for women with HMB.

  10. Tensor-Based Morphometry Reveals Volumetric Deficits in Moderate=Severe Pediatric Traumatic Brain Injury.

    Science.gov (United States)

    Dennis, Emily L; Hua, Xue; Villalon-Reina, Julio; Moran, Lisa M; Kernan, Claudia; Babikian, Talin; Mink, Richard; Babbitt, Christopher; Johnson, Jeffrey; Giza, Christopher C; Thompson, Paul M; Asarnow, Robert F

    2016-05-01

    Traumatic brain injury (TBI) can cause widespread and prolonged brain degeneration. TBI can affect cognitive function and brain integrity for many years after injury, often with lasting effects in children, whose brains are still immature. Although TBI varies in how it affects different individuals, image analysis methods such as tensor-based morphometry (TBM) can reveal common areas of brain atrophy on magnetic resonance imaging (MRI), secondary effects of the initial injury, which will differ between subjects. Here we studied 36 pediatric moderate to severe TBI (msTBI) participants in the post-acute phase (1-6 months post-injury) and 18 msTBI participants who returned for their chronic assessment, along with well-matched controls at both time-points. Participants completed a battery of cognitive tests that we used to create a global cognitive performance score. Using TBM, we created three-dimensional (3D) maps of individual and group differences in regional brain volumes. At both the post-acute and chronic time-points, the greatest group differences were expansion of the lateral ventricles and reduction of the lingual gyrus in the TBI group. We found a number of smaller clusters of volume reduction in the cingulate gyrus, thalamus, and fusiform gyrus, and throughout the frontal, temporal, and parietal cortices. Additionally, we found extensive associations between our cognitive performance measure and regional brain volume. Our results indicate a pattern of atrophy still detectable 1-year post-injury, which may partially underlie the cognitive deficits frequently found in TBI.

  11. Tensor-Based Morphometry Reveals Volumetric Deficits in Moderate=Severe Pediatric Traumatic Brain Injury

    Science.gov (United States)

    Hua, Xue; Villalon-Reina, Julio; Moran, Lisa M.; Kernan, Claudia; Babikian, Talin; Mink, Richard; Babbitt, Christopher; Johnson, Jeffrey; Giza, Christopher C.; Thompson, Paul M.; Asarnow, Robert F.

    2016-01-01

    Abstract Traumatic brain injury (TBI) can cause widespread and prolonged brain degeneration. TBI can affect cognitive function and brain integrity for many years after injury, often with lasting effects in children, whose brains are still immature. Although TBI varies in how it affects different individuals, image analysis methods such as tensor-based morphometry (TBM) can reveal common areas of brain atrophy on magnetic resonance imaging (MRI), secondary effects of the initial injury, which will differ between subjects. Here we studied 36 pediatric moderate to severe TBI (msTBI) participants in the post-acute phase (1–6 months post-injury) and 18 msTBI participants who returned for their chronic assessment, along with well-matched controls at both time-points. Participants completed a battery of cognitive tests that we used to create a global cognitive performance score. Using TBM, we created three-dimensional (3D) maps of individual and group differences in regional brain volumes. At both the post-acute and chronic time-points, the greatest group differences were expansion of the lateral ventricles and reduction of the lingual gyrus in the TBI group. We found a number of smaller clusters of volume reduction in the cingulate gyrus, thalamus, and fusiform gyrus, and throughout the frontal, temporal, and parietal cortices. Additionally, we found extensive associations between our cognitive performance measure and regional brain volume. Our results indicate a pattern of atrophy still detectable 1-year post-injury, which may partially underlie the cognitive deficits frequently found in TBI. PMID:26393494

  12. Redox signaling during hypoxia in mammalian cells

    Directory of Open Access Journals (Sweden)

    Kimberly A. Smith

    2017-10-01

    Full Text Available Hypoxia triggers a wide range of protective responses in mammalian cells, which are mediated through transcriptional and post-translational mechanisms. Redox signaling in cells by reactive oxygen species (ROS such as hydrogen peroxide (H2O2 occurs through the reversible oxidation of cysteine thiol groups, resulting in structural modifications that can change protein function profoundly. Mitochondria are an important source of ROS generation, and studies reveal that superoxide generation by the electron transport chain increases during hypoxia. Other sources of ROS, such as the NAD(PH oxidases, may also generate oxidant signals in hypoxia. This review considers the growing body of work indicating that increased ROS signals during hypoxia are responsible for regulating the activation of protective mechanisms in diverse cell types.

  13. Migraine induced by hypoxia

    DEFF Research Database (Denmark)

    Arngrim, Nanna; Schytz, Henrik Winther; Britze, Josefine

    2016-01-01

    in the visual cortex were measured by proton magnetic resonance spectroscopy. The circumference of cranial arteries was measured by 3 T high-resolution magnetic resonance angiography. Hypoxia induced migraine-like attacks in eight patients compared to one patient after sham (P = 0.039), aura in three...... and possible aura in 4 of 15 patients. Hypoxia did not change glutamate concentration in the visual cortex compared to sham, but increased lactate concentration (P = 0.028) and circumference of the cranial arteries (P ... suggests that hypoxia may provoke migraine headache and aura symptoms in some patients. The mechanisms behind the migraine-inducing effect of hypoxia should be further investigated....

  14. The Rendu-Osler-Weber Disease Revealed by a Refractory Hypoxemia and Severe Cerebral Fat Embolism

    Directory of Open Access Journals (Sweden)

    Leonel Barreto

    2013-01-01

    Full Text Available The Rendu-Osler-Weber disease is a genetic disease which may lead to severe hemorrhage and less frequently to severe organ dysfunction. We report the case of a 22-year-old patient with no personal medical history who was involved in a motorcycle accident and exhibited severe complications related to large arteriovenous pulmonary shunts during his ICU stay. The patient developed an unexplained severe hypoxemia which was attributed to several arteriovenous shunts of the pulmonary vasculature by a contrast study during a transesophageal echocardiographic examination. The course was subsequently complicated by a prolonged coma associated with hemiplegia which was attributed to a massive paradoxical fat embolism in the setting of an untreated femoral fracture. In addition to hemorrhagic complications which may lead to intractable shock, arteriovenous malformations associated with the Rendu-Osler-Weber disease may involve the pulmonary vasculature and result in unexpected complications, such as hypoxemia or severe cerebral fat embolism in high-risk patients.

  15. Selective vulnerability in brain hypoxia

    DEFF Research Database (Denmark)

    Cervos-Navarro, J.; Diemer, Nils Henrik

    1991-01-01

    Neuropathology, selective vulnerability, brain hypoxia, vascular factors, excitotoxicity, ion homeostasis......Neuropathology, selective vulnerability, brain hypoxia, vascular factors, excitotoxicity, ion homeostasis...

  16. Cuticle ultrastructure, cuticular lipid composition, and gene expression in hypoxia-stressed Arabidopsis stems and leaves.

    Science.gov (United States)

    Kim, Hyojin; Choi, Dongsu; Suh, Mi Chung

    2017-06-01

    An increased permeability of the cuticle is closely associated with downregulation of genes involved in cuticular lipid synthesis in hypoxia-stressed Arabidopsis and may allow plants to cope with oxygen deficiency. The hydrophobic cuticle layer consisting of cutin polyester and cuticular wax is the first barrier to protect the aerial parts of land plants from environmental stresses. In the present study, we investigated the role of cuticle membrane in Arabidopsis responses to oxygen deficiency. TEM analysis showed that the epidermal cells of hypoxia-treated Arabidopsis stems and leaves possessed a thinner electron-translucent cuticle proper and a more electron-dense cuticular layer. A reduction in epicuticular wax crystal deposition was observed in SEM images of hypoxia-treated Arabidopsis stem compared with normoxic control. Cuticular transpiration was more rapid in hypoxia-stressed leaves than in normoxic control. Total wax and cutin loads decreased by approximately 6-12 and 12-22%, respectively, and the levels of C29 alkanes, secondary alcohols, and ketones, C16:0 ω-hydroxy fatty acids, and C18:2 dicarboxylic acids were also prominently reduced in hypoxia-stressed Arabidopsis leaves and/or stems relative to normoxic control. Genome-wide transcriptome and quantitative RT-PCR analyses revealed that the expression of several genes involved in the biosynthesis and transport of cuticular waxes and cutin monomers were downregulated more than fourfold, but no significant alterations were detected in the transcript levels of fatty acid biosynthetic genes, BCCP2, PDH-E1α, and ENR1 in hypoxia-treated Arabidopsis stems and leaves compared with normoxic control. Taken together, an increased permeability of the cuticle is closely associated with downregulation of genes involved in cuticular lipid synthesis in hypoxia-stressed Arabidopsis. The present study elucidates one of the cuticle-related adaptive responses that may allow plants to cope with low oxygen levels.

  17. Cancer cell-associated cytoplasmic B7–H4 is induced by hypoxia through hypoxia-inducible factor-1α and promotes cancer cell proliferation

    Energy Technology Data Exchange (ETDEWEB)

    Jeon, You-Kyoung [Department of Microbiology and Immunology, Inje University College of Medicine, Busan 614-735 (Korea, Republic of); Advanced Research Center for Multiple Myeloma, Inje University College of Medicine, Busan 614-735 (Korea, Republic of); Park, Sae-Gwang; Choi, Il-Whan [Department of Microbiology and Immunology, Inje University College of Medicine, Busan 614-735 (Korea, Republic of); Lee, Soo-Woong [Advanced Research Center for Multiple Myeloma, Inje University College of Medicine, Busan 614-735 (Korea, Republic of); Lee, Sang Min [Department of Internal Medicine, Division of Hematology/Oncology, Busan Paik Hospital, Inje University, Busan 614-735 (Korea, Republic of); Choi, Inhak, E-mail: miccih@inje.ac.kr [Department of Microbiology and Immunology, Inje University College of Medicine, Busan 614-735 (Korea, Republic of); Advanced Research Center for Multiple Myeloma, Inje University College of Medicine, Busan 614-735 (Korea, Republic of)

    2015-04-03

    Aberrant B7–H4 expression in cancer tissues serves as a novel prognostic biomarker for poor survival in patients with cancer. However, the factor(s) that induce cancer cell-associated B7–H4 remain to be fully elucidated. We herein demonstrate that hypoxia upregulates B7–H4 transcription in primary CD138{sup +} multiple myeloma cells and cancer cell lines. In support of this finding, analysis of the Multiple Myeloma Genomics Portal (MMGP) data set revealed a positive correlation between the mRNA expression levels of B7–H4 and the endogenous hypoxia marker carbonic anhydrogenase 9. Hypoxia-induced B7–H4 expression was detected in the cytoplasm, but not in cancer cell membranes. Chromatin immunoprecipitation analysis demonstrated binding of hypoxia-inducible factor-1α (HIF-1α) to proximal hypoxia-response element (HRE) sites within the B7–H4 promoter. Knockdown of HIF-1α and pharmacological inhibition of HIF-1α diminished B7–H4 expression. Furthermore, knockdown of cytoplasmic B7–H4 in MCF-7 decreased the S-phase cell population under hypoxia. Finally, MMGP analysis revealed a positive correlation between the transcript levels of B7–H4 and proliferation-related genes including MKI67, CCNA1, and Myc in several patients with multiple myeloma. Our results provide insight into the mechanisms underlying B7–H4 upregulation and its role in cancer cell proliferation in a hypoxic tumor microenvironment. - Highlights: • Hypoxia upregulates B7–H4 transcription and protein expression. • Hypoxia-induced B7–H4 is detected in the cytoplasm, but not on membrane. • ChIP assay reveals a binding of HIF-1α to B7–H4 promoter at HRE site. • Knockdown and pharmacological inhibition of HIF-1α reduce B7–H4 expression. • B7–H4 knockdown decrease the number of cells in S-phase of cell cycle.

  18. Severe neutropenia revealing a rare presentation of dengue fever: a case report.

    Science.gov (United States)

    Shourick, J; Dinh, A; Matt, M; Salomon, J; Davido, B

    2017-08-17

    Arboviruses are a common cause of fever in the returned traveler often associated with leucopenia, especially lymphopenia and thrombocytopenia. Transient neutropenia has been described in a few cases of arboviruses. However, prolonged and severe neutropenia (dengue fever, especially in the returned traveler in Europe. A 26-year-old healthy female without any medical past history, flying back from Thailand, presented a transient fever with severe neutropenia (dengue fever. Outcome was favorable without any antimicrobial therapy. Physicians should be wary of possible unusual presentation of dengue fever with prolonged neutropenia. Although such biological sign is more often associated with malaria or severe bacterial infection, it may be a sign of arbovirus.

  19. Sputum transcriptomics reveal upregulation of IL-1 receptor family members in patients with severe asthma

    NARCIS (Netherlands)

    Rossios, Christos; Pavlidis, Stelios; Hoda, Uruj; Kuo, Chih-Hsi; Wiegman, Coen; Russell, Kirsty; Sun, Kai; Loza, Matthew J.; Baribaud, Frederic; Durham, Andrew L.; Ojo, Oluwaseun; Lutter, Rene; Rowe, Anthony; Bansal, Aruna; Auffray, Charles; Sousa, Ana; Corfield, Julie; Djukanovic, Ratko; Guo, Yike; Sterk, Peter J.; Chung, Kian Fan; Adcock, Ian M.

    2018-01-01

    Sputum analysis in asthmatic patients is used to define airway inflammatory processes and might guide therapy. We sought to determine differential gene and protein expression in sputum samples from patients with severe asthma (SA) compared with nonsmoking patients with mild/moderate asthma. Induced

  20. Analysis of Complement C3 Gene Reveals Susceptibility to Severe Preeclampsia

    Directory of Open Access Journals (Sweden)

    A. Inkeri Lokki

    2017-05-01

    Full Text Available Preeclampsia (PE is a common vascular disease of pregnancy with genetic predisposition. Dysregulation of the complement system has been implicated, but molecular mechanisms are incompletely understood. In this study, we determined the potential linkage of severe PE to the most central complement gene, C3. Three cohorts of Finnish patients and controls were recruited for a genetic case-control study. Participants were genotyped using Sequenom genotyping and Sanger sequencing. Initially, we studied 259 Finnish patients with severe PE and 426 controls from the Southern Finland PE and the Finnish population-based PE cohorts. We used a custom-made single nucleotide polymorphism (SNP genotyping assay consisting of 98 SNPs in 18 genes that encode components of the complement system. Following the primary screening, C3 was selected as the candidate gene and consequently Sanger sequenced. Fourteen SNPs from C3 were also genotyped by a Sequenom panel in 960 patients with severe PE and 705 controls, including already sequenced individuals. Three of the 43 SNPs observed within C3 were associated with severe PE: rs2287845 (p = 0.038, OR = 1.158, rs366510 (p = 0.039, OR = 1.158, and rs2287848 (p = 0.041, OR = 1.155. We also discovered 16 SNP haplotypes with extreme linkage disequilibrium in the middle of the gene with a protective (p = 0.044, OR = 0.628 or a predisposing (p = 0.011, OR = 2.110 effect to severe PE depending on the allele combination. Genetic variants associated with PE are located in key domains of C3 and could thereby influence the function of C3. This is, as far as we are aware, the first candidate gene in the complement system with an association to a clinically relevant PE subphenotype, severe PE. The result highlights a potential role for the complement system in the pathogenesis of PE and may help in defining prognostic and therapeutic subgroups of preeclamptic women.

  1. Multiple severe typhoons in recent history revealed by coral boulders of northwestern Luzon, Philippines

    Science.gov (United States)

    Gong, Shou-Yeh; Wu, Tso-Ren; Liu, Sze-Chieh; Shen, Chuan-Chou; Siringan, Fernando; Lin, Han-Wei

    2017-04-01

    Meter-sized coral boulders occurred on Holocene reef flat at Pasuquin, Ilocos Norte and Cabugao, Ilocos Sur, Philippines. Boulders larger than 3 meters were located and measured by field survey and UAV photogrammetry. Boulders now distributed 45-140 m away from edge of Holocene reef flat, and above highest high tide. The lithology of those boulders is the same as the underlying Holocene coral reef at the sites, hence believed to be broken from reef edge locally. Fossil corals in those boulders mostly appeal not in upward-growing attitude but overturned or tilted. Several tens of photos were taken around selected boulders from different angles, and 3D models were established from the photos. Dimension and volumes were calculated from 3D models. Boulder volumes can be estimated much more accurately this way than simply multiple X, Y, and Z as many previous studies did. The volumes of boulders larger than 3 m in length vary from 10-52.6 m3. Assuming 2.1 g/cm3 for wet density, weights of boulders are estimated to range from 21-110 metric tons. Boulders of such size and weight obviously can't be moved by normal waves, and likely dislodged by Extreme Wave Event (EWE). Small and well-preserved corals were found in depressions on boulder surface and interpreted to represent timing of final displacement. Corals found on seven boulders at Pasuquin were 230Th dated to be 1782, 1904, 1946, 1957, 1978 and 2003 AD respectively. No tsunami was reported in historical records in northern Luzon for those years, but several documented typhoons could be responsible for displacement of each of those boulders. Another Porites boulder at Cabugao was dated to be tilted five times from 673-838 AD, averaging one EWE every 33 years. Such frequent occurrence of EWE is unlikely resulted from tsunami. Therefore, those coral boulders at Pasuquin and Cabugao are interpreted to be displaced by severe typhoons.

  2. de Toni-Fanconi-Debré syndrome with Leigh syndrome revealing severe muscle cytochrome c oxidase deficiency

    NARCIS (Netherlands)

    Ogier, H.; Lombes, A.; Scholte, H. R.; Poll-The, B. T.; Fardeau, M.; Alcardi, J.; Vignes, B.; Niaudet, P.; Saudubray, J. M.

    1988-01-01

    We describe a patient with severe muscle cytochrome c oxidase deficiency who had de Toni-Fanconi-Debré syndrome and acute neurologic deterioration resembling Leigh syndrome, without clear evidence of muscle abnormality. Metabolic investigations revealed elevated cerebrospinal fluid lactate values

  3. Quantitative Susceptibility Mapping Reveals an Association between Brain Iron Load and Depression Severity

    Directory of Open Access Journals (Sweden)

    Shun Yao

    2017-08-01

    Full Text Available Previous studies have detected abnormal serum ferritin levels in patients with depression; however, the results have been inconsistent. This study used quantitative susceptibility mapping (QSM for the first time to examine brain iron concentration in depressed patients and evaluated whether it is related to severity. We included three groups of age- and gender-matched participants: 30 patients with mild-moderate depression (MD, 14 patients with major depression disorder (MDD and 20 control subjects. All participants underwent MR scans with a 3D gradient-echo sequence reconstructing for QSM and performed the 17-item Hamilton Depression Rating Scale (HDRS test. In MDD, the susceptibility value in the bilateral putamen was significantly increased compared with MD or control subjects. In addition, a significant difference was also observed in the left thalamus in MDD patients compared with controls. However, the susceptibility values did not differ between MD patients and controls. The susceptibility values positively correlated with the severity of depression as indicated by the HDRS scores. Our results provide evidence that brain iron deposition may be associated with depression and may even be a biomarker for investigating the pathophysiological mechanism of depression.

  4. Intermittent Hypoxia Causes Inflammation and Injury to Human Adult Cardiac Myocytes.

    Science.gov (United States)

    Wu, Jing; Stefaniak, Joanna; Hafner, Christina; Schramel, Johannes Peter; Kaun, Christoph; Wojta, Johann; Ullrich, Roman; Tretter, Verena Eva; Markstaller, Klaus; Klein, Klaus Ulrich

    2016-02-01

    Intermittent hypoxia may occur in a number of clinical scenarios, including interruption of myocardial blood flow or breathing disorders such as obstructive sleep apnea. Although intermittent hypoxia has been linked to cardiovascular and cerebrovascular disease, the effect of intermittent hypoxia on the human heart is not fully understood. Therefore, in the present study, we compared the cellular responses of cultured human adult cardiac myocytes (HACMs) exposed to intermittent hypoxia and different conditions of continuous hypoxia and normoxia. HACMs were exposed to intermittent hypoxia (0%-21% O2), constant mild hypoxia (10% O2), constant severe hypoxia (0% O2), or constant normoxia (21% O2), using a novel cell culture bioreactor with gas-permeable membranes. Cell proliferation, lactate dehydrogenase release, vascular endothelial growth factor release, and cytokine (interleukin [IL] and macrophage migration inhibitory factor) release were assessed at baseline and after 8, 24, and 72 hours of exposure. A signal transduction pathway finder array was performed to determine the changes in gene expression. In comparison with constant normoxia and constant mild hypoxia, intermittent hypoxia induced earlier and greater inflammatory response and extent of cell injury as evidenced by lower cell numbers and higher lactate dehydrogenase, vascular endothelial growth factor, and proinflammatory cytokine (IL-1β, IL-6, IL-8, and macrophage migration inhibitory factor) release. Constant severe hypoxia showed more detrimental effects on HACMs at later time points. Pathway analysis demonstrated that intermittent hypoxia primarily altered gene expression in oxidative stress, Wnt, Notch, and hypoxia pathways. Intermittent and constant severe hypoxia, but not constant mild hypoxia or normoxia, induced inflammation and cell injury in HACMs. Cell injury occurred earliest and was greatest after intermittent hypoxia exposure. Our in vitro findings suggest that intermittent hypoxia

  5. Transcriptomics reveal several gene expression patterns in the piezophile Desulfovibrio hydrothermalis in response to hydrostatic pressure.

    Directory of Open Access Journals (Sweden)

    Amira Amrani

    Full Text Available RNA-seq was used to study the response of Desulfovibrio hydrothermalis, isolated from a deep-sea hydrothermal chimney on the East-Pacific Rise at a depth of 2,600 m, to various hydrostatic pressure growth conditions. The transcriptomic datasets obtained after growth at 26, 10 and 0.1 MPa identified only 65 differentially expressed genes that were distributed among four main categories: aromatic amino acid and glutamate metabolisms, energy metabolism, signal transduction, and unknown function. The gene expression patterns suggest that D. hydrothermalis uses at least three different adaptation mechanisms, according to a hydrostatic pressure threshold (HPt that was estimated to be above 10 MPa. Both glutamate and energy metabolism were found to play crucial roles in these mechanisms. Quantitation of the glutamate levels in cells revealed its accumulation at high hydrostatic pressure, suggesting its role as a piezolyte. ATP measurements showed that the energy metabolism of this bacterium is optimized for deep-sea life conditions. This study provides new insights into the molecular mechanisms linked to hydrostatic pressure adaptation in sulfate-reducing bacteria.

  6. Reanalysis of RNA-sequencing data reveals several additional fusion genes with multiple isoforms.

    Science.gov (United States)

    Kangaspeska, Sara; Hultsch, Susanne; Edgren, Henrik; Nicorici, Daniel; Murumägi, Astrid; Kallioniemi, Olli

    2012-01-01

    RNA-sequencing and tailored bioinformatic methodologies have paved the way for identification of expressed fusion genes from the chaotic genomes of solid tumors. We have recently successfully exploited RNA-sequencing for the discovery of 24 novel fusion genes in breast cancer. Here, we demonstrate the importance of continuous optimization of the bioinformatic methodology for this purpose, and report the discovery and experimental validation of 13 additional fusion genes from the same samples. Integration of copy number profiling with the RNA-sequencing results revealed that the majority of the gene fusions were promoter-donating events that occurred at copy number transition points or involved high-level DNA-amplifications. Sequencing of genomic fusion break points confirmed that DNA-level rearrangements underlie selected fusion transcripts. Furthermore, a significant portion (>60%) of the fusion genes were alternatively spliced. This illustrates the importance of reanalyzing sequencing data as gene definitions change and bioinformatic methods improve, and highlights the previously unforeseen isoform diversity among fusion transcripts.

  7. Reanalysis of RNA-sequencing data reveals several additional fusion genes with multiple isoforms.

    Directory of Open Access Journals (Sweden)

    Sara Kangaspeska

    Full Text Available RNA-sequencing and tailored bioinformatic methodologies have paved the way for identification of expressed fusion genes from the chaotic genomes of solid tumors. We have recently successfully exploited RNA-sequencing for the discovery of 24 novel fusion genes in breast cancer. Here, we demonstrate the importance of continuous optimization of the bioinformatic methodology for this purpose, and report the discovery and experimental validation of 13 additional fusion genes from the same samples. Integration of copy number profiling with the RNA-sequencing results revealed that the majority of the gene fusions were promoter-donating events that occurred at copy number transition points or involved high-level DNA-amplifications. Sequencing of genomic fusion break points confirmed that DNA-level rearrangements underlie selected fusion transcripts. Furthermore, a significant portion (>60% of the fusion genes were alternatively spliced. This illustrates the importance of reanalyzing sequencing data as gene definitions change and bioinformatic methods improve, and highlights the previously unforeseen isoform diversity among fusion transcripts.

  8. Transcriptomics Reveal Several Gene Expression Patterns in the Piezophile Desulfovibrio hydrothermalis in Response to Hydrostatic Pressure

    Science.gov (United States)

    Amrani, Amira; Bergon, Aurélie; Holota, Hélène; Tamburini, Christian; Garel, Marc; Ollivier, Bernard; Imbert, Jean; Dolla, Alain; Pradel, Nathalie

    2014-01-01

    RNA-seq was used to study the response of Desulfovibrio hydrothermalis, isolated from a deep-sea hydrothermal chimney on the East-Pacific Rise at a depth of 2,600 m, to various hydrostatic pressure growth conditions. The transcriptomic datasets obtained after growth at 26, 10 and 0.1 MPa identified only 65 differentially expressed genes that were distributed among four main categories: aromatic amino acid and glutamate metabolisms, energy metabolism, signal transduction, and unknown function. The gene expression patterns suggest that D. hydrothermalis uses at least three different adaptation mechanisms, according to a hydrostatic pressure threshold (HPt) that was estimated to be above 10 MPa. Both glutamate and energy metabolism were found to play crucial roles in these mechanisms. Quantitation of the glutamate levels in cells revealed its accumulation at high hydrostatic pressure, suggesting its role as a piezolyte. ATP measurements showed that the energy metabolism of this bacterium is optimized for deep-sea life conditions. This study provides new insights into the molecular mechanisms linked to hydrostatic pressure adaptation in sulfate-reducing bacteria. PMID:25215865

  9. Revealing the meteorological drivers of the September 2015 severe dust event in the Eastern Mediterranean

    Directory of Open Access Journals (Sweden)

    P. Gasch

    2017-11-01

    Full Text Available In September 2015 one of the severest and most unusual dust events on record occurred in the Eastern Mediterranean. Surprisingly, operational dust transport models were unable to forecast the event. This study details the reasons for this failure and presents simulations of the event at convection-permitting resolution using the modelling system ICON-ART. The results allow for an in-depth analysis of the influence of the synoptic situation, the complex interaction of multiple driving atmospheric systems and the mineral dust radiative effect on the dust event. A comparison of the results with observations reveals the quality of the simulation results with respect to structure and timing of the dust transport. The forecast of the dust event is improved decisively. The event is triggered by the unusually early occurrence of an active Red Sea trough situation with an easterly axis over Mesopotamia. The connected sustained organized mesoscale convection produces multiple cold-pool outflows responsible for intense dust emissions. Complexity is added by the interaction with an intense heat low, the inland-penetrating Eastern Mediterranean sea breeze and the widespread occurrence of supercritical flow conditions and subsequent hydraulic jumps in the vicinity of the Dead Sea Rift Valley. The newly implemented mineral dust radiation interaction leads to systematically more intense and faster propagating cold-pool outflows.

  10. Marchiafava-Bignami disease with dementia: severe cerebral metabolic depression revealed by PET. Case report

    International Nuclear Information System (INIS)

    Pappata, S.; Chabriat, H.; Levasseur, M.; Legault-Demare, F.; Baron, J.C.

    1994-01-01

    The Cerebral Metabolic Rate of Glucose (CMRGlu) was measured with positron emission tomography and 18 F-FDG in a patient with Marchiafava-Bignami Disease (MBD)-related dementia. Despite MRI evidence of lesions essentially limited to the corpus callosum (CC), but consistent with the cognitive pattern of cortical dementia, the CMRGlu was markedly reduced in the frontal and temporo-parieto-occipital association cortices. Disruption of cortico-cortical networks crossing the CC presumably contributed to, but may not in and by itself explain, the severity of the clinical-metabolic findings in this patient. An additional role could be played by microscopic white matter lesions and/or neocortical neuronal loss, which have been occasionally observed in post-mortem studies of MBD patients. (authors)

  11. Asymmetric distribution of hypoxia-inducible factor α regulates dorsoventral axis establishment in the early sea urchin embryo.

    Science.gov (United States)

    Chang, Wei-Lun; Chang, Yi-Cheng; Lin, Kuan-Ting; Li, Han-Ru; Pai, Chih-Yu; Chen, Jen-Hao; Su, Yi-Hsien

    2017-08-15

    Hypoxia signaling is an ancient pathway by which animals can respond to low oxygen. Malfunction of this pathway disturbs hypoxic acclimation and can result in various diseases, including cancers. The role of hypoxia signaling in early embryogenesis remains unclear. Here, we show that in the blastula of the sea urchin Strongylocentrotus purpuratus , hypoxia-inducible factor α (HIFα), the downstream transcription factor of the hypoxia pathway, is localized and transcriptionally active on the future dorsal side. This asymmetric distribution is attributable to its oxygen-sensing ability. Manipulations of the HIFα level entrained the dorsoventral axis, as the side with the higher level of HIFα tends to develop into the dorsal side. Gene expression analyses revealed that HIFα restricts the expression of nodal to the ventral side and activates several genes encoding transcription factors on the dorsal side. We also observed that intrinsic hypoxic signals in the early embryos formed a gradient, which was disrupted under hypoxic conditions. Our results reveal an unprecedented role of the hypoxia pathway in animal development. © 2017. Published by The Company of Biologists Ltd.

  12. Re-inspection of small RNA sequence datasets reveals several novel human miRNA genes.

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    Thomas Birkballe Hansen

    Full Text Available BACKGROUND: miRNAs are key players in gene expression regulation. To fully understand the complex nature of cellular differentiation or initiation and progression of disease, it is important to assess the expression patterns of as many miRNAs as possible. Thereby, identifying novel miRNAs is an essential prerequisite to make possible a comprehensive and coherent understanding of cellular biology. METHODOLOGY/PRINCIPAL FINDINGS: Based on two extensive, but previously published, small RNA sequence datasets from human embryonic stem cells and human embroid bodies, respectively [1], we identified 112 novel miRNA-like structures and were able to validate miRNA processing in 12 out of 17 investigated cases. Several miRNA candidates were furthermore substantiated by including additional available small RNA datasets, thereby demonstrating the power of combining datasets to identify miRNAs that otherwise may be assigned as experimental noise. CONCLUSIONS/SIGNIFICANCE: Our analysis highlights that existing datasets are not yet exhaustedly studied and continuous re-analysis of the available data is important to uncover all features of small RNA sequencing.

  13. Hypoxia and hypoxia mimetics decrease aquaporin 5 (AQP5 expression through both hypoxia inducible factor-1α and proteasome-mediated pathways.

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    Jitesh D Kawedia

    Full Text Available The alveolar epithelium plays a central role in gas exchange and fluid transport, and is therefore critical for normal lung function. Since the bulk of water flux across this epithelium depends on the membrane water channel Aquaporin 5 (AQP5, we asked whether hypoxia had any effect on AQP5 expression. We show that hypoxia causes a significant (70% decrease in AQP5 expression in the lungs of mice exposed to hypoxia. Hypoxia and the hypoxia mimetic, cobalt, also caused similar decreases in AQP5 mRNA and protein expression in the mouse lung epithelial cell line MLE-12. The action of hypoxia and cobalt on AQP5 transcription was demonstrated by directly quantifying heternonuclear RNA by real-time PCR. Dominant negative mutants of Hypoxia Inducible Factor (HIF-1α and HIF-1α siRNA blocked the action of cobalt, showing that HIF-1α is a key component in this mechanism. The proteasome inhibitors, lactacystin or proteasome inhibitor-III completely abolished the effect of hypoxia and cobalt both at the protein and mRNA level indicating that the proteasome pathway is probably involved not only for the stability of HIF-1α protein, but for the stability of unidentified transcription factors that regulate AQP5 transcription. These studies reveal a potentially important physiological mechanism linking hypoxic stress and membrane water channels.

  14. Hypoxia and Hypoxia Mimetics Decrease Aquaporin 5 (AQP5) Expression through Both Hypoxia Inducible Factor-1α and Proteasome-Mediated Pathways

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    Kawedia, Jitesh D.; Yang, Fan; Sartor, Maureen A.; Gozal, David; Czyzyk-Krzeska, Maria; Menon, Anil G.

    2013-01-01

    The alveolar epithelium plays a central role in gas exchange and fluid transport, and is therefore critical for normal lung function. Since the bulk of water flux across this epithelium depends on the membrane water channel Aquaporin 5 (AQP5), we asked whether hypoxia had any effect on AQP5 expression. We show that hypoxia causes a significant (70%) decrease in AQP5 expression in the lungs of mice exposed to hypoxia. Hypoxia and the hypoxia mimetic, cobalt, also caused similar decreases in AQP5 mRNA and protein expression in the mouse lung epithelial cell line MLE-12. The action of hypoxia and cobalt on AQP5 transcription was demonstrated by directly quantifying heternonuclear RNA by real-time PCR. Dominant negative mutants of Hypoxia Inducible Factor (HIF-1α) and HIF-1α siRNA blocked the action of cobalt, showing that HIF-1α is a key component in this mechanism. The proteasome inhibitors, lactacystin or proteasome inhibitor-III completely abolished the effect of hypoxia and cobalt both at the protein and mRNA level indicating that the proteasome pathway is probably involved not only for the stability of HIF-1α protein, but for the stability of unidentified transcription factors that regulate AQP5 transcription. These studies reveal a potentially important physiological mechanism linking hypoxic stress and membrane water channels. PMID:23469202

  15. Effects of hypoxia and hypercapnia on geniohyoid contractility and endurance.

    Science.gov (United States)

    Salmone, R J; Van Lunteren, E

    1991-08-01

    Sleep apnea and other respiratory diseases produce hypoxemia and hypercapnia, factors that adversely affect skeletal muscle performance. To examine the effects of these chemical alterations on force production by an upper airway dilator muscle, the contractile and endurance characteristics of the geniohyoid muscle were examined in situ during severe hypoxia (arterial PO2 less than 40 Torr), mild hypoxia (PO2 45-65 Torr), and hypercapnia (PCO2 55-80 Torr) and compared with hyperoxic-normocapnic conditions in anesthetized cats. Muscles were studied at optimal length, and contractile force was assessed in response to supramaximal electrical stimulation of the hypoglossal nerve (n = 7 cats) or geniohyoid muscle (n = 2 cats). There were no significant changes in the twitch kinetics or force-frequency curve of the geniohyoid muscle during hypoxia or hypercapnia. However, the endurance of the geniohyoid, as reflected in the fatigue index (ratio of force at 2 min to initial force in response to 40-Hz stimulation at a duty cycle 0.33), was significantly reduced by severe hypoxia but not by hypercapnia or mild hypoxia. In addition, the downward shift in the force-frequency curve after the repetitive stimulation protocol was greater during hypoxia than hyperoxia, especially at higher frequencies. In conclusion, the ability of the geniohyoid muscle to maintain force output during high levels of activation is adversely affected by severe hypoxia but not mild hypoxia or hypercapnia. However, none of these chemical perturbations affected muscle contractility acutely.

  16. Nitroimidazoles and imaging hypoxia

    International Nuclear Information System (INIS)

    Nunn, A.; Linder, K.; Strauss, H.W.

    1995-01-01

    A class of compounds known to undergo different intracellular metabolism depending on the availability of oxygen in tissue, the nitroimidazoles, have been advocated for imaging hypoxic tissue. In the presence of normal oxygen levels the molecule is immediately reoxidized. In hypoxic tissue the low oxygen concentration is not able to effectively compete to reoxidize the molecule and further reduction appears to take place. The association is not irreversible. Nitroimidazoles for in vivo imaging using radiohalogenated derivatives of misonidazole have recently been employed in patients. Two major problems with fluoromisonidazole are its relatively low concentration within the lesion and the need to wait several hours to permit clearance of the agent from the normoxic background tissue. Even with high-resolution positron emission tomographic imaging, this combination of circumstances makes successful evaluation of hypoxic lesions a challenge. Single-photon agents, with their longer half-lives and comparable biological properties, offer a greater opportunity for successful imaging. In 1992 technetium-99m labeled nitroimidazoles were described that seem to have at least comparable in vivo characteristics. Laboratory studies have demonstrated preferential binding of these agents to hypoxic tissue in the myocardium, in the brain, and in tumors. These investigations indicate that imaging can provide direct evidence of tissue with low oxygen levels that is viable. Even from this early vantage point the utility of measuring tissue oxygen levels with external imaging suggests that hypoxia imaging could play a major role in clinical decision making. (orig./MG)

  17. Chenodeoxycholic Acid Reduces Hypoxia Inducible Factor-1α Protein and Its Target Genes.

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    Yunwon Moon

    Full Text Available This study evaluated HIF-1α inhibitors under different hypoxic conditions, physiological hypoxia (5% O2 and severe hypoxia (0.1% O2. We found that chenodeoxy cholic acid (CDCA reduced the amount of HIF-1α protein only under physiological hypoxia but not under severe hypoxia without decreasing its mRNA level. By using a proteasome inhibitor MG132 and a translation inhibitor cyclohexamide, we showed that CDCA reduced HIF-1α protein by decreasing its translation but not by enhancing its degradation. The following findings indicated that farnesoid X receptor (FXR, a CDCA receptor and its target gene, Small heterodimer partner (SHP are not involved in this effect of CDCA. Distinctly from CDCA, MG132 prevented SHP and an exogenous FXR agonist, GW4064 from reducing HIF-1α protein. Furthermore a FXR antagonist, guggulsterone failed to prevent CDCA from decreasing HIF-1α protein. Furthermore, guggulsterone by itself reduced HIF-1α protein even in the presence of MG132. These findings suggested that CDCA and guggulsterone reduced the translation of HIF-1α in a mechanism which FXR and SHP are not involved. This study reveals novel therapeutic functions of traditional nontoxic drugs, CDCA and guggulsterone, as inhibitors of HIF-1α protein.

  18. The severity of nocturnal hypoxia but not abdominal adiposity is associated with insulin resistance in non-obese men with sleep apnea.

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    Anne-Laure Borel

    Full Text Available BACKGROUND: Beyond obesity, sleep apnea syndrome is frequently associated with excess abdominal adiposity that could contribute to the deteriorated cardiometabolic risk profile of apneic patients. METHODS: The present study addressed the respective contribution of the severity of sleep apnea syndrome and excess abdominal adiposity to the cardiometabolic risk profile of 38 non obese men with polysomnography-diagnosed sleep apnea syndrome (apnea-hypopnea index >15 events/hour. These otherwise healthy men performed a 75g-oral glucose tolerance test (OGTT with plasma lipid/inflammatory and redox profiles. Twenty-one apneic men with high-waist circumference (>94 cm were compared to 17 apneic men with low-waist circumference. RESULTS: Apneic men with high-waist circumference had higher AUC glucose and AUC insulin than apneic men with low-waist circumference. Accordingly, apneic men with high-waist circumference had higher hepatic insulin resistance as reflected by higher HOMA-resistance index, and lower global insulin sensitivity as reflected by lower insulin sensitivity index of Matsuda (derived from OGTT. The sleep structure and the apnea-hypopnea index were not different between the two groups. However, apneic men with high-waist circumference presented with lower mean nocturnal oxyhemoglobin (SpO2. In the 38 men, waist circumference and mean nocturnal SpO2 were inversely correlated (r = -0.43, p = 0.011 and were both associated with plasma glucose/insulin homeostasis indices: the higher the waist circumference, the lower the mean nocturnal SpO2, the lower the insulin-sensitivity. Finally, in multivariable regression model, mean nocturnal SpO2 and not waist circumference was associated with insulin-resistance. CONCLUSION: Thus, excess abdominal adiposity in non obese apneic men was associated with a deteriorated insulin-sensitivity that could be driven by a more severe nocturnal hypoxemia.

  19. Signaling hypoxia by hypoxia-inducible factor protein hydroxylases: a historical overview and future perspectives

    Science.gov (United States)

    Bishop, Tammie; Ratcliffe, Peter J

    2014-01-01

    By the early 1900s, the close matching of oxygen supply with demand was recognized to be a fundamental requirement for physiological function, and multiple adaptive responses to environment hypoxia had been described. Nevertheless, the widespread operation of mechanisms that directly sense and respond to levels of oxygen in animal cells was not appreciated for most of the twentieth century with investigators generally stressing the regulatory importance of metabolic products. Work over the last 25 years has overturned that paradigm. It has revealed the existence of a set of “oxygen-sensing” 2-oxoglutarate dependent dioxygenases that catalyze the hydroxylation of specific amino acid residues and thereby control the stability and activity of hypoxia-inducible factor. The hypoxia-inducible factor hydroxylase pathway regulates a massive transcriptional cascade that is operative in essentially all animal cells. It transduces a wide range of responses to hypoxia, extending well beyond the classical boundaries of hypoxia physiology. Here we review the discovery and elucidation of these pathways, and consider the opportunities and challenges that have been brought into focus by the findings, including new implications for the integrated physiology of hypoxia and therapeutic approaches to ischemic/hypoxic disease. PMID:27774477

  20. Thirty Minutes of Hypobaric Hypoxia Provokes Alterations of Immune Response, Haemostasis, and Metabolism Proteins in Human Serum

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    Jochen Hinkelbein

    2017-08-01

    Full Text Available Hypobaric hypoxia (HH during airline travel induces several (patho- physiological reactions in the human body. Whereas severe hypoxia is investigated thoroughly, very little is known about effects of moderate or short-term hypoxia, e.g. during airline flights. The aim of the present study was to analyse changes in serum protein expression and activation of signalling cascades in human volunteers staying for 30 min in a simulated altitude equivalent to airline travel. After approval of the local ethics committee, 10 participants were exposed to moderate hypoxia (simulation of 2400 m or 8000 ft for 30 min in a hypobaric pressure chamber. Before and after hypobaric hypoxia, serum was drawn, centrifuged, and analysed by two-dimensional gel electrophoresis (2-DIGE and matrix-assisted laser desorption/ionization followed by time-of-flight mass spectrometry (MALDI-TOF. Biological functions of regulated proteins were identified using functional network analysis (GeneMania®, STRING®, and Perseus® software. In participants, oxygen saturation decreased from 98.1 ± 1.3% to 89.2 ± 1.8% during HH. Expression of 14 spots (i.e., 10 proteins: ALB, PGK1, APOE, GAPDH, C1QA, C1QB, CAT, CA1, F2, and CLU was significantly altered. Bioinformatic analysis revealed an association of the altered proteins with the signalling cascades “regulation of haemostasis” (four proteins, “metabolism” (five proteins, and “leukocyte mediated immune response” (five proteins. Even though hypobaric hypoxia was short and moderate (comparable to an airliner flight, analysis of protein expression in human subjects revealed an association to immune response, protein metabolism, and haemostasis

  1. Hypoxia targeting copper complexes

    International Nuclear Information System (INIS)

    Dearling, J.L.

    1998-11-01

    The importance and incidence of tumour hypoxia, its measurement and current treatments available, including pharmacological and radiopharmacological methods of targeting hypoxia, are discussed. A variety of in vitro and in vivo methods for imposing hypoxia have been developed and are reviewed. Copper, its chemistry, biochemistry and radiochemistry, the potential for use of copper radionuclides and its use to date in this field is considered with particular reference to the thiosemicarbazones. Their biological activity, metal chelation, in vitro and in vivo studies of their radiocopper complexes and the potential for their use as hypoxia targeting radiopharmaceuticals is described. The reduction of the copper(II) complex to copper(l), its pivotal importance in their biological behaviour, and the potential for manipulation of this to effect hypoxia selectivity are described. An in vitro method for assessing the hypoxia selectivity of radiopharmaceuticals is reported. The rapid deoxygenation and high viability of a mammalian cell culture in this system is discussed and factors which may affect the cellular uptake of a radiopharmaceutical are described. The design, synthesis and complexation with copper and radiocopper of a range of bis(thiosemicarbazones) is reported. Synthesis of these compounds is simple giving high yields of pure products. The characteristics of the radiocopper complexes ( 64 Cu) including lipophilicity and redox activity are reported (reduction potentials in the range -0.314 - -0.590 V). High cellular uptakes of the radiocopper complexes of the ligands, in hypoxic and normoxic EMT6 and CHO320 cells, were observed. Extremes of selectivity are shown ranging from the hypoxia selective 64 Cu(II)ATSM to normoxic cell selective 64 Cu(II)GTS. The selectivities observed are compared with the physico chemical characteristics of the complexes. A good correlation exists between selectivity of the complex and its Cu(II)/Cu(I) reduction potential, with hypoxia

  2. Kinetic modeling in PET imaging of hypoxia

    Science.gov (United States)

    Li, Fan; Joergensen, Jesper T; Hansen, Anders E; Kjaer, Andreas

    2014-01-01

    Tumor hypoxia is associated with increased therapeutic resistance leading to poor treatment outcome. Therefore the ability to detect and quantify intratumoral oxygenation could play an important role in future individual personalized treatment strategies. Positron Emission Tomography (PET) can be used for non-invasive mapping of tissue oxygenation in vivo and several hypoxia specific PET tracers have been developed. Evaluation of PET data in the clinic is commonly based on visual assessment together with semiquantitative measurements e.g. standard uptake value (SUV). However, dynamic PET contains additional valuable information on the temporal changes in tracer distribution. Kinetic modeling can be used to extract relevant pharmacokinetic parameters of tracer behavior in vivo that reflects relevant physiological processes. In this paper, we review the potential contribution of kinetic analysis for PET imaging of hypoxia. PMID:25250200

  3. Inhibition of calcium uptake during hypoxia in developing zebrafish is mediated by hypoxia-inducible factor.

    Science.gov (United States)

    Kwong, Raymond W M; Kumai, Yusuke; Tzaneva, Velislava; Azzi, Estelle; Hochhold, Nina; Robertson, Cayleih; Pelster, Bernd; Perry, Steve F

    2016-12-15

    The present study investigated the potential role of hypoxia-inducible factor (HIF) in calcium homeostasis in developing zebrafish (Danio rerio). It was demonstrated that zebrafish raised in hypoxic water (30 mmHg; control, 155 mmHg P O 2 ) until 4 days post-fertilization exhibited a substantial reduction in whole-body Ca 2+ levels and Ca 2+ uptake. Ca 2+ uptake in hypoxia-treated fish did not return to pre-hypoxia (control) levels within 2 h of transfer back to normoxic water. Results from real-time PCR showed that hypoxia decreased the whole-body mRNA expression levels of the epithelial Ca 2+ channel (ecac), but not plasma membrane Ca 2+ -ATPase (pmca2) or Na + /Ca 2+ -exchanger (ncx1b). Whole-mount in situ hybridization revealed that the number of ecac-expressing ionocytes was reduced in fish raised in hypoxic water. These findings suggested that hypoxic treatment suppressed the expression of ecac, thereby reducing Ca 2+ influx. To further evaluate the potential mechanisms for the effects of hypoxia on Ca 2+ regulation, a functional gene knockdown approach was employed to prevent the expression of HIF-1αb during hypoxic treatment. Consistent with a role for HIF-1αb in regulating Ca 2+ balance during hypoxia, the results demonstrated that the reduction of Ca 2+ uptake associated with hypoxic exposure was not observed in fish experiencing HIF-1αb knockdown. Additionally, the effects of hypoxia on reducing the number of ecac-expressing ionocytes was less pronounced in HIF-1αb-deficient fish. Overall, the current study revealed that hypoxic exposure inhibited Ca 2+ uptake in developing zebrafish, probably owing to HIF-1αb-mediated suppression of ecac expression. © 2016. Published by The Company of Biologists Ltd.

  4. Upregulation of transcription factor NRF2-mediated oxidative stress response pathway in rat brain under short-term chronic hypobaric hypoxia.

    Science.gov (United States)

    Sethy, Niroj Kumar; Singh, Manjulata; Kumar, Rajesh; Ilavazhagan, Govindasamy; Bhargava, Kalpana

    2011-03-01

    Exposure to high altitude (and thus hypobaric hypoxia) induces electrophysiological, metabolic, and morphological modifications in the brain leading to several neurological clinical syndromes. Despite the known fact that hypoxia episodes in brain are a common factor for many neuropathologies, limited information is available on the underlying cellular and molecular mechanisms. In this study, we investigated the temporal effect of short-term (0-12 h) chronic hypobaric hypoxia on global gene expression of rat brain followed by detailed canonical pathway analysis and regulatory network identification. Our analysis revealed significant alteration of 33, 17, 53, 81, and 296 genes (p stress response pathway and genes were detected at all time points suggesting activation of NRF2-ARE antioxidant defense system. The results were further validated by assessing the expression levels of selected genes in temporal as well as brain regions with quantitative RT-PCR and western blot. In conclusion, our whole brain approach with temporal monitoring of gene expression patterns during hypobaric hypoxia has resulted in (1) deciphering sequence of pathways and signaling networks activated during onset of hypoxia, and (2) elucidation of NRF2-orchestrated antioxidant response as a major intrinsic defense mechanism. The results of this study will aid in better understanding and management of hypoxia-induced brain pathologies.

  5. Hypoxia Enhances Immunosuppression by Inhibiting CD4+ Effector T Cell Function and Promoting Treg Activity

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    Astrid M. Westendorf

    2017-03-01

    Full Text Available Background/Aims: Hypoxia occurs in many pathological conditions, including inflammation and cancer. Within this context, hypoxia was shown to inhibit but also to promote T cell responses. Due to this controversial function, we aimed to explore whether an insufficient anti-tumour response during colitis-associated colon cancer could be ascribed to a hypoxic microenvironment. Methods: Colitis-associated colon cancer was induced in wildtype mice, and hypoxia as well as T cell immunity were analysed in the colonic tumour tissues. In addition, CD4+ effector T cells and regulatory T cells were cultured under normoxic and hypoxic conditions and examined regarding their phenotype and function. Results: We observed severe hypoxia in the colon of mice suffering from colitis-associated colon cancer that was accompanied by a reduced differentiation of CD4+ effector T cells and an enhanced number and suppressive activity of regulatory T cells. Complementary ex vivo and in vitro studies revealed that T cell stimulation under hypoxic conditions inhibited the differentiation, proliferation and IFN-γ production of TH1 cells and enhanced the suppressive capacity of regulatory T cells. Moreover, we identified an active role for HIF-1α in the modulation of CD4+ T cell functions under hypoxic conditions. Conclusion: Our data indicate that oxygen availability can function as a local modulator of CD4+ T cell responses and thus influences tumour immune surveillance in inflammation-associated colon cancer.

  6. Pimonidazole: a novel hypoxia marker for complementary study of tumor hypoxia and tumor biology

    International Nuclear Information System (INIS)

    Varia, Mahesh A.; Kennedy, Andrew S.; Calkins-Adams, Dennise P.; Rinker, Lillian; Novotny, Debra; Fowler, Wesley C.; Raleigh, James A.

    1997-01-01

    relationship of the increasing extent of hypoxia with the observed values of cell proliferation marker MIB-1 and for VEGF in contiguous sections. As immunostaining for tumor hypoxia increases, immunostaining for the cell proliferation marker decreases. These preliminary observations suggest that tumor hypoxia is inversely related to proliferation and appears to be directly related to VEGF expression at low and intermediate, but not high, levels of tumor hypoxia. Data obtained from the Chalkley point counting method and an independent computer image analysis method for the quantitative assessment of immunostaining revealed a good correlation. Conclusions: Pimonidazole binding is a novel immunohistochemical method for the study of microenvironmental hypoxia and this method is feasible in a clinical setting. Because the marker detects hypoxia at a cellular level, not only can the spatial patterns of hypoxia be investigated relative to adjacent histological landmarks but more importantly, it offers the opportunity to study the role of tumor hypoxia in tumor biological processes such as cell proliferation, apoptosis, and metastases using cellular and molecular markers. Finally, the computerized image analysis system offered a convenient, rapid, and reliable method for quantitative assessment

  7. Response of skeletal muscle mitochondria to hypoxia.

    Science.gov (United States)

    Hoppeler, Hans; Vogt, Michael; Weibel, Ewald R; Flück, Martin

    2003-01-01

    This review explores the current concepts relating the structural and functional modifications of skeletal muscle mitochondria to the molecular mechanisms activated when organisms are exposed to a hypoxic environment. In contrast to earlier assumptions it is now established that permanent or long-term exposure to severe environmental hypoxia decreases the mitochondrial content of muscle fibres. Oxidative muscle metabolism is shifted towards a higher reliance on carbohydrates as a fuel, and intramyocellular lipid substrate stores are reduced. Moreover, in muscle cells of mountaineers returning from the Himalayas, we find accumulations of lipofuscin, believed to be a mitochondrial degradation product. Low mitochondrial contents are also observed in high-altitude natives such as Sherpas. In these subjects high-altitude performance seems to be improved by better coupling between ATP demand and supply pathways as well as better metabolite homeostasis. The hypoxia-inducible factor 1 (HIF-1) has been identified as a master regulator for the expression of genes involved in the hypoxia response, such as genes coding for glucose transporters, glycolytic enzymes and vascular endothelial growth factor (VEGF). HIF-1 achieves this by binding to hypoxia response elements in the promoter regions of these genes, whereby the increase of HIF-1 in hypoxia is the consequence of a reduced degradation of its dominant subunit HIF-1a. A further mechanism that seems implicated in the hypoxia response of muscle mitochondria is related to the formation of reactive oxygen species (ROS) in mitochondria during oxidative phosphorylation. How exactly ROS interfere with HIF-1a as well as MAP kinase and other signalling pathways is debated. The current evidence suggests that mitochondria themselves could be important players in oxygen sensing.

  8. Expression of DDX3 is directly modulated by hypoxia inducible factor-1 alpha in breast epithelial cells.

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    Mahendran Botlagunta

    2011-03-01

    Full Text Available DEAD box protein, DDX3, is aberrantly expressed in breast cancer cells ranging from weakly invasive to aggressive phenotypes and functions as an important regulator of cancer cell growth and survival. Here, we demonstrate that hypoxia inducible factor-1α is a transcriptional activator of DDX3 in breast cancer cells. Within the promoter region of the human DDX3 gene, we identified three putative hypoxia inducible factor-1 responsive elements. By luciferase reporter assays in combination with mutated hypoxia inducible factor-1 responsive elements, we determined that the hypoxia inducible factor-1 responsive element at position -153 relative to the translation start site is essential for transcriptional activation of DDX3 under hypoxic conditions. We also demonstrated that hypoxia inducible factor-1 binds to the DDX3 promoter and that the binding is specific, as revealed by siRNA against hypoxia inducible factor-1 and chromatin immunoprecipitation assays. Thus, the activation of DDX3 expression during hypoxia is due to the direct binding of hypoxia inducible factor-1 to hypoxia responsive elements in the DDX3 promoter. In addition, we observed a significant overlap in the protein expression pattern of hypoxia inducible factor-1α and DDX3 in MDA-MB-231 xenograft tumors. Taken together, our results demonstrate, for the first time, the role of DDX3 as a hypoxia-inducible gene that exhibits enhanced expression through the interaction of hypoxia inducible factor-1 with hypoxia inducible factor-1 responsive elements in its promoter region.

  9. Understanding and exploiting the genomic response to hypoxia

    International Nuclear Information System (INIS)

    Giaccia, A.J.

    2003-01-01

    The tumor microenvironment influences both therapeutic outcome and malignant progression. Of the many factors that may be altered in the tumor microenvironment, changes in tumor oxygenation have been strongly associated with a lower probability of local tumor control and survival. In vitro studies indicate that cells exposed to a low oxygen environment exhibit multiple phenotypes, including cell-cycle arrest, increased expression of pro-angiogenic genes, increased invasive capacity, increased apoptosis, increased anaerobic metabolism and altered differentiation programs. While the mechanistic basis of hypoxia as an impediment to radiotherapy and chemotherapy is well understood, it is unclear what changes in the cellular phenotype are important in understanding how hypoxia modifies malignant progression. One insight into how hypoxia modulates malignant progression comes from understanding the critical transcriptional regulators of gene expression under hypoxic conditions such as hypoxia inducible factor 1 (HIF-1) as well as changes in gene expression in untransformed and transformed cells. Overall, about 1.5% of the genome is found to be transcriptionally responsive to changes in oxygenation. Most importantly, the coordinated changes in gene expression under hypoxic conditions underscore the physiologic basis for altering gene expression in response to a low oxygen environment. In addition, some hypoxia-induced genes exhibit increased expression after reoxygenation, suggesting that they are regulated both by hypoxia and oxidative stress. Analysis of the genomic response to hypoxia has several therapeutic uses. First, it allows one to ask the question of what the cellular consequences are to inhibition of the transcriptional response to hypoxia such as by targeting the HIF-1 transcription factor. While the effect of loss of HIF-1 in tumors leads to inhibition of tumor growth, it does not eliminate tumors. In fact, studies indicate that inhibition of HIF-1 leads to a

  10. Protective effect of astrocyte-conditioned medium on neurons following hypoxia and mechanical injury

    Directory of Open Access Journals (Sweden)

    YAN Ji-wen

    2013-02-01

    Full Text Available 【Abstract】Objective: To investigate the protec-tive effect of mouse astrocyte-conditioned medium (ACM on hypoxic and mechanically injured neurons by a cell model in vitro, and to explore the possible mechanism. Methods: The model of hypoxic neuronal injury was caused by 3% O 2 in three-gas incubator. Neurons were cul-tured with ordinary medium or 20% ACM respectively and randomly divided into hypoxic group (hypoxia for 4, 8, 24 h and marked as H4R0, H8R0, H24R0 and hypoxia reoxygenation group (H4R24, H8R24, H24R24. Mechanical injury model was developed by scratching neurons cultured in 20% ACM or ordinary medium to different degrees. Neu-rons in both medium were divided into normal control group, mild, moderate and severe injury groups. The 20% ACM was added 24 h before hypoxia/reoxygenation or mechanical injury. The morphology and survival of neurons were observed and counted by trypan blue staining. The concentration of NO, lactic dehydrogenase (LDH and membrane ATPase activity were detected by corresponding kits. Results: It was showed that 20% ACM can obviously promote the survival rate of hypoxia/reoxygenated neurons and scratched neurons as well. The morphology and num-ber of neurons exposed to hypoxia or scratch injury showed great difference between groups with or without ACM treatment. Compared with control group, the concentration of NO and LDH was much lower in hypoxic/reoxygenated neurons treated with 20% ACM, and the ATPase activity was higher. For the mechanical injury model, neurons with moderate injury also revealed a lower NO and LDH concen-tration than the control group. All the differences were sta-tistically significant (P<0.05. Conclusion: ACM can promote the survival and func-tional recovery of neurons following hypoxia or scratching to a certain degree. The mechanism may be associated with reducing the synthesis and release of NO and LDH as well as increasing the activity of membrane ATPase. Key words: Glial cell line

  11. Specific inhibition of hypoxia-inducible factor (HIF)-1 alpha activation and of vascular endothelial growth factor (VEGF) production by flavonoids.

    Science.gov (United States)

    Hasebe, Yuki; Egawa, Kiyoshi; Yamazaki, Yoko; Kunimoto, Setsuko; Hirai, Yasuaki; Ida, Yoshiteru; Nose, Kiyoshi

    2003-10-01

    Screening using a reporter under the control of the hypoxia-response element (HRE) identified several flavonoids and homoisoflavonoids that inhibit the activation of HRE under hypoxic conditions. Among various compounds, isorhamnetin, luteolin, quercetin, and methyl ophiopogonanone B (MOB) were effective at 3 to 9 microg/ml in inhibiting the reporter activity. The expression of vascular endothelial growth factor (VEGF) mRNA during hypoxia was also inhibited by MOB in HepG2 cells, but the effective doses were 10 to 20 microg/ml. MOB caused destabilization of hypoxia-inducible factor (HIF)-1alpha, as revealed by Western blotting, that was dependent on proteasome activity and the tumor suppressor, p53. The tubular formation and migration of human umbilical vein endothelial cells was also inhibited by MOB. MOB is expected to act as an inhibitor of angiogenesis.

  12. Tissue hypoxia during ischemic stroke: adaptive clues from hypoxia-tolerant animal models.

    Science.gov (United States)

    Nathaniel, Thomas I; Williams-Hernandez, Ashley; Hunter, Anan L; Liddy, Caroline; Peffley, Dennis M; Umesiri, Francis E; Imeh-Nathaniel, Adebobola

    2015-05-01

    The treatment and prevention of hypoxic/ischemic brain injury in stroke patients remain a severe and global medical issue. Numerous clinical studies have resulted in a failure to develop chemical neuroprotection for acute, ischemic stroke. Over 150 estimated clinical trials of ischemic stroke treatments have been done, and more than 200 drugs and combinations of drugs for ischemic and hemorrhagic strokes have been developed. Billions of dollars have been invested for new scientific breakthroughs with only limited success. The revascularization of occluded cerebral arteries such as anti-clot treatments of thrombolysis has proven effective, but it can only be used in a 3-4.5h time frame after the onset of a stroke, and not for every patient. This review is about novel insights on how to resist tissue hypoxia from unconventional animal models. Ability to resist tissue hypoxia is an extraordinary ability that is not common in many laboratory animals such as rat and mouse models. For example, we can learn from a naked mole-rat, Chrysemys picta, how to actively regulate brain metabolic activity to defend the brain against fluctuating oxygen tension and acute bouts of oxidative stress following the onset of a stroke. Additionally, a euthermic arctic ground squirrel can teach us how the brain of a stroke patient can remain well oxygenated during tissue hypoxia with no evidence of cellular stress. In this review, we discuss how these animals provide us with a system to gain insight into the possible mechanisms of tissue hypoxia/ischemia. This issue is of clinical significance to stroke patients. We describe specific physiological and molecular adaptations employed by different animals' models of hypoxia tolerance in aquatic and terrestrial environments. We highlight how these adaptations might provide potential clues on strategies to adapt for the clinical management of tissue hypoxia during conditions such as stroke where oxygen demand fails to match the supply. Copyright

  13. The expanding universe of hypoxia.

    Science.gov (United States)

    Zhang, Huafeng; Semenza, Gregg L

    2008-07-01

    Reduced oxygen availability (hypoxia) is sensed and transduced into changes in the activity or expression of cellular macromolecules. These responses impact on virtually all areas of biology and medicine. In this meeting report, we summarize major developments in the field that were presented at the 2008 Keystone Symposium on Cellular, Physiological, and Pathogenic Responses to Hypoxia.

  14. Preclinical evidence of mitochondrial nicotinamide adenine dinucleotide as an effective alarm parameter under hypoxia

    Science.gov (United States)

    Shi, Hua; Sun, Nannan; Mayevsky, Avraham; Zhang, Zhihong; Luo, Qingming

    2014-01-01

    Early detection of tissue hypoxia in the intensive care unit is essential for effective treatment. Reduced nicotinamide adenine dinucleotide (NADH) has been suggested to be the most sensitive indicator of tissue oxygenation at the mitochondrial level. However, no experimental evidence comparing the kinetics of changes in NADH and other physiological parameters has been provided. The aim of this study is to obtain the missing data in a systematic and reliable manner. We constructed four acute hypoxia models, including hypoxic hypoxia, hypemic hypoxia, circulatory hypoxia, and histogenous hypoxia, and measured NADH fluorescence, tissue reflectance, cerebral blood flow, respiration, and electrocardiography simultaneously from the induction of hypoxia until death. We found that NADH was not always the first onset parameter responding to hypoxia. The order of responses was mainly affected by the cause of hypoxia. However, NADH reached its alarm level earlier than the other monitored parameters, ranging from several seconds to >10 min. As such, we suggest that the NADH can be used as a hypoxia indicator, although the exact level that should be used must be further investigated. When the NADH alarm is detected, the body still has a chance to recover if appropriate and timely treatment is provided.

  15. [Effects of interleukin-18 and hypoxia-inducible factor-1α in serum and gingival tissues of rat model with periodontitis exposed to chronic intermittent hypoxia].

    Science.gov (United States)

    Wang, Bin; Wang, Xiaoqin

    2015-08-01

    This study evaluates the expression of interleukin-18 (IL-18) and hypoxia-inducible factor (HIF)-lα in rat periodontitis model exposed to normoxia and chronic intermittent hypoxia (CIH) environments. The possible correlation between periodontitis and obstructive sleep apnea-hypopnea syndrome (OSAHS) was also investigated. Methods: Thirty-two Sprague-Dawley (SD) rats were randomly assigned into four groups: normoxia control, normoxia periodontitis, hypoxia control, and hypoxia periodontitis groups. The periodontitis models were established by ligating the bilateral maxillary second molars and employing high-carbohydrate diets. Rats in hypoxia control and hypoxia periodontitis groups were exposed to CIH treatment mimicking a moderately severe OSAHS condition. All animals were sacrificed after eight weeks, and the clinical periodontal indexes were detected. The levels of IL-18 and HIF-1α in serum and gingival tissues were determined using enzyme-linked immunosorbent assay (ELISA). The correlation between attachment loss (AL) and the levels of IL-18 and HIF-lα in hypoxia periodontitis group was evaluated. The levels of IL-18 and HIF-lα in hypoxia periodontitis group were significantly higher than that in normoxia periodontitis and hypoxia control groups (Pperiodontal tissues, which is correlated with IL-18 and HIF-lα levels.

  16. Morphological evaluation of the cerebral blood vessels in the late gestation fetal sheep following hypoxia in utero.

    Science.gov (United States)

    Baburamani, Ana A; Lo, Camden; Castillo-Melendez, Margie; Walker, David W

    2013-01-01

    Hypoxia can significantly contribute to the development of permanent brain injury in the term neonate; however the response of cerebral blood vessels is not well understood. This study aimed to quantitatively measure vascular density and morphology using laminin immunohistochemistry as a marker of blood vessels, and determine the effects of a single, severe bout of hypoxia (umbilical cord occlusion, UCO) late in gestation on the developing cerebrovasculature in fetal sheep. At 124-126 days gestation singleton fetal sheep underwent surgery for implantation of catheters and placement of an inflatable cuff around the umbilical cord. A 10 min UCO or sham UCO (n=5) occurred at 132 days gestation. Fetal brains were collected at 24 h (n=5) or 48 h (n=4) after UCO for vascular density and morphology analysis of laminin immunohistochemistry. 48 h following a single, brief bout of severe hypoxia late in gestation decreased vascular density was seen in the caudate nucleus and no changes in vascular morphology occurred. However closer analysis revealed a significant shift in the frequency of smaller (≤10 μm) to larger (≤100 μm) perimeter blood vessels in periventricular and subcortical white matter. Close examination of the frequency distribution of vascular perimeter highlights that alterations in vascular morphology persist in the near term fetal brain for up to 48 h following a brief (10 min) hypoxia in white but not gray matter. These findings suggest that the near term brain may still be vulnerable to white matter injury following in utero hypoxia. Copyright © 2012 Elsevier Inc. All rights reserved.

  17. Hypoxia inhibits colonic ion transport via activation of AMP kinase.

    LENUS (Irish Health Repository)

    Collins, Danielle

    2012-02-01

    BACKGROUND AND AIMS: Mucosal hypoxia is a common endpoint for many pathological processes including ischemic colitis, colonic obstruction and anastomotic failure. Previous studies suggest that hypoxia modulates colonic mucosal function through inhibition of chloride secretion. However, the molecular mechanisms underlying this observation are poorly understood. AMP-activated protein kinase (AMPK) is a metabolic energy regulator found in a wide variety of cells and has been linked to cystic fibrosis transmembrane conductance regulator (CFTR) mediated chloride secretion in several different tissues. We hypothesized that AMPK mediates many of the acute effects of hypoxia on human and rat colonic electrolyte transport. METHODS: The fluorescent chloride indicator dye N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide was used to measure changes in intracellular chloride concentrations in isolated single rat colonic crypts. Ussing chamber experiments in human colonic mucosa were conducted to evaluate net epithelial ion transport. RESULTS: This study demonstrates that acute hypoxia inhibits electrogenic chloride secretion via AMPK mediated inhibition of CFTR. Pre-treatment of tissues with the AMPK inhibitor 6-[4-(2-piperidin-1-yl-ethoxy)-phenyl)]-3-pyridin-4-yl-pyyrazolo [1,5-a] pyrimidine (compound C) in part reversed the effects of acute hypoxia on chloride secretion. CONCLUSION: We therefore suggest that AMPK is a key component of the adaptive cellular response to mucosal hypoxia in the colon. Furthermore, AMPK may represent a potential therapeutic target in diseased states or in prevention of ischemic intestinal injury.

  18. HRGFish: A database of hypoxia responsive genes in fishes

    Science.gov (United States)

    Rashid, Iliyas; Nagpure, Naresh Sahebrao; Srivastava, Prachi; Kumar, Ravindra; Pathak, Ajey Kumar; Singh, Mahender; Kushwaha, Basdeo

    2017-02-01

    Several studies have highlighted the changes in the gene expression due to the hypoxia response in fishes, but the systematic organization of the information and the analytical platform for such genes are lacking. In the present study, an attempt was made to develop a database of hypoxia responsive genes in fishes (HRGFish), integrated with analytical tools, using LAMPP technology. Genes reported in hypoxia response for fishes were compiled through literature survey and the database presently covers 818 gene sequences and 35 gene types from 38 fishes. The upstream fragments (3,000 bp), covered in this database, enables to compute CG dinucleotides frequencies, motif finding of the hypoxia response element, identification of CpG island and mapping with the reference promoter of zebrafish. The database also includes functional annotation of genes and provides tools for analyzing sequences and designing primers for selected gene fragments. This may be the first database on the hypoxia response genes in fishes that provides a workbench to the scientific community involved in studying the evolution and ecological adaptation of the fish species in relation to hypoxia.

  19. Imaging tumor hypoxia: Blood-borne delivery of imaging agents is fundamentally different in hypoxia subtypes

    Directory of Open Access Journals (Sweden)

    Peter Vaupel

    2014-03-01

    Full Text Available Hypoxic tissue subvolumes are a hallmark feature of solid malignant tumors, relevant for cancer therapy and patient outcome because they increase both the intrinsic aggressiveness of tumor cells and their resistance to several commonly used anticancer strategies. Pathogenetic mechanisms leading to hypoxia are diverse, may coexist within the same tumor and are commonly grouped according to the duration of their effects. Chronic hypoxia is mainly caused by diffusion limitations resulting from enlarged intercapillary distances and adverse diffusion geometries and — to a lesser extent — by hypoxemia, compromised perfusion or long-lasting microregional flow stops. Conversely, acute hypoxia preferentially results from transient disruptions in perfusion. While each of these features of the tumor microenvironment can contribute to a critical reduction of oxygen availability, the delivery of imaging agents (as well as nutrients and anticancer agents may be compromised or remain unaffected. Thus, a critical appraisal of the effects of the various mechanisms leading to hypoxia with regard to the blood-borne delivery of imaging agents is necessary to judge their ability to correctly represent the hypoxic phenotype of solid malignancies.

  20. Brain blood flow and blood pressure during hypoxia in the epaulette shark Hemiscyllium ocellatum, a hypoxia-tolerant elasmobranch.

    Science.gov (United States)

    Söderström, V; Renshaw, G M; Nilsson, G E

    1999-04-01

    The key to surviving hypoxia is to protect the brain from energy depletion. The epaulette shark (Hemiscyllium ocellatum) is an elasmobranch able to resist energy depletion and to survive hypoxia. Using epi-illumination microscopy in vivo to observe cerebral blood flow velocity on the brain surface, we show that cerebral blood flow in the epaulette shark is unaffected by 2 h of severe hypoxia (0.35 mg O2 l-1 in the respiratory water, 24 C). Thus, the epaulette shark differs from other hypoxia- and anoxia-tolerant species studied: there is no adenosine-mediated increase in cerebral blood flow such as that occurring in freshwater turtles and cyprinid fish. However, blood pressure showed a 50 % decrease in the epaulette shark during hypoxia, indicating that a compensatory cerebral vasodilatation occurs to maintain cerebral blood flow. We observed an increase in cerebral blood flow velocity when superfusing the normoxic brain with adenosine (making sharks the oldest vertebrate group in which this mechanism has been found). The adenosine-induced increase in cerebral blood flow velocity was reduced by the adenosine receptor antagonist aminophylline. Aminophylline had no effect upon the maintenance of cerebral blood flow during hypoxia, however, indicating that adenosine is not involved in maintaining cerebral blood flow in the epaulette shark during hypoxic hypotension.

  1. Chronic Intermittent Hypoxia Induces Atherosclerosis

    OpenAIRE

    Savransky, Vladimir; Nanayakkara, Ashika; Li, Jianguo; Bevans, Shannon; Smith, Philip L.; Rodriguez, Annabelle; Polotsky, Vsevolod Y.

    2007-01-01

    Rationale: Obstructive sleep apnea, a condition leading to chronic intermittent hypoxia (CIH), is associated with hyperlipidemia, atherosclerosis, and a high cardiovascular risk. A causal link between obstructive sleep apnea and atherosclerosis has not been established.

  2. Network-based association of hypoxia-responsive genes with cardiovascular diseases

    International Nuclear Information System (INIS)

    Wang, Rui-Sheng; Oldham, William M; Loscalzo, Joseph

    2014-01-01

    Molecular oxygen is indispensable for cellular viability and function. Hypoxia is a stress condition in which oxygen demand exceeds supply. Low cellular oxygen content induces a number of molecular changes to activate regulatory pathways responsible for increasing the oxygen supply and optimizing cellular metabolism under limited oxygen conditions. Hypoxia plays critical roles in the pathobiology of many diseases, such as cancer, heart failure, myocardial ischemia, stroke, and chronic lung diseases. Although the complicated associations between hypoxia and cardiovascular (and cerebrovascular) diseases (CVD) have been recognized for some time, there are few studies that investigate their biological link from a systems biology perspective. In this study, we integrate hypoxia genes, CVD genes, and the human protein interactome in order to explore the relationship between hypoxia and cardiovascular diseases at a systems level. We show that hypoxia genes are much closer to CVD genes in the human protein interactome than that expected by chance. We also find that hypoxia genes play significant bridging roles in connecting different cardiovascular diseases. We construct a hypoxia-CVD bipartite network and find several interesting hypoxia-CVD modules with significant gene ontology similarity. Finally, we show that hypoxia genes tend to have more CVD interactors in the human interactome than in random networks of matching topology. Based on these observations, we can predict novel genes that may be associated with CVD. This network-based association study gives us a broad view of the relationships between hypoxia and cardiovascular diseases and provides new insights into the role of hypoxia in cardiovascular biology. (paper)

  3. Population genetics of IFITM3 in Portugal and Central Africa reveals a potential modifier of influenza severity.

    Science.gov (United States)

    David, Susana; Correia, Vanessa; Antunes, Liliana; Faria, Ricardo; Ferrão, José; Faustino, Paula; Nunes, Baltazar; Maltez, Fernando; Lavinha, João; Rebelo de Andrade, Helena

    2018-03-01

    Influenza epidemics are a serious global public health and economic problem. The IFITM3 allele (rs12252-C) was suggested as a population-based genetic risk factor for severe influenza virus infection by A(H1N1)pdm09. We analyzed the population genetics of IFITM3 variants in the Portuguese general population (n = 200) and Central Africans (largely Angolan) (n = 148) as well as its association to influenza severity in Portuguese patients (n = 41). Seven SNPs, within the 352 bp IFITM3 amplicon around rs12252, were identified. SNP distributions in the Portuguese appeared at an intermediate level between the Africans and other Europeans. According to HapMap, rs34481144 belongs to the same linkage disequilibrium (LD) block as rs12252 and is in strong LD with rs6421983. A negative association with severe relative to mild disease was observed for allele rs34481144-A, indicating a protective effect under the dominant model. Moreover, haplotype Hap4 with rs34481144-A, not including rs12252-C, was significantly associated to mild influenza. Conversely, although with borderline significance, haplotype Hap1 with rs34481144-G, not including rs12252-C, was associated to severe disease. Moreover, in comparison to the general Portuguese population, statistical significant differences in the frequencies of the protective allele rs34481144-A in the severe disease group, the deleterious Hap1 in the mild disease group, and the protective Hap4 in the severe disease group were observed. The population attributable risk (PAR) for the targeted rs34481144 allele or genotype was of 55.91 and 64.44% in the general population and the mildly infected individuals, respectively. Implication of these variants in disease phenotype needs further validation, namely through functional analysis as is discussed.

  4. Hypoxia, Oxidative Stress and Fat

    Directory of Open Access Journals (Sweden)

    Nikolaus Netzer

    2015-06-01

    Full Text Available Metabolic disturbances in white adipose tissue in obese individuals contribute to the pathogenesis of insulin resistance and the development of type 2 diabetes mellitus. Impaired insulin action in adipocytes is associated with elevated lipolysis and increased free fatty acids leading to ectopic fat deposition in liver and skeletal muscle. Chronic adipose tissue hypoxia has been suggested to be part of pathomechanisms causing dysfunction of adipocytes. Hypoxia can provoke oxidative stress in human and animal adipocytes and reduce the production of beneficial adipokines, such as adiponectin. However, time-dose responses to hypoxia relativize the effects of hypoxic stress. Long-term exposure of fat cells to hypoxia can lead to the production of beneficial substances such as leptin. Knowledge of time-dose responses of hypoxia on white adipose tissue and the time course of generation of oxidative stress in adipocytes is still scarce. This paper reviews the potential links between adipose tissue hypoxia, oxidative stress, mitochondrial dysfunction, and low-grade inflammation caused by adipocyte hypertrophy, macrophage infiltration and production of inflammatory mediators.

  5. Hypoxia-Induced Signaling Promotes Prostate Cancer Progression: Exosomes Role as Messenger of Hypoxic Response in Tumor Microenvironment

    Science.gov (United States)

    Deep, Gagan; Panigrahi, Gati K.

    2017-01-01

    Prostate cancer (PCA) is the leading malignancy in men and the second leading cause of cancer-related deaths. Hypoxia (low O2 condition) is considered an early event in prostate carcinogenesis associated with an aggressive phenotype. In fact, clinically, hypoxia and hypoxia-related biomarkers are associated with treatment failure and disease progression. Hypoxia-inducible factor 1 (HIF-1) is the key factor that is activated under hypoxia, and mediates adaptation of cells to hypoxic conditions through regulating the expression of genes associated with angiogenesis, epithelial-to-mesenchymal transition (EMT), metastasis, survival, proliferation, metabolism, stemness, hormone-refractory progression, and therapeutic resistance. Besides HIF-1, several other signaling pathways including PI3K/Akt/mTOR, NADPH oxidase (NOX), Wnt/β-catenin, and Hedgehog are activated in cancer cells under hypoxic conditions, and also contribute in hypoxia-induced biological effects in HIF-1-dependent and -independent manners. Hypoxic cancer cells cause extensive changes in the tumor microenvironment both local and distant, and recent studies have provided ample evidence supporting the crucial role of nanosized vesicles “exosomes” in mediating hypoxia-induced tumor microenvironment remodeling. Exosomes’ role has been reported in hypoxia-induced angiogenesis, stemness, activation of cancer-associated fibroblasts (CAFs), and EMT. Together, existing literature suggests that hypoxia plays a predominant role in PCA growth and progression, and PCA could be effectively prevented and treated via targeting hypoxia/hypoxia-related signaling pathways. PMID:27279239

  6. Hypoxia induces copper stable isotope fractionation in hepatocellular carcinoma, in a HIF-independent manner.

    Science.gov (United States)

    Bondanese, Victor P; Lamboux, Aline; Simon, Melanie; Lafont, Jérôme E; Albalat, Emmanuelle; Pichat, Sylvain; Vanacker, Jean-Marc; Telouk, Philippe; Balter, Vincent; Oger, Philippe; Albarède, Francis

    2016-11-09

    Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer, with increasing incidence worldwide. The unrestrained proliferation of tumour cells leads to tumour hypoxia which in turn promotes cancer aggressiveness. While changes in the concentration of copper (Cu) have long been observed upon cancerization, we have recently reported that the isotopic composition of copper is also altered in several types of cancer. In particular, we showed that in hepatocellular carcinoma, tumour tissue contains heavier copper compared to the surrounding parenchyma. However, the reasons behind such isotopic signature remained elusive. Here we show that hypoxia causes heavy copper enrichment in several human cell lines. We also demonstrate that this effect of hypoxia is pH, HIF-1 and -2 independent. Our data identify a previously unrecognized cellular process associated with hypoxia, and suggests that in vivo tumour hypoxia determines copper isotope fractionation in HCC and other solid cancers.

  7. A genetically encoded biosensor for visualising hypoxia responses in vivo

    Directory of Open Access Journals (Sweden)

    Tvisha Misra

    2017-02-01

    Full Text Available Cells experience different oxygen concentrations depending on location, organismal developmental stage, and physiological or pathological conditions. Responses to reduced oxygen levels (hypoxia rely on the conserved hypoxia-inducible factor 1 (HIF-1. Understanding the developmental and tissue-specific responses to changing oxygen levels has been limited by the lack of adequate tools for monitoring HIF-1 in vivo. To visualise and analyse HIF-1 dynamics in Drosophila, we used a hypoxia biosensor consisting of GFP fused to the oxygen-dependent degradation domain (ODD of the HIF-1 homologue Sima. GFP-ODD responds to changing oxygen levels and to genetic manipulations of the hypoxia pathway, reflecting oxygen-dependent regulation of HIF-1 at the single-cell level. Ratiometric imaging of GFP-ODD and a red-fluorescent reference protein reveals tissue-specific differences in the cellular hypoxic status at ambient normoxia. Strikingly, cells in the larval brain show distinct hypoxic states that correlate with the distribution and relative densities of respiratory tubes. We present a set of genetic and image analysis tools that enable new approaches to map hypoxic microenvironments, to probe effects of perturbations on hypoxic signalling, and to identify new regulators of the hypoxia response.

  8. Obstructive sleep apnea and cancer: effects of intermittent hypoxia?

    Science.gov (United States)

    Kukwa, Wojciech; Migacz, Ewa; Druc, Karolina; Grzesiuk, Elzbieta; Czarnecka, Anna M

    2015-01-01

    Obstructive sleep apnea (OSA) is a common disorder characterized by pauses in regular breathing. Apneic episodes lead to recurrent hypoxemia-reoxygenation cycles with concomitant cellular intermittent hypoxia. Studies suggest that intermittent hypoxia in OSA may influence tumorigenesis. This review presents recent articles on the potential role of OSA in cancer development. Relevant research has focused on: molecular pathways mediating the influence of intermittent hypoxia on tumor physiology, animal and epidemiological human studies linking OSA and cancer. Current data relating OSA to risk of neoplastic disease remain scarce, but recent studies reveal the potential for a strong relation. More work is, therefore, needed on the impact of OSA on many cancer-related aspects. Results may offer enlightenment for improved cancer diagnosis and treatment.

  9. Is hypoxia training good for muscles and exercise performance?

    Science.gov (United States)

    Vogt, Michael; Hoppeler, Hans

    2010-01-01

    Altitude training has become very popular among athletes as a means to further increase exercise performance at sea level or to acclimatize to competition at altitude. Several approaches have evolved during the last few decades, with "live high-train low" and "live low-train high" being the most popular. This review focuses on functional, muscular, and practical aspects derived from extensive research on the "live low-train high" approach. According to this, subjects train in hypoxia but remain under normoxia for the rest of the time. It has been reasoned that exercising in hypoxia could increase the training stimulus. Hypoxia training studies published in the past have varied considerably in altitude (2300-5700 m) and training duration (10 days to 8 weeks) and the fitness of the subjects. The evidence from muscle structural, biochemical, and molecular findings point to a specific role of hypoxia in endurance training. However, based on the available performance capacity data such as maximal oxygen uptake (Vo(2)max) and (maximal) power output, hypoxia as a supplement to training is not consistently found to be advantageous for performance at sea level. Stronger evidence exists for benefits of hypoxic training on performance at altitude. "Live low-train high" may thus be considered when altitude acclimatization is not an option. In addition, the complex pattern of gene expression adaptations induced by supplemental training in hypoxia, but not normoxia, suggest that muscle tissue specifically responds to hypoxia. Whether and to what degree these gene expression changes translate into significant changes in protein concentrations that are ultimately responsible for observable structural or functional phenotypes remains open. It is conceivable that the global functional markers such as Vo(2)max and (maximal) power output are too coarse to detect more subtle changes that might still be functionally relevant, at least to high-level athletes.

  10. Assessment of hypoxia and TNF-alpha response by a vector with HRE and NF-kappaB response elements.

    Science.gov (United States)

    Chen, Zhilin; Eadie, Ashley L; Hall, Sean R; Ballantyne, Laurel; Ademidun, David; Tse, M Yat; Pang, Stephen C; Melo, Luis G; Ward, Christopher A; Brunt, Keith R

    2017-01-01

    Hypoxia and inflammatory cytokine activation (H&I) are common processes in many acute and chronic diseases. Thus, a single vector that responds to both hypoxia and inflammatory cytokines, such as TNF-alpha, is useful for assesing the severity of such diseases. Adaptation to hypoxia is regulated primarily by hypoxia inducible transcription factor (HIF alpha) nuclear proteins that engage genes containing a hypoxia response element (HRE). Inflammation activates a multitude of cytokines, including TNF-alpha, that invariably modulate activation of the nuclear factor kappa B (NF-kB) transcription factor. We constructed a vector that encompassed both a hypoxia response element (HRE), and a NF-kappaB responsive element. We show that this vector was functionally responsive to both hypoxia and TNF-alpha, in vitro and in vivo . Thus, this vector might be suitable for the detection and assessment of hypoxia or TNF-alpha.

  11. Mechanisms of c-myc degradation by nickel compounds and hypoxia.

    Directory of Open Access Journals (Sweden)

    Qin Li

    2009-12-01

    Full Text Available Nickel (Ni compounds have been found to cause cancer in humans and animal models and to transform cells in culture. At least part of this effect is mediated by stabilization of hypoxia inducible factor (HIF1a and activating its downstream signaling. Recent studies reported that hypoxia signaling might either antagonize or enhance c-myc activity depending on cell context. We investigated the effect of nickel on c-myc levels, and demonstrated that nickel, hypoxia, and other hypoxia mimetics degraded c-myc protein in a number of cancer cells (A549, MCF-7, MDA-453, and BT-474. The degradation of the c-Myc protein was mediated by the 26S proteosome. Interestingly, knockdown of both HIF-1alpha and HIF-2alpha attenuated c-Myc degradation induced by Nickel and hypoxia, suggesting the functional HIF-1alpha and HIF-2alpha was required for c-myc degradation. Further studies revealed two potential pathways mediated nickel and hypoxia induced c-myc degradation. Phosphorylation of c-myc at T58 was significantly increased in cells exposed to nickel or hypoxia, leading to increased ubiquitination through Fbw7 ubiquitin ligase. In addition, nickel and hypoxia exposure decreased USP28, a c-myc de-ubiquitinating enzyme, contributing to a higher steady state level of c-myc ubiquitination and promoting c-myc degradation. Furthermore, the reduction of USP28 protein by hypoxia signaling is due to both protein degradation and transcriptional repression. Nickel and hypoxia exposure significantly increased the levels of dimethylated H3 lysine 9 at the USP28 promoter and repressed its expression. Our study demonstrated that Nickel and hypoxia exposure increased c-myc T58 phosphorylation and decreased USP28 protein levels in cancer cells, which both lead to enhanced c-myc ubiquitination and proteasomal degradation.

  12. Whole-exome sequencing of a patient with severe and complex hemostatic abnormalities reveals a possible contributing frameshift mutation in C3AR1

    DEFF Research Database (Denmark)

    Leinøe, Eva; Nielsen, Ove Juul; Jønson, Lars

    2016-01-01

    -threatening coagulation disorder causing recurrent venous thromboembolic events, severe thrombocytopenia, and subdural hematomas. Whole-exome sequencing revealed a frameshift mutation (C3AR1 c.355-356dup, p.Asp119Alafs*19) resulting in a premature stop codon in C3AR1 (Complement Component 3a Receptor 1). Based...

  13. A novel Drosophila injury model reveals severed axons are cleared through a Draper/MMP-1 signaling cascade

    Science.gov (United States)

    Purice, Maria D; Ray, Arpita; Münzel, Eva Jolanda; Pope, Bernard J; Park, Daniel J; Speese, Sean D; Logan, Mary A

    2017-01-01

    Neural injury triggers swift responses from glia, including glial migration and phagocytic clearance of damaged neurons. The transcriptional programs governing these complex innate glial immune responses are still unclear. Here, we describe a novel injury assay in adult Drosophila that elicits widespread glial responses in the ventral nerve cord (VNC). We profiled injury-induced changes in VNC gene expression by RNA sequencing (RNA-seq) and found that responsive genes fall into diverse signaling classes. One factor, matrix metalloproteinase-1 (MMP-1), is induced in Drosophila ensheathing glia responding to severed axons. Interestingly, glial induction of MMP-1 requires the highly conserved engulfment receptor Draper, as well as AP-1 and STAT92E. In MMP-1 depleted flies, glia do not properly infiltrate neuropil regions after axotomy and, as a consequence, fail to clear degenerating axonal debris. This work identifies Draper-dependent activation of MMP-1 as a novel cascade required for proper glial clearance of severed axons. DOI: http://dx.doi.org/10.7554/eLife.23611.001 PMID:28825401

  14. Optical Imaging of Tumor Hypoxia and Evaluation of Efficacy of a Hypoxia-Targeting Drug in Living Animals

    Directory of Open Access Journals (Sweden)

    Hiroshi Harada

    2005-07-01

    Full Text Available Solid tumors containing more hypoxic regions show a more malignant phenotype by increasing the expression of genes encoding angiogenic and metastatic factors. Hypoxia-inducible factor-1 (HIF-1 is a master transcriptional activator of such genes, and thus, imaging and targeting hypoxic tumor cells where HIF-1 is active are important in cancer therapy. In the present study, HIF-1 activity was monitored via an optical in vivo imaging system by using a luciferase reporter gene under the regulation of an artificial HIF-1-dependent promoter, 5HRE. To monitor tumor hypoxia, we isolated a stable reporter-transfectant, HeLa/5HRE-Luc, which expressed more than 100-fold luciferase in response to hypoxic stress, and observed bioluminescence from its xenografts. Immunohistochemical analysis of the xenografts with a hypoxia marker, pimonidazole, confirmed that the luciferase-expressing cells were hypoxic. Evaluation of the efficacy of a hypoxia-targeting prodrug, TOP3, using this optical imaging system revealed that hypoxic cells were significantly diminished by TOP3 treatment. Immunohistochemical analysis of the TOP3-treated xenografts confirmed that hypoxic cells underwent apoptosis and were removed after TOP3 treatment. These results demonstrate that this model system using the 5HRE-luciferase reporter construct provides qualitative information (hypoxic status of solid tumors and enables one to conveniently evaluate the efficacy of cancer therapy on hypoxia in malignant solid tumors.

  15. Carbohydrate management, anaerobic metabolism, and adenosine levels in the armoured catfish, Liposarcus pardalis (castelnau), during hypoxia.

    Science.gov (United States)

    Maccormack, Tyson James; Lewis, Johanne Mari; Almeida-Val, Vera Maria Fonseca; Val, Adalberto Luis; Driedzic, William Robert

    2006-04-01

    The armoured catfish, Liposarcus pardalis, tolerates severe hypoxia at high temperatures. Although this species can breathe air, it also has a strong anaerobic metabolism. We assessed tissue to plasma glucose ratios and glycogen and lactate in a number of tissues under "natural" pond hypoxia, and severe aquarium hypoxia without aerial respiration. Armour lactate content and adenosine in brain and heart were also investigated. During normoxia, tissue to plasma glucose ratios in gill, brain, and heart were close to one. Hypoxia increased plasma glucose and decreased tissue to plasma ratios to less than one, suggesting glucose phosphorylation is activated more than uptake. High normoxic white muscle glucose relative to plasma suggests gluconeogenesis or active glucose uptake. Excess muscle glucose may serve as a metabolic reserve since hypoxia decreased muscle to plasma glucose ratios. Mild pond hypoxia changed glucose management in the absence of lactate accumulation. Lactate was elevated in all tissues except armour following aquarium hypoxia; however, confinement in aquaria increased armour lactate, even under normoxia. A stress-associated acidosis may contribute to armour lactate sequestration. High plasma lactate levels were associated with brain adenosine accumulation. An increase in heart adenosine was triggered by confinement in aquaria, although not by hypoxia alone.

  16. Pallid bands in feathers and associated stable isotope signatures reveal effects of severe weather stressors on fledgling sparrows.

    Science.gov (United States)

    Ross, Jeremy D; Kelly, Jeffrey F; Bridge, Eli S; Engel, Michael H; Reinking, Dan L; Boyle, W Alice

    2015-01-01

    In August 2013, we observed a high incidence (44%) of synchronous bands of reduced melanin (a type of fault bar we have termed "pallid bands") across the rectrices of juvenile Grasshopper Sparrows (Ammodrammus savannarum) captured near El Reno, Oklahoma. Earlier that year, on May 31, the site was struck by a severe storm which rained hailstones exceeding 5.5 cm diameter and spawned an historic 4.2 km-wide tornado stressor had induced the pallid bands. An assessment of Grasshopper Sparrow nesting phenology indicated that a large number of nestlings were likely growing tail feathers when the storm hit. The pallid bands were restricted to the distal half of feathers and their widths significantly increased as a function of distance from the tip (i.e., age at formation). We predicted that if stress had caused these pallid bands, then a spike in circulating δ (15)N originating from tissue catabolism during the stress response would have been incorporated into the developing feather. From 18 juveniles captured at the site in August we measured δ (15)N and δ (13)C stable isotope ratios within four to five 0.25-0.40 mg feather sections taken from the distal end of a tail feather; the pallid band, if present, was contained within only one section. After accounting for individual and across-section variation, we found support for our prediction that feather sections containing or located immediately proximal to pallid bands (i.e., the pallid band region) would show significantly higher δ (15)N than sections outside this region. In contrast, the feathers of juveniles with pallid bands compared to normal appearing juveniles showed significantly lower δ (15)N. A likely explanation is that the latter individuals hatched after the May 31 storm and had consumed a trophically-shifted diet relative to juveniles with pallid bands. Considering this, the juveniles of normal appearance were significantly less abundant within our sample relative to expectations from past cohorts (z

  17. Pallid bands in feathers and associated stable isotope signatures reveal effects of severe weather stressors on fledgling sparrows

    Directory of Open Access Journals (Sweden)

    Jeremy D. Ross

    2015-03-01

    Full Text Available In August 2013, we observed a high incidence (44% of synchronous bands of reduced melanin (a type of fault bar we have termed “pallid bands” across the rectrices of juvenile Grasshopper Sparrows (Ammodrammus savannarum captured near El Reno, Oklahoma. Earlier that year, on May 31, the site was struck by a severe storm which rained hailstones exceeding 5.5 cm diameter and spawned an historic 4.2 km-wide tornado <8 km to the south of the site. We hypothesized that this stressor had induced the pallid bands. An assessment of Grasshopper Sparrow nesting phenology indicated that a large number of nestlings were likely growing tail feathers when the storm hit. The pallid bands were restricted to the distal half of feathers and their widths significantly increased as a function of distance from the tip (i.e., age at formation. We predicted that if stress had caused these pallid bands, then a spike in circulating δ15N originating from tissue catabolism during the stress response would have been incorporated into the developing feather. From 18 juveniles captured at the site in August we measured δ15N and δ13C stable isotope ratios within four to five 0.25–0.40 mg feather sections taken from the distal end of a tail feather; the pallid band, if present, was contained within only one section. After accounting for individual and across-section variation, we found support for our prediction that feather sections containing or located immediately proximal to pallid bands (i.e., the pallid band region would show significantly higher δ15N than sections outside this region. In contrast, the feathers of juveniles with pallid bands compared to normal appearing juveniles showed significantly lower δ15N. A likely explanation is that the latter individuals hatched after the May 31 storm and had consumed a trophically-shifted diet relative to juveniles with pallid bands. Considering this, the juveniles of normal appearance were significantly less abundant

  18. Cannabis microbiome sequencing reveals several mycotoxic fungi native to dispensary grade Cannabis flowers [version 2; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Kevin McKernan

    2016-05-01

    Full Text Available The Center for Disease Control estimates 128,000 people in the U.S. are hospitalized annually due to food borne illnesses. This has created a demand for food safety testing targeting the detection of pathogenic mold and bacteria on agricultural products. This risk extends to medical Cannabis and is of particular concern with inhaled, vaporized and even concentrated Cannabis products . As a result, third party microbial testing has become a regulatory requirement in the medical and recreational Cannabis markets, yet knowledge of the Cannabis microbiome is limited. Here we describe the first next generation sequencing survey of the fungal communities found in dispensary based Cannabis flowers by ITS2 sequencing, and demonstrate the sensitive detection of several toxigenic Penicillium and Aspergillus species, including P. citrinum and P. paxilli, that were not detected by one or more culture-based methods currently in use for safety testing.

  19. Serum Metabolomics Reveals Serotonin as a Predictor of Severe Dengue in the Early Phase of Dengue Fever

    Science.gov (United States)

    Thein, Tun Linn; Fang, Jinling; Pang, Junxiong; Ooi, Eng Eong; Leo, Yee Sin; Ong, Choon Nam; Tannenbaum, Steven R.

    2016-01-01

    Effective triage of dengue patients early in the disease course for in- or out-patient management would be useful for optimal healthcare resource utilization while minimizing poor clinical outcome due to delayed intervention. Yet, early prognosis of severe dengue is hampered by the heterogeneity in clinical presentation and routine hematological and biochemical measurements in dengue patients that collectively correlates poorly with eventual clinical outcome. Herein, untargeted liquid-chromatography mass spectrometry metabolomics of serum from patients with dengue fever (DF) and dengue hemorrhagic fever (DHF) in the febrile phase (1.5) in the serum, among which are two products of tryptophan metabolism–serotonin and kynurenine. Serotonin, involved in platelet aggregation and activation decreased significantly, whereas kynurenine, an immunomodulator, increased significantly in patients with DHF, consistent with thrombocytopenia and immunopathology in severe dengue. To sensitively and accurately evaluate serotonin levels as prognostic biomarkers, we implemented stable-isotope dilution mass spectrometry and used convalescence samples as their own controls. DHF serotonin was significantly 1.98 fold lower in febrile compared to convalescence phase, and significantly 1.76 fold lower compared to DF in the febrile phase of illness. Thus, serotonin alone provided good prognostic utility (Area Under Curve, AUC of serotonin = 0.8). Additionally, immune mediators associated with DHF may further increase the predictive ability than just serotonin alone. Nine cytokines, including IFN-γ, IL-1β, IL-4, IL-8, G-CSF, MIP-1β, FGF basic, TNFα and RANTES were significantly different between DF and DHF, among which IFN-γ ranked top by multivariate statistics. Combining serotonin and IFN-γ improved the prognosis performance (AUC = 0.92, sensitivity = 77.8%, specificity = 95.8%), suggesting this duplex panel as accurate metrics for the early prognosis of DHF. PMID:27055163

  20. Hypoxia-inducible factor-2α (HIF-2α), but not HIF-1α, is essential for hypoxic induction of class III β-tubulin expression in human glioblastoma cells.

    Science.gov (United States)

    Bordji, Karim; Grandval, Alexandra; Cuhna-Alves, Leilane; Lechapt-Zalcman, Emmanuèle; Bernaudin, Myriam

    2014-12-01

    Glioblastoma multiforme (GBM) is the deadliest form of primary brain cancer. Several reports have indicated aberrant levels of βIII-tubulin (βIII-t) in human GBM. βIII-t overexpression was linked to increasing malignancy in glial tumors and described to determine the onset of resistance to chemotherapy. Furthermore, a linkage was suggested between the induction of βIII-t expression and hypoxia, a hallmark of GBM. We investigated the role of hypoxia-inducible factor (HIF)-1α and HIF-2α in the regulation of the βIII-t gene (TUBB3) in GBM cells cultured in either normoxia or hypoxia. We report for the first time that HIF-2α, but not HIF-1α, is involved in hypoxia-induced βIII-t expression in GBM cells. By gene-reporter experiments and site-directed mutagenesis, we found that two overlapping hypoxia response elements located in the 3' UTR of the gene were involved in the activation of TUBB3. This occurred through an enhanced binding of HIF-2α to the 3' region, as revealed by an electrophoretic mobility shift assay. Conversely, the promoter of TUBB3 was shown to be inactive. In addition, we observed that HIF-1α exhibits a repressive effect on βIII-t expression in cells cultured in normoxia. These results show that both HIF-α isoforms have opposing effects on βIII-t expression in GBM cells. Finally, we observed that hypoxia-induced βIII-t expression is well correlated with the kinetics of HIF-2α protein stabilization. The evidence for a direct linkage between HIF-2α and increased expression of βIII-t by hypoxia suggests that an anti-HIF-2α strategy (i.e. by downregulating βIII-t) could be of potential interest for improving the treatment of GBM. © 2014 FEBS.

  1. Ten-year review reveals changing trends and severity of allergic reactions to nuts and other foods.

    Science.gov (United States)

    Johnson, Jennifer; Malinovschi, Andrei; Alving, Kjell; Lidholm, Jonas; Borres, Magnus P; Nordvall, Lennart

    2014-08-01

    Over the past few decades, the incidence of food allergies has risen and Sweden has increased its import of peanuts and exotic nuts, such as cashew nuts, which may cause severe allergic reactions. This study aimed to retrospectively investigate paediatric emergency visits due to food reactions over a 10-year period, focusing on reactions to peanuts and tree nuts. Emergency visits to Uppsala University Children's Hospital, Sweden, between September 2001 and December 2010, were reviewed, and cases containing diagnostic codes for anaphylaxis, allergic reactions or allergy and hypersensitivity not caused by drugs or biological substances were retrieved. We analysed 703 emergency visits made by 578 individuals with food allergies. Peanuts and tree nuts accounted for 50% of the food allergies and were more frequently associated with adrenaline treatment and hospitalisation than other foods. Cashew nut reactions increased over the study period, and together with peanuts, they were responsible for more anaphylactic reactions than hazelnuts. Peanut and tree nut reactions were more likely to result in adrenaline treatment and hospitalisation than other food reactions. Peanut and cashew nut reactions were more likely to cause anaphylaxis than hazelnuts. Cashew nut reactions increased during the study period. ©2014 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

  2. Physiological determinants of human acute hypoxia tolerance.

    Science.gov (United States)

    2013-11-01

    AbstractIntroduction. We investigated possible physiological determinants of variability in hypoxia tolerance in subjects given a 5-minute normobaric exposure to 25,000 ft equivalent. Physiological tolerance to hypoxia was defined as the magnitude of...

  3. Gene Expression Programs in Response to Hypoxia: Cell Type Specificity and Prognostic Significance in Human Cancers.

    Directory of Open Access Journals (Sweden)

    2006-01-01

    Full Text Available BACKGROUND: Inadequate oxygen (hypoxia triggers a multifaceted cellular response that has important roles in normal physiology and in many human diseases. A transcription factor, hypoxia-inducible factor (HIF, plays a central role in the hypoxia response; its activity is regulated by the oxygen-dependent degradation of the HIF-1alpha protein. Despite the ubiquity and importance of hypoxia responses, little is known about the variation in the global transcriptional response to hypoxia among different cell types or how this variation might relate to tissue- and cell-specific diseases. METHODS AND FINDINGS: We analyzed the temporal changes in global transcript levels in response to hypoxia in primary renal proximal tubule epithelial cells, breast epithelial cells, smooth muscle cells, and endothelial cells with DNA microarrays. The extent of the transcriptional response to hypoxia was greatest in the renal tubule cells. This heightened response was associated with a uniquely high level of HIF-1alpha RNA in renal cells, and it could be diminished by reducing HIF-1alpha expression via RNA interference. A gene-expression signature of the hypoxia response, derived from our studies of cultured mammary and renal tubular epithelial cells, showed coordinated variation in several human cancers, and was a strong predictor of clinical outcomes in breast and ovarian cancers. In an analysis of a large, published gene-expression dataset from breast cancers, we found that the prognostic information in the hypoxia signature was virtually independent of that provided by the previously reported wound signature and more predictive of outcomes than any of the clinical parameters in current use. CONCLUSIONS: The transcriptional response to hypoxia varies among human cells. Some of this variation is traceable to variation in expression of the HIF1A gene. A gene-expression signature of the cellular response to hypoxia is associated with a significantly poorer prognosis

  4. A Special Extract of Bacopa monnieri (CDRI-08-Restored Memory in CoCl2-Hypoxia Mimetic Mice Is Associated with Upregulation of Fmr-1 Gene Expression in Hippocampus

    Directory of Open Access Journals (Sweden)

    Anupama Rani

    2015-01-01

    Full Text Available Fragile X mental retardation protein (FMRP is a neuronal translational repressor and has been implicated in learning, memory, and cognition. However, the role of Bacopa monnieri extract (CDRI-08 in enhancing cognitive abilities in hypoxia-induced memory impairment via Fmr-1 gene expression is not known. Here, we have studied effects of CDRI-08 on the expression of Fmr-1 gene in the hippocampus of well validated cobalt chloride (CoCl2-induced hypoxia mimetic mice and analyzed the data with alterations in spatial memory. Results obtained from Morris water maze test suggest that CoCl2 treatment causes severe loss of spatial memory and CDRI-08 is capable of reversing it towards that in the normal control mice. Our semiquantitative RT-PCR, Western blot, and immunofluorescence microscopic data reveal that CoCl2-induced hypoxia significantly upregulates the expression of Hif-1α and downregulates the Fmr-1 expression in the hippocampus, respectively. Further, CDRI-08 administration reverses the memory loss and this is correlated with significant downregulation of Hif-1α and upregulation of Fmr-1 expression. Our data are novel and may provide mechanisms of hypoxia-induced impairments in the spatial memory and action of CDRI-08 in the recovery of hypoxia led memory impairment involving Fmr-1 gene encoded protein called FMRP.

  5. Hypoxia-Induced Autophagy Is Mediated through Hypoxia-Inducible Factor Induction of BNIP3 and BNIP3L via Their BH3 Domains▿ †

    OpenAIRE

    Bellot, Grégory; Garcia-Medina, Raquel; Gounon, Pierre; Chiche, Johanna; Roux, Danièle; Pouysségur, Jacques; Mazure, Nathalie M.

    2009-01-01

    While hypoxia-inducible factor (HIF) is a major actor in the cell survival response to hypoxia, HIF also is associated with cell death. Several studies implicate the HIF-induced putative BH3-only proapoptotic genes bnip3 and bnip3l in hypoxia-mediated cell death. We, like others, do not support this assertion. Here, we clearly demonstrate that the hypoxic microenvironment contributes to survival rather than cell death by inducing autophagy. The ablation of Beclin1, a major actor of autophagy,...

  6. In Vivo Imaging of Retinal Hypoxia in a Model of Oxygen-Induced Retinopathy.

    Science.gov (United States)

    Uddin, Md Imam; Evans, Stephanie M; Craft, Jason R; Capozzi, Megan E; McCollum, Gary W; Yang, Rong; Marnett, Lawrence J; Uddin, Md Jashim; Jayagopal, Ashwath; Penn, John S

    2016-08-05

    Ischemia-induced hypoxia elicits retinal neovascularization and is a major component of several blinding retinopathies such as retinopathy of prematurity (ROP), diabetic retinopathy (DR) and retinal vein occlusion (RVO). Currently, noninvasive imaging techniques capable of detecting and monitoring retinal hypoxia in living systems do not exist. Such techniques would greatly clarify the role of hypoxia in experimental and human retinal neovascular pathogenesis. In this study, we developed and characterized HYPOX-4, a fluorescence-imaging probe capable of detecting retinal-hypoxia in living animals. HYPOX-4 dependent in vivo and ex vivo imaging of hypoxia was tested in a mouse model of oxygen-induced retinopathy (OIR). Predicted patterns of retinal hypoxia were imaged by HYPOX-4 dependent fluorescence activity in this animal model. In retinal cells and mouse retinal tissue, pimonidazole-adduct immunostaining confirmed the hypoxia selectivity of HYPOX-4. HYPOX-4 had no effect on retinal cell proliferation as indicated by BrdU assay and exhibited no acute toxicity in retinal tissue as indicated by TUNEL assay and electroretinography (ERG) analysis. Therefore, HYPOX-4 could potentially serve as the basis for in vivo fluorescence-based hypoxia-imaging techniques, providing a tool for investigators to understand the pathogenesis of ischemic retinopathies and for physicians to address unmet clinical needs.

  7. The effect of hypobaric hypoxia on multichannel EEG signal complexity.

    Science.gov (United States)

    Papadelis, Christos; Kourtidou-Papadeli, Chrysoula; Bamidis, Panagiotis D; Maglaveras, Nikos; Pappas, Konstantinos

    2007-01-01

    The objective of this study was the development and evaluation of nonlinear electroencephalography parameters which assess hypoxia-induced EEG alterations, and describe the temporal characteristics of different hypoxic levels' residual effect upon the brain electrical activity. Multichannel EEG, pO2, pCO2, ECG, and respiration measurements were recorded from 10 subjects exposed to three experimental conditions (100% oxygen, hypoxia, recovery) at three-levels of reduced barometric pressure. The mean spectral power of EEG under each session and altitude were estimated for the standard bands. Approximate Entropy (ApEn) of EEG segments was calculated, and the ApEn's time-courses were smoothed by a moving average filter. On the smoothed diagrams, parameters were defined. A significant increase in total power and power of theta and alpha bands was observed during hypoxia. Visual interpretation of ApEn time-courses revealed a characteristic pattern (decreasing during hypoxia and recovering after oxygen re-administration). The introduced qEEG parameters S1 and K1 distinguished successfully the three hypoxic conditions. The introduced parameters based on ApEn time-courses are assessing reliably and effectively the different hypoxic levels. ApEn decrease may be explained by neurons' functional isolation due to hypoxia since decreased complexity corresponds to greater autonomy of components, although this interpretation should be further supported by electrocorticographic animal studies. The introduced qEEG parameters seem to be appropriate for assessing the hypoxia-related neurophysiological state of patients in the hyperbaric chambers in the treatment of decompression sickness, carbon dioxide poisoning, and mountaineering.

  8. Placental Hypoxia During Early Pregnancy Causes Maternal Hypertension and Placental Insufficiency in the Hypoxic Guinea Pig Model.

    Science.gov (United States)

    Thompson, Loren P; Pence, Laramie; Pinkas, Gerald; Song, Hong; Telugu, Bhanu P

    2016-12-01

    Chronic placental hypoxia is one of the root causes of placental insufficiencies that result in pre-eclampsia and maternal hypertension. Chronic hypoxia causes disruption of trophoblast (TB) development, invasion into maternal decidua, and remodeling of maternal spiral arteries. The pregnant guinea pig shares several characteristics with humans such as hemomonochorial placenta, villous subplacenta, deep TB invasion, and remodeling of maternal arteries, and is an ideal animal model to study placental development. We hypothesized that chronic placental hypoxia of the pregnant guinea pig inhibits TB invasion and alters spiral artery remodeling. Time-mated pregnant guinea pigs were exposed to either normoxia (NMX) or three levels of hypoxia (HPX: 16%, 12%, or 10.5% O 2 ) from 20 day gestation until midterm (39-40 days) or term (60-65 days). At term, HPX (10.5% O 2 ) increased maternal arterial blood pressure (HPX 57.9 ± 2.3 vs. NMX 40.4 ± 2.3, P < 0.001), decreased fetal weight by 16.1% (P < 0.05), and increased both absolute and relative placenta weights by 10.1% and 31.8%, respectively (P < 0.05). At midterm, there was a significant increase in TB proliferation in HPX placentas as confirmed by increased PCNA and KRT7 staining and elevated ESX1 (TB marker) gene expression (P < 0.05). Additionally, quantitative image analysis revealed decreased invasion of maternal blood vessels by TB cells. In summary, this animal model of placental HPX identifies several aspects of abnormal placental development, including increased TB proliferation and decreased migration and invasion of TBs into the spiral arteries, the consequences of which are associated with maternal hypertension and fetal growth restriction. © 2016 by the Society for the Study of Reproduction, Inc.

  9. Hypoxia-targeting antitumor prodrugs and photosensitizers

    International Nuclear Information System (INIS)

    Zhang Zhouen; Nishimoto, S.I.

    2006-01-01

    Tumor hypoxia has been identified as a key subject for tumor therapy, since hypoxic tumor cells show resistance to treatment of tumor tissues by radiotherapy, chemotherapy and phototherapy. For improvement of tumor radiotherapy, we have proposed a series of radiation-activated prodrugs that could selectively release antitumor agent 5-fluorouracil or 5-fluorodeoxyuridine under hypoxic conditions. Recently, we attempted to develop two families of novel hypoxia-targeting antitumor agents, considering that tumor-hypoxic environment is favorable to biological and photochemical reductions. The first family of prodrugs was derived from camptothecin as a potent topoisomerase I inhibitor and several bioreductive motifs. These prodrugs could be activated by NADPH-cytochrome P450 reductase or DT-diaphorase to release free camptothecin, and thereby showed hypoxia-selective cytotoxictiy towards tumor cells. These prodrugs were also applicable to the real-time monitoring of activation and antitumor effect by fluorometry. Furthermore, the camptothecin-bioreductive motif conjugates was confirmed to show an oxygen-independent DAN photocleaving activity, which could overcome a drawback of back electron transfer occurring in the photosensitized one-electron oxidation of DNA. Thus, these camptothecin derivatives could be useful to both chemotherapy and phototherapy for hypoxic tumor cells. The second family of prodrugs harnessed UV light for cancer therapy, incorporating the antitumor agent 5-fluorourcil and the photolabile 2-nitrobenzyl chromophores. The attachment of a tumor-homing cyclic peptide CNGRC was also employed to construct the prototype of tumor-targeting photoactiaved antitumor prodrug. These novel prodrugs released high yield of 5-fluorourcil upon UV irradiation at λ ex =365 nm, while being quite stable in the dark. The photoactivation mechanism was also clarified by means of nanosecond laser flash photolysis. (authors)

  10. Transcriptome analysis of the spalax hypoxia survival response includes suppression of apoptosis and tight control of angiogenesis

    Directory of Open Access Journals (Sweden)

    Malik Assaf

    2012-11-01

    Full Text Available Abstract Background The development of complex responses to hypoxia has played a key role in the evolution of mammals, as inadequate response to this condition is frequently associated with cardiovascular diseases, developmental disorders, and cancers. Though numerous studies have used mice and rats in order to explore mechanisms that contribute to hypoxia tolerance, these studies are limited due to the high sensitivity of most rodents to severe hypoxia. The blind subterranean mole rat Spalax is a hypoxia tolerant rodent, which exhibits unique longevity and therefore has invaluable potential in hypoxia and cancer research. Results Using microarrays, transcript abundance was measured in brain and muscle tissues from Spalax and rat individuals exposed to acute and chronic hypoxia for varying durations. We found that Spalax global gene expression response to hypoxia differs from that of rat and is characterized by the activation of functional groups of genes that have not been strongly associated with the response to hypoxia in hypoxia sensitive mammals. Using functional enrichment analysis of Spalax hypoxia induced genes we found highly significant overrepresentation of groups of genes involved in anti apoptosis, cancer, embryonic/sexual development, epidermal growth factor receptor binding, coordinated suppression and activation of distinct groups of transcription factors and membrane receptors, in addition to angiogenic related processes. We also detected hypoxia induced increases of different critical Spalax hub gene transcripts, including antiangiogenic genes associated with cancer tolerance in Down syndrome human individuals. Conclusions This is the most comprehensive study of Spalax large scale gene expression response to hypoxia to date, and the first to use custom Spalax microarrays. Our work presents novel patterns that may underlie mechanisms with critical importance to the evolution of hypoxia tolerance, with special relevance to

  11. Multiple roles of hypoxia in ovarian function: roles of hypoxia-inducible factor-related and -unrelated signals during the luteal phase

    OpenAIRE

    Nishimura, Ryo; Okuda, Kiyoshi

    2015-01-01

    There is increasing interest in the role of oxygen conditions in the microenvironment of organs because of the discovery of a hypoxia-specific transcription factor, namely hypoxia-inducible factor (HIF) 1. Ovarian function has several phases that change day by day, including ovulation, follicular growth and corpus luteum formation and regression. These phases are regulated by many factors, including pituitary hormones and local hormones, such as steroids, peptides and cytokines, as well as ox...

  12. Decreased "ineffective erythropoiesis" preserves polycythemia in mice under long-term hypoxia.

    Science.gov (United States)

    Harada, Tomonori; Tsuboi, Isao; Hirabayashi, Yukio; Kosaku, Kazuhiro; Naito, Michiko; Hara, Hiroyuki; Inoue, Tohru; Aizawa, Shin

    2015-05-01

    Hypoxia induces innumerable changes in humans and other animals, including an increase in peripheral red blood cells (polycythemia) caused by the activation of erythropoiesis mediated by increased erythropoietin (EPO) production. However, the elevation of EPO is limited and levels return to normal ranges under normoxia within 5-7 days of exposure to hypoxia, whereas polycythemia continues for as long as hypoxia persists. We investigated erythropoiesis in bone marrow and spleens from mouse models of long-term normobaric hypoxia (10 % O2) to clarify the mechanism of prolonged polycythemia in chronic hypoxia. The numbers of erythroid colony-forming units (CFU-E) in the spleen remarkably increased along with elevated serum EPO levels indicating the activation of erythropoiesis during the first 7 days of hypoxia. After 14 days of hypoxia, the numbers of CFU-E returned to normoxic levels, whereas polycythemia persisted for >140 days. Flow cytometry revealed a prolonged increase in the numbers of TER119-positive cells (erythroid cells derived from pro-erythroblasts through mature erythrocyte stages), especially the TER119 (high) CD71 (high) population, in bone marrow. The numbers of annexin-V-positive cells among the TER119-positive cells particularly declined under chronic hypoxia, suggesting that the numbers of apoptotic cells decrease during erythroid cell maturation. Furthermore, RT-PCR analysis showed that the RNA expression of BMP-4 and stem cell factor that reduces apoptotic changes during erythroid cell proliferation and maturation was increased in bone marrow under hypoxia. These findings indicated that decreased apoptosis of erythroid cells during erythropoiesis contributes to polycythemia in mice during chronic exposure to long-term hypoxia.

  13. Neuroprotective effect of peroxiredoxin 6 against hypoxia-induced retinal ganglion cell damage

    Directory of Open Access Journals (Sweden)

    Kumar Anil

    2010-10-01

    Full Text Available Abstract Background The ability to respond to changes in the extra-intracellular environment is prerequisite for cell survival. Cellular responses to the environment include elevating defense systems, such as the antioxidant defense system. Hypoxia-evoked reactive oxygen species (ROS-driven oxidative stress is an underlying mechanism of retinal ganglion cell (RGC death that leads to blinding disorders. The protein peroxiredoxin 6 (PRDX6 plays a pleiotropic role in negatively regulating death signaling in response to stressors, and thereby stabilizes cellular homeostasis. Results We have shown that RGCs exposed to hypoxia (1% or hypoxia mimetic cobalt chloride display reduced expression of PRDX6 with higher ROS expression and activation of NF-κB. These cells undergo apoptosis, while cells with over-expression of PRDX6 demonstrate resistance against hypoxia-driven RGC death. The RGCs exposed to hypoxia either with 1% oxygen or cobalt chloride (0-400 μM, revealed ~30%-70% apoptotic cell death after 48 and 72 h of exposure. Western analysis and real-time PCR showed elevated expression of PRDX6 during hypoxia at 24 h, while PRDX6 protein and mRNA expression declined from 48 h onwards following hypoxia exposure. Concomitant with this, RGCs showed increased ROS expression and activation of NF-κB with IkB phosphorylation/degradation, as examined with H2DCF-DA and transactivation assays. These hypoxia-induced adverse reactions could be reversed by over-expression of PRDX6. Conclusion Because an abundance of PRDX6 in cells was able to attenuate hypoxia-induced RGC death, the protein could possibly be developed as a novel therapeutic agent acting to postpone RGC injury and delay the progression of glaucoma and other disorders caused by the increased-ROS-generated death signaling related to hypoxia.

  14. Hypoxia Impacts on Food Web Linkages in a Pelagic Ecosystem

    Science.gov (United States)

    Sato, M.; Horne, J. K.; Parker-Stetter, S. L.; Essington, T.; Keister, J. E.; Moriarty, P.; Li, L.

    2016-02-01

    Low dissolved oxygen (DO), or hypoxia, causes significant disturbances on aquatic organisms, but the consequences for key food web linkages is not well understood. Here, we tested how the intensity of low DO events governs the degree of spatial overlap between pelagic zooplanktivorous fish and their zooplankton prey, fish feeding rates, and community compositions of zooplankton. We hypothesized that the greater sensitivity of fish to DO compared to zooplankton would lead to diminished spatial overlap at moderate DO and reduced feeding rates of fish, while severe hypoxia would amplify spatial overlap by preventing zooplankton from using deep refuge habitats leading to increased fish feeding rates. We also hypothesized shifts in zooplankton community composition towards less energetically profitable taxa such as small copepods and gelatinous species. We used a combination of multifrequency acoustic and net sampling for detecting distributions and abundance of zooplankton and pelagic fish in Hood Canal, WA, a seasonally hypoxic fjord. We employed a sampling design which paired hypoxic regions of Hood Canal with normoxic regions sampled prior to, during, and after the onset of hypoxia in two years. Contrary to our hypotheses, we found that fish and zooplankton did not change their horizontal and vertical distributions during periods and in locations with low DO levels. Consequently, the vertical overlap between fish and zooplankton did not change with DO. Fish feeding rates and the dominant zooplankton prey did not change with hypoxia events. The apparent resilience of fish to low DO in our system may be explained by decreased metabolic oxygen demand due to cool temperatures, increased availability and accessibility to their prey in low DO waters, or potential increase in predation risk at shallower depth. This study highlights the importance of both temperature and DO, instead of hypoxia threshold alone, in evaluating the impacts of hypoxia on pelagic communities.

  15. Plasma volume in acute hypoxia

    DEFF Research Database (Denmark)

    Poulsen, T D; Klausen, T; Richalet, J P

    1998-01-01

    Exposure to acute hypoxia is associated with changes in body fluid homeostasis and plasma volume (PV). This study compared a dye dilution technique using Evans' blue (PV[Evans']) with a carbon monoxide (CO) rebreathing method (PV[CO]) for measurements of PV in ten normal subjects at sea level...

  16. Preeclampsia, Hypoxia, Thrombosis, and Inflammation

    Directory of Open Access Journals (Sweden)

    Amir A. Shamshirsaz

    2012-01-01

    Full Text Available Reductions in uteroplacental flow initiate a cascade of molecular effects leading to hypoxia, thrombosis, inflammation, and endothelial cell dysfunction resulting in untoward pregnancy outcomes. In this review, we detail these effects and their relationship to preeclampsia (PE and intrauterine growth restriction (IUGR.

  17. Hepcidin: A Critical Regulator Of Iron Metabolism During Hypoxia

    Science.gov (United States)

    2011-01-01

    inducible factor (HIF)/hypoxia response element ( HRE ) system, as well as recent evidence indicating that localized adipose hypoxia due to obesity may...mechanisms by which hypoxia affects hepcidin expression, to include a review of the hypoxia inducible factor (HIF)/hypoxia response element ( HRE ) system, as...a battery of genes are induced by the hypoxia inducible factor (HIF)/hypoxia response element ( HRE ) system. The HIF system senses O2 levels through

  18. Hypoxia promotes apoptosis of neuronal cells through hypoxia-inducible factor-1α-microRNA-204-B-cell lymphoma-2 pathway.

    Science.gov (United States)

    Wang, Xiuwen; Li, Ji; Wu, Dongjin; Bu, Xiangpeng; Qiao, Yong

    2016-01-01

    Neuronal cells are highly sensitive to hypoxia and may be subjected to apoptosis when exposed to hypoxia. Several apoptosis-related genes and miRNAs involve in hypoxia-induced apoptosis. This study aimed to examine the role of HIF1α-miR-204-BCL-2 pathway in hypoxia-induced apoptosis in neuronal cells. Annexin V/propidium iodide assay was performed to analyze cell apoptosis in AGE1.HN and PC12 cells under hypoxic or normoxic conditions. The expression of BCL-2 and miR-204 were determined by Western blot and qRT-PCR. The effects of miR-204 overexpression or knockdown on the expression of BCL-2 were evaluated by luciferase assay and Western blot under hypoxic or normoxic conditions. HIF-1α inhibitor YC-1 and siHIF-1α were employed to determine the effect of HIF-1α on the up-regulation of miR-204 and down-regulation of BCL-2 induced by hypoxia. Apoptosis assay showed the presence of apoptosis induced by hypoxia in neuronal cells. Moreover, we found that hypoxia significantly down-regulated the expression of BCL-2, and increased the mRNA level of miR-204 in neuronal cells than that in control. Bioinformatic analysis and luciferase reporter assay demonstrated that miR-204 directly targeted and regulated the expression of BCL-2. Specifically, the expression of BCL-2 was inhibited by miR-204 mimic and enhanced by miR-204 inhibitor. Furthermore, we detected that hypoxia induced cell apoptosis via HIF-1α/miR-204/BCL-2 in neuronal cells. This study demonstrated that HIF-1α-miR-204-BCL-2 pathway contributed to apoptosis of neuronal cells induced by hypoxia, which could potentially be exploited to prevent spinal cord ischemia-reperfusion injury. © 2015 by the Society for Experimental Biology and Medicine.

  19. Hypoxia-induced retinal neovascularization in zebrafish embryos: a potential model of retinopathy of prematurity.

    Science.gov (United States)

    Wu, Yu-Ching; Chang, Chao-Yuan; Kao, Alex; Hsi, Brian; Lee, Shwu-Huey; Chen, Yau-Hung; Wang, I-Jong

    2015-01-01

    Retinopathy of prematurity, formerly known as a retrolental fibroplasia, is a leading cause of infantile blindness worldwide. Retinopathy of prematurity is caused by the failure of central retinal vessels to reach the retinal periphery, creating a nonperfused peripheral retina, resulting in retinal hypoxia, neovascularization, vitreous hemorrhage, vitreoretinal fibrosis, and loss of vision. We established a potential retinopathy of prematurity model by using a green fluorescent vascular endothelium zebrafish transgenic line treated with cobalt chloride (a hypoxia-inducing agent), followed by GS4012 (a vascular endothelial growth factor inducer) at 24 hours postfertilization, and observed that the number of vascular branches and sprouts significantly increased in the central retinal vascular trunks 2-4 days after treatment. We created an angiography method by using tetramethylrhodamine dextran, which exhibited severe vascular leakage through the vessel wall into the surrounding retinal tissues. The quantification of mRNA extracted from the heads of the larvae by using real-time quantitative polymerase chain reaction revealed a twofold increase in vegfaa and vegfr2 expression compared with the control group, indicating increased vascular endothelial growth factor signaling in the hypoxic condition. In addition, we demonstrated that the hypoxic insult could be effectively rescued by several antivascular endothelial growth factor agents such as SU5416, bevacizumab, and ranibizumab. In conclusion, we provide a simple, highly reproducible, and clinically relevant retinopathy of prematurity model based on zebrafish embryos; this model may serve as a useful platform for clarifying the mechanisms of human retinopathy of prematurity and its progression.

  20. Transcriptomic and proteomic analyses of the Aspergillus fumigatus hypoxia response using an oxygen-controlled fermenter

    Directory of Open Access Journals (Sweden)

    Barker Bridget M

    2012-02-01

    Full Text Available Abstract Background Aspergillus fumigatus is a mold responsible for the majority of cases of aspergillosis in humans. To survive in the human body, A. fumigatus must adapt to microenvironments that are often characterized by low nutrient and oxygen availability. Recent research suggests that the ability of A. fumigatus and other pathogenic fungi to adapt to hypoxia contributes to their virulence. However, molecular mechanisms of A. fumigatus hypoxia adaptation are poorly understood. Thus, to better understand how A. fumigatus adapts to hypoxic microenvironments found in vivo during human fungal pathogenesis, the dynamic changes of the fungal transcriptome and proteome in hypoxia were investigated over a period of 24 hours utilizing an oxygen-controlled fermenter system. Results Significant increases in transcripts associated with iron and sterol metabolism, the cell wall, the GABA shunt, and transcriptional regulators were observed in response to hypoxia. A concomitant reduction in transcripts was observed with ribosome and terpenoid backbone biosynthesis, TCA cycle, amino acid metabolism and RNA degradation. Analysis of changes in transcription factor mRNA abundance shows that hypoxia induces significant positive and negative changes that may be important for regulating the hypoxia response in this pathogenic mold. Growth in hypoxia resulted in changes in the protein levels of several glycolytic enzymes, but these changes were not always reflected by the corresponding transcriptional profiling data. However, a good correlation overall (R2 = 0.2, p A. fumigatus. Conclusions Taken together, our data suggest a robust cellular response that is likely regulated both at the transcriptional and post-transcriptional level in response to hypoxia by the human pathogenic mold A. fumigatus. As with other pathogenic fungi, the induction of glycolysis and transcriptional down-regulation of the TCA cycle and oxidative phosphorylation appear to major

  1. cGMP-Phosphodiesterase Inhibition Prevents Hypoxia-Induced Cell Death Activation in Porcine Retinal Explants.

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    Lorena Olivares-González

    Full Text Available Retinal hypoxia and oxidative stress are involved in several retinal degenerations including diabetic retinopathy, glaucoma, central retinal artery occlusion, or retinopathy of prematurity. The second messenger cyclic guanosine monophosphate (cGMP has been reported to be protective for neuronal cells under several pathological conditions including ischemia/hypoxia. The purpose of this study was to evaluate whether the accumulation of cGMP through the pharmacological inhibition of phosphodiesterase (PDE with Zaprinast prevented retinal degeneration induced by mild hypoxia in cultures of porcine retina. Exposure to mild hypoxia (5% O2 for 24h reduced cGMP content and induced retinal degeneration by caspase dependent and independent (PARP activation mechanisms. Hypoxia also produced a redox imbalance reducing antioxidant response (superoxide dismutase and catalase activities and increasing superoxide free radical release. Zaprinast reduced mild hypoxia-induced cell death through inhibition of caspase-3 or PARP activation depending on the cell layer. PDE inhibition also ameliorated the effects of mild hypoxia on antioxidant response and the release of superoxide radical in the photoreceptor layer. The use of a PKG inhibitor, KT5823, suggested that cGMP-PKG pathway is involved in cell survival and antioxidant response. The inhibition of PDE, therefore, could be useful for reducing retinal degeneration under hypoxic/ischemic conditions.

  2. Correlation between the organism response to acute hypoxia and individual radiosensitivity of rats

    International Nuclear Information System (INIS)

    Grigor'ev, A.Yu.; Silin, D.Ya.

    1988-01-01

    A study was made of a correlation between the response of basal metabolism to acute hypoxia and the life span of rats after irradiation resulting in the development of a cerebral form of radiation sickness. The more radiosensitive animals consumed a larger amount of oxygen, exhaled a smaller amount of carbon dioxide and showd an increased normal expiratory exchange per minute. After the effect of acure hypoxia all the indices under study revealed an opposite picture

  3. The prognostic value of temporal in vitro and in vivo derived hypoxia gene-expression signatures in breast cancer

    International Nuclear Information System (INIS)

    Starmans, Maud H.W.; Chu, Kenneth C.; Haider, Syed; Nguyen, Francis; Seigneuric, Renaud; Magagnin, Michael G.; Koritzinsky, Marianne; Kasprzyk, Arek; Boutros, Paul C.; Wouters, Bradly G.

    2012-01-01

    Background and purpose: Recent data suggest that in vitro and in vivo derived hypoxia gene-expression signatures have prognostic power in breast and possibly other cancers. However, both tumour hypoxia and the biological adaptation to this stress are highly dynamic. Assessment of time-dependent gene-expression changes in response to hypoxia may thus provide additional biological insights and assist in predicting the impact of hypoxia on patient prognosis. Materials and methods: Transcriptome profiling was performed for three cell lines derived from diverse tumour-types after hypoxic exposure at eight time-points, which include a normoxic time-point. Time-dependent sets of co-regulated genes were identified from these data. Subsequently, gene ontology (GO) and pathway analyses were performed. The prognostic power of these novel signatures was assessed in parallel with previous in vitro and in vivo derived hypoxia signatures in a large breast cancer microarray meta-dataset (n = 2312). Results: We identified seven recurrent temporal and two general hypoxia signatures. GO and pathway analyses revealed regulation of both common and unique underlying biological processes within these signatures. None of the new or previously published in vitro signatures consisting of hypoxia-induced genes were prognostic in the large breast cancer dataset. In contrast, signatures of repressed genes, as well as the in vivo derived signatures of hypoxia-induced genes showed clear prognostic power. Conclusions: Only a subset of hypoxia-induced genes in vitro demonstrates prognostic value when evaluated in a large clinical dataset. Despite clear evidence of temporal patterns of gene-expression in vitro, the subset of prognostic hypoxia regulated genes cannot be identified based on temporal pattern alone. In vivo derived signatures appear to identify the prognostic hypoxia induced genes. The prognostic value of hypoxia-repressed genes is likely a surrogate for the known importance of

  4. Metabolic depression and the evolution of hypoxia tolerance in threespine stickleback, Gasterosteus aculeatus.

    Science.gov (United States)

    Regan, Matthew D; Gill, Ivan S; Richards, Jeffrey G

    2017-11-01

    Anthropogenic increases in global temperature and agricultural runoff are increasing the prevalence of aquatic hypoxia throughout the world. We investigated the potential for a relatively rapid evolution of hypoxia tolerance using two isolated (for less than 11 000 years) populations of threespine stickleback: one from a lake that experiences long-term hypoxia (Alta Lake, British Columbia) and one from a lake that does not (Trout Lake, British Columbia). Loss-of-equilibrium (LOE) experiments revealed that the Alta Lake stickleback were significantly more tolerant of hypoxia than the Trout Lake stickleback, and calorimetry experiments revealed that the enhanced tolerance of Alta Lake stickleback may be associated with their ability to depress metabolic rate (as indicated by metabolic heat production) by 33% in hypoxia. The two populations showed little variation in their capacities for O 2 extraction and anaerobic metabolism. These results reveal that intraspecific variation in hypoxia tolerance can develop over relatively short geological timescales, as can metabolic rate depression, a complex biochemical response that may be favoured in long-term hypoxic environments. © 2017 The Author(s).

  5. The zebrafish miR-125c is induced under hypoxic stress via hypoxia-inducible factor 1α and functions in cellular adaptations and embryogenesis.

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    He, Yan; Huang, Chun-Xiao; Chen, Nan; Wu, Meng; Huang, Yan; Liu, Hong; Tang, Rong; Wang, Wei-Min; Wang, Huan-Ling

    2017-09-26

    Hypoxia is a unique environmental stress. Hypoxia inducible factor-lα (HIF-lα) is a major transcriptional regulator of cellular adaptations to hypoxic stress. MicroRNAs (miRNAs) as posttranscriptional gene expression regulators occupy a crucial role in cell survival under low-oxygen environment. Previous evidences suggested that miR-125c is involved in hypoxia adaptation, but its precise biological roles and the regulatory mechanism underlying hypoxic responses remain unknown. The present study showed that zebrafish miR-125c is upregulated by hypoxia in a Hif-lα-mediated manner in vitro and in vivo . Dual-luciferase assay revealed that cdc25a is a novel target of miR-125c. An inverse correlation between miR-125c and cdc25a was further confirmed in vivo , suggesting miR-125c as a crucial physiological inhibitor of cdc25a which responds to cellular hypoxia. Overexpression of miR-125c suppressed cell proliferation, led to cell cycle arrest at the G1 phase in ZF4 cells and induced apoptotic responses during embryo development. More importantly, miR-125c overexpression resulted in severe malformation and reduction of motility during zebrafish embryonic development. Taken together, we conclude that miR-125c plays a pivotal role in cellular adaptations to hypoxic stress at least in part through the Hif-1α/miR-125c/cdc25a signaling and has great impact on zebrafish early embryonic development.

  6. Exercise Improves Mood State in Normobaric Hypoxia.

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    Seo, Yongsuk; Fennell, Curtis; Burns, Keith; Pollock, Brandon S; Gunstad, John; McDaniel, John; Glickman, Ellen

    2015-11-01

    The purpose of this study was to quantify the efficacy of using exercise to alleviate the impairments in mood state associated with hypoxic exposure. Nineteen young, healthy men completed Automated Neuropsychological Assessment Metrics-4(th) Edition (ANAM4) versions of the mood state test before hypoxia exposure, after 60 min of hypoxia exposure (12.5% O(2)), and during and after two intensities of cycling exercise (40% and 60% adjusted Vo(2max)) under the same hypoxic conditions. Peripheral oxygen saturation (Spo(2)) and regional cerebral oxygen saturation (rSo(2)) were continuously monitored. At rest in hypoxia, Total Mood Disturbance (TMD) was significantly increased compared to baseline in both the 40% and 60% groups. TMD was significantly decreased during exercise compared to rest in hypoxia. TMD was also significantly decreased during recovery compared to rest in hypoxia. Spo(2) significantly decreased at 60 min rest in hypoxia, during exercise, and recovery compared to baseline. Regional cerebral oxygen saturation was also reduced at 60 min rest in hypoxia, during exercise, and recovery compared to baseline. The current study demonstrated that exercise at 40% and 60% of adjusted Vo(2max) attenuated the adverse effects of hypoxia on mood. These findings may have significant applied value, as negative mood states are known to impair performance in hypoxia. Further studies are needed to replicate the current finding and to clarify the possible mechanisms associated with the potential benefits of exercise on mood state in normobaric hypoxia.

  7. Approximate Simulation of Acute Hypobaric Hypoxia with Normobaric Hypoxia

    Science.gov (United States)

    Conkin, J.; Wessel, J. H., III

    2011-01-01

    INTRODUCTION. Some manufacturers of reduced oxygen (O2) breathing devices claim a comparable hypobaric hypoxia (HH) training experience by providing F(sub I) O2 pO2) of the target altitude. METHODS. Literature from investigators and manufacturers indicate that these devices may not properly account for the 47 mmHg of water vapor partial pressure that reduces the inspired partial pressure of O2 (P(sub I) O2). Nor do they account for the complex reality of alveolar gas composition as defined by the Alveolar Gas Equation. In essence, by providing iso-pO2 conditions for normobaric hypoxia (NH) as for HH exposures the devices ignore P(sub A)O2 and P(sub A)CO2 as more direct agents to induce signs and symptoms of hypoxia during acute training exposures. RESULTS. There is not a sufficient integrated physiological understanding of the determinants of P(sub A)O2 and P(sub A)CO2 under acute NH and HH given the same hypoxic pO2 to claim a device that provides isohypoxia. Isohypoxia is defined as the same distribution of hypoxia signs and symptoms under any circumstances of equivalent hypoxic dose, and hypoxic pO2 is an incomplete hypoxic dose. Some devices that claim an equivalent HH experience under NH conditions significantly overestimate the HH condition, especially when simulating altitudes above 10,000 feet (3,048 m). CONCLUSIONS. At best, the claim should be that the devices provide an approximate HH experience since they only duplicate the ambient pO2 at sea level as at altitude (iso-pO2 machines). An approach to reduce the overestimation is to at least provide machines that create the same P(sub I)O2 (iso-P(sub I)O2 machines) conditions at sea level as at the target altitude, a simple software upgrade.

  8. Hypoxia regulates the expression of the neuromedin B receptor through a mechanism dependent on hypoxia-inducible factor-1α.

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    Hyun-Joo Park

    Full Text Available The neuromedin B receptor (NMB-R, a member of the mammalian bombesin receptor family, is frequently overexpressed in various tumors. In the present study, we found that exposure to hypoxic conditions increases the levels of NMBR mRNA and protein in breast cancer cells, which are tightly regulated by hypoxia-inducible factor-1α (HIF-1α. We confirmed the effect of HIF-1α on NMBR transcription by performing an NMBR promoter-driven reporter assay and then identified a functional hypoxia-responsive element (HRE in the human NMBR promoter region. Further, the binding of HIF-1α to the NMBR promoter was corroborated by electrophoretic mobility shift and chromatin immunoprecipitation assays, which showed that HIF-1α specifically and directly bound to the NMBR promoter in response to hypoxia. Immunohistochemical analysis of a xenograft and a human breast cancer tissue array revealed a significant correlation between NMB-R and HIF-1α expression. Taken together, our findings indicate that hypoxia induces NMB-R expression through a novel mechanism to regulate HIF-1α expression in breast cancer cells.

  9. Hypoxia-induced oxidative base modifications in the VEGF hypoxia-response element are associated with transcriptionally active nucleosomes.

    Science.gov (United States)

    Ruchko, Mykhaylo V; Gorodnya, Olena M; Pastukh, Viktor M; Swiger, Brad M; Middleton, Natavia S; Wilson, Glenn L; Gillespie, Mark N

    2009-02-01

    Reactive oxygen species (ROS) generated in hypoxic pulmonary artery endothelial cells cause transient oxidative base modifications in the hypoxia-response element (HRE) of the VEGF gene that bear a conspicuous relationship to induction of VEGF mRNA expression (K.A. Ziel et al., FASEB J. 19, 387-394, 2005). If such base modifications are indeed linked to transcriptional regulation, then they should be detected in HRE sequences associated with transcriptionally active nucleosomes. Southern blot analysis of the VEGF HRE associated with nucleosome fractions prepared by micrococcal nuclease digestion indicated that hypoxia redistributed some HRE sequences from multinucleosomes to transcriptionally active mono- and dinucleosome fractions. A simple PCR method revealed that VEGF HRE sequences harboring oxidative base modifications were found exclusively in mononucleosomes. Inhibition of hypoxia-induced ROS generation with myxathiozol prevented formation of oxidative base modifications but not the redistribution of HRE sequences into mono- and dinucleosome fractions. The histone deacetylase inhibitor trichostatin A caused retention of HRE sequences in compacted nucleosome fractions and prevented formation of oxidative base modifications. These findings suggest that the hypoxia-induced oxidant stress directed at the VEGF HRE requires the sequence to be repositioned into mononucleosomes and support the prospect that oxidative modifications in this sequence are an important step in transcriptional activation.

  10. Hypoxia signaling pathways: modulators of oxygen-related organelles

    Science.gov (United States)

    Schönenberger, Miriam J.; Kovacs, Werner J.

    2015-01-01

    Oxygen (O2) is an essential substrate in cellular metabolism, bioenergetics, and signaling and as such linked to the survival and normal function of all metazoans. Low O2 tension (hypoxia) is a fundamental feature of physiological processes as well as pathophysiological conditions such as cancer and ischemic diseases. Central to the molecular mechanisms underlying O2 homeostasis are the hypoxia-inducible factors-1 and -2 alpha (HIF-1α and EPAS1/HIF-2α) that function as master regulators of the adaptive response to hypoxia. HIF-induced genes promote characteristic tumor behaviors, including angiogenesis and metabolic reprogramming. The aim of this review is to critically explore current knowledge of how HIF-α signaling regulates the abundance and function of major O2-consuming organelles. Abundant evidence suggests key roles for HIF-1α in the regulation of mitochondrial homeostasis. An essential adaptation to sustained hypoxia is repression of mitochondrial respiration and induction of glycolysis. HIF-1α activates several genes that trigger mitophagy and represses regulators of mitochondrial biogenesis. Several lines of evidence point to a strong relationship between hypoxia, the accumulation of misfolded proteins in the endoplasmic reticulum, and activation of the unfolded protein response. Surprisingly, although peroxisomes depend highly on molecular O2 for their function, there has been no evidence linking HIF signaling to peroxisomes. We discuss our recent findings that establish HIF-2α as a negative regulator of peroxisome abundance and suggest a mechanism by which cells attune peroxisomal function with O2 availability. HIF-2α activation augments peroxisome turnover by pexophagy and thereby changes lipid composition reminiscent of peroxisomal disorders. We discuss potential mechanisms by which HIF-2α might trigger pexophagy and place special emphasis on the potential pathological implications of HIF-2α-mediated pexophagy for human health. PMID:26258123

  11. Hypoxia-inducible factor-1α induces multidrug resistance protein in colon cancer

    Directory of Open Access Journals (Sweden)

    Lv Y

    2015-07-01

    Full Text Available Yingqian Lv, Shan Zhao, Jinzhu Han, Likang Zheng, Zixin Yang, Li Zhao Department of Oncology, The Second Hospital, Hebei Medical University, Shijiazhuang, Hebei Province, People’s Republic of China Abstract: Multidrug resistance is the major cause of chemotherapy failure in many solid tumors, including colon cancer. Hypoxic environment is a feature for all solid tumors and is important for the development of tumor resistance to chemotherapy. Hypoxia-inducible factor (HIF-1α is the key transcription factor that mediates cellular response to hypoxia. HIF-1α has been shown to play an important role in tumor resistance; however, the mechanism is still not fully understood. Here, we found that HIF-1α and the drug resistance-associated gene multidrug resistance associated protein 1 (MRP1 were induced by treatment of colon cancer cells with the hypoxia-mimetic agent cobalt chloride. Inhibition of HIF-1α by RNA interference and dominant-negative protein can significantly reduce the induction of MRP1 by hypoxia. Bioinformatics analysis showed that a hypoxia response element is located at -378 to -373 bp upstream of the transcription start site of MRP1 gene. Luciferase reporter assay combined with mutation analysis confirmed that this element is essential for hypoxia-mediated activation of MRP gene. Furthermore, RNA interference revealed that HIF-1α is necessary for this hypoxia-driven activation of MRP1 promoter. Importantly, chromatin immunoprecipitation analysis demonstrated that HIF-1α could directly bind to this HRE site in vivo. Together, these data suggest that MRP1 is a downstream target gene of HIF-1α, which provides a potential novel mechanism for HIF-1α-mediated drug resistance in colon cancer and maybe other solid tumors as well. Keywords: hypoxia, hypoxia-inducible factor-1α, multidrug resistance associated protein, transcriptional regulation, chemotherapy tolerance

  12. Abnormal regional spontaneous neuronal activity associated with symptom severity in treatment-naive patients with obsessive-compulsive disorder revealed by resting-state functional MRI.

    Science.gov (United States)

    Qiu, Linlin; Fu, Xiangshuai; Wang, Shuai; Tang, Qunfeng; Chen, Xingui; Cheng, Lin; Zhang, Fuquan; Zhou, Zhenhe; Tian, Lin

    2017-02-15

    A large number of neuroimaging studies have revealed the dysfunction of brain activities in obsessive-compulsive disorder (OCD) during various tasks. However, regional spontaneous activity abnormalities in OCD are gradually being revealed. In this current study, we aimed to investigate cerebral regions with abnormal spontaneous activity using resting-state functional magnetic resonance imaging (fMRI) and further explored the relationship between the spontaneous neuronal activity and symptom severity of patients with OCD. Thirty-one patients with OCD and 32 age-and sex-matched normal controls received the fMRI scans and fractional amplitude of low-frequency fluctuation (fALFF) approach was applied to identify the abnormal brain activity. We found that patients with OCD showed decreased fALFF not only in the cortical-striato-thalamo-cortical (CSTC) circuits like the thalamus, but also in other cerebral systems like the cerebellum, the parietal cortex and the temporal cortex. Additionally, OCD patients demonstrated significant associations between decreased fALFF and obsessive-compulsive symptom severity in the thalamus, the paracentral lobule and the cerebellum. Our results provide evidence for abnormal spontaneous neuronal activity in distributed cerebral areas and support the notion that brain areas outside the CSTC circuits may also play an important role in the pathophysiology of OCD. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Causes of Acute Intranatal and Postnatal Hypoxia in Neonatal Infants

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    S. A. Perepelitsa

    2012-01-01

    Full Text Available Objective: to study the causes of acute intranatal hypoxia and reveal a relationship of placental changes to respiratory failure (RF in newborn infants. Subjects and methods. The investigation included 252 neonates with the complicated course of an early neonatal period. Their gestational age was 26 weeks to 40 weeks, birth weight varied from 850 g to 4100 g. 95.3% of the newborn infants were born with a low Apgar score and RF, which required mechanical ventilation immediately after birth. The neonatal status was clinically evaluated; the values of blood gas composition and acid-base balance were recorded; the pathogen was discharged from the tracheobronchial tree; chest X-ray survey and placental morphological examination were performed. Results. The main cause of neonatal respiratory failure is chronic intrauterine hypoxia caused by placental inflammatory changes and fetal-placental blood circulatory disorders, which gives rise to preterm delivery, cerebral hemodynamic disorders, and neonatal amniotic fluid aspiration. Bacteriological examination of tracheobronchial aspirations showed that no microflora growth occured in the majority of the newborns acute intranatal hypoxia. Enterococcus faecalis and Staphylococcus epidermidis were isolated in 12.3% and 8.7%, respectively. Growth of в-hemolytic streptococcus was observed in 2.8% of cases. The rate of microbial association specific only for rate premature infants with neonatal respiratory distress syndrome (NRDS was 4.8%. Conclusion. Placental changes causing fetal-placental circulatory disorders were ascertained to be responsible for acute intranatal and postnatal neonatal hypoxia. Placental inflammatory changes occurred in the majority of cases, as confirmed by bacteriological examinations of neonatal infants. Isolation of the varying microbial flora in infants with RF to a greater extent is, indicative of the infectious process occurring in the maternal body. Key words: acute intranatal

  14. Dynamics and distribution of natural and human-caused hypoxia

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    Rabalais, N. N.; Díaz, R. J.; Levin, L. A.; Turner, R. E.; Gilbert, D.; Zhang, J.

    2010-02-01

    Water masses can become undersaturated with oxygen when natural processes alone or in combination with anthropogenic processes produce enough organic carbon that is aerobically decomposed faster than the rate of oxygen re-aeration. The dominant natural processes usually involved are photosynthetic carbon production and microbial respiration. The re-supply rate is indirectly related to its isolation from the surface layer. Hypoxic water masses (hypoxic areas has been exacerbated by any combination of interactions that increase primary production and accumulation of organic carbon leading to increased respiratory demand for oxygen below a seasonal or permanent pycnocline. Nutrient loading is likely to increase further as population growth and resource intensification rises, especially with increased dependency on crops using fertilizers, burning of fossil fuels, urbanization, and waste water generation. It is likely that the occurrence and persistence of hypoxia will be even more widespread and have more impacts than presently observed. Global climate change will further complicate the causative factors in both natural and human-caused hypoxia. The likelihood of strengthened stratification alone, from increased surface water temperature as the global climate warms, is sufficient to worsen hypoxia where it currently exists and facilitate its formation in additional waters. Increased precipitation that increases freshwater discharge and flux of nutrients will result in increased primary production in the receiving waters up to a point. The interplay of increased nutrients and stratification where they occur will aggravate and accelerate hypoxia. Changes in wind fields may expand oxygen minimum zones onto more continental shelf areas. On the other hand, not all regions will experience increased precipitation, some oceanic water temperatures may decrease as currents shift, and frequency and severity of tropical storms may increase and temporarily disrupt hypoxia more

  15. Perinatal Hypoxia and Ischemia in Animal Models of Schizophrenia

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    Dimitri Hefter

    2018-03-01

    Full Text Available Intrauterine or perinatal complications constitute a major risk for psychiatric diseases. Infants who suffered from hypoxia–ischemia (HI are at twofold risk to develop schizophrenia in later life. Several animal models attempt to reproduce these complications to study the yet unknown steps between an insult in early life and outbreak of the disease decades later. However, it is very challenging to find the right type and severity of insult leading to a disease-like phenotype in the animal, but not causing necrosis and focal neurological deficits. By contrast, too mild, repetitive insults may even be protective via conditioning effects. Thus, it is not surprising that animal models of hypoxia lead to mixed results. To achieve clinically translatable findings, better protocols are urgently needed. Therefore, we compare widely used models of hypoxia and HI and propose future directions for the field.

  16. Oxidative stress and apoptosis after acute respiratory hypoxia and reoxygenation in rat brain

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    Debora Coimbra-Costa

    2017-08-01

    Full Text Available Acute hypoxia increases the formation of reactive oxygen species (ROS in the brain. However, the effect of reoxygenation, unavoidable to achieve full recovery of the hypoxic organ, has not been clearly established. The aim of the present study was to evaluate the effects of exposition to acute severe respiratory hypoxia followed by reoxygenation on the evolution of oxidative stress and apoptosis in the brain. We investigated the effect of in vivo acute severe normobaric hypoxia (rats exposed to 7% O2 for 6 h and reoxygenation in normoxia (21% O2 for 24 h or 48 h on oxidative stress markers, the antioxidant system and apoptosis in the brain. After respiratory hypoxia we found increased levels of HIF-1α expression, lipid peroxidation, protein oxidation and nitric oxide in brain extracts. Antioxidant defence systems such as superoxide dismutase (SOD, reduced glutathione (GSH and glutathione peroxidase (GPx and the reduced/oxidized glutathione (GSH/GSSG ratio were significantly decreased in the brain. After 24 h of reoxygenation, oxidative stress parameters and the anti-oxidant system returned to control values. Regarding the apoptosis parameters, acute hypoxia increased cytochrome c, AIF and caspase 3 activity in the brain. The apoptotic effect is greatest after 24 h of reoxygenation. Immunohistochemistry suggests that CA3 and dentate gyrus in the hippocampus seem more susceptible to hypoxia than the cortex. Severe acute hypoxia increases oxidative damage, which in turn could activate apoptotic mechanisms. Our work is the first to demonstrate that after 24 h of reoxygenation oxidative stress is attenuated, while apoptosis is maintained mainly in the hippocampus, which may, in fact, be the cause of impaired brain function. Keywords: Antioxidants, Apoptosis, Normobaric hypoxia, Oxidative stress, Reoxygenation

  17. Brain hypoxia imaging

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    Song, Ho Chun [Chonnam National University Medical School, Gwangju (Korea, Republic of)

    2007-04-15

    The measurement of pathologically low levels of tissue pO{sub 2} is an important diagnostic goal for determining the prognosis of many clinically important diseases including cardiovascular insufficiency, stroke and cancer. The target tissues nowadays have mostly been tumors or the myocardium, with less attention centered on the brain. Radiolabelled nitroimidazole or derivatives may be useful in identifying the hypoxic cells in cerebrovascular disease or traumatic brain injury, and hypoxic-ischemic encephalopathy. In acute stroke, the target of therapy is the severely hypoxic but salvageable tissue. {sup 18}F-MISO PET and {sup 99m}Tc-EC-metronidazole SPECT in patients with acute ischemic stroke identified hypoxic tissues and ischemic penumbra, and predicted its outcome. A study using {sup 123}I-IAZA in patient with closed head injury detected the hypoxic tissues after head injury. Up till now these radiopharmaceuticals have drawbacks due to its relatively low concentration with hypoxic tissues associated with/without low blood-brain barrier permeability and the necessity to wait a long time to achieve acceptable target to background ratios for imaging in acute ischemic stroke. It is needed to develop new hypoxic marker exhibiting more rapid localization in the hypoxic region in the brain. And then, the hypoxic brain imaging with imidazoles or non-imidazoles may be very useful in detecting the hypoxic tissues, determining therapeutic strategies and developing therapeutic drugs in several neurological disease, especially, in acute ischemic stroke.

  18. Air-breathing behavior and physiological responses to hypoxia and air exposure in the air-breathing loricariid fish, Pterygoplichthys anisitsi.

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    da Cruz, André Luis; da Silva, Hugo Ribeiro; Lundstedt, Lícia Maria; Schwantes, Arno Rudi; Moraes, Gilberto; Klein, Wilfried; Fernandes, Marisa Narciso

    2013-04-01

    Hypoxic water and episodic air exposure are potentially life-threatening conditions that fish in tropical regions can face during the dry season. This study investigated the air-breathing behavior, oxygen consumption, and respiratory responses of the air-breathing (AB) armored catfish Pterygoplichthys anisitsi. The hematological parameters and oxygen-binding characteristics of whole blood and stripped hemoglobin and the intermediate metabolism of selected tissue in normoxia, different hypoxic conditions, and after air exposure were also examined. In normoxia, this species exhibited high activity at night and AB behavior (2-5 AB h(-1)). The exposure to acute severe hypoxia elicited the AB behavior (4 AB h(-1)) during the day. Under progressive hypoxia without access to the water surface, the fish were oxyregulators with a critical O2 tension, calculated as the inspired water O2 pressure, as 47 ± 2 mmHg. At water O2 tensions lower than 40 mmHg, the fish exhibited continuous apnea behavior. The blood exhibited high capacity for transporting O2, having a cathodic hemoglobin component with a high Hb-O2 affinity. Under severe hypoxia, the fish used anaerobic metabolism to maintain metabolic rate. Air exposure revealed physiological and biochemical traits similar to those observed under normoxic conditions.

  19. Cytoglobin expression is upregulated in all tissues upon hypoxia: an in vitro and in vivo study by quantitative real-time PCR

    International Nuclear Information System (INIS)

    Fordel, E.; Geuens, E.; Dewilde, S.; Rottiers, P.; Carmeliet, P.; Grooten, J.; Moens, L.

    2004-01-01

    The vertebrate globin family has been extended with two members: neuroglobin and cytoglobin. We here investigate the changes of expression levels upon hypoxia of cytoglobin in parallel with neuroglobin, in vivo and in vitro, by using real-time quantitative PCR. Our data prove that cytoglobin is upregulated upon hypoxia in all tissues. The mechanism of induction of cytoglobin is regulated by the hypoxia-inducible factor 1, a posttranscriptionally regulated transcription factor controlling several hypoxia-inducible genes. The latter is argumented by: (1) cytoglobin is significantly upregulated upon hypoxia and this is dependent on the tissue and severity of hypoxia; (2) the regulation of cytoglobin expression in HIF-1 (+/-) knockout mice is affected; (3) the variations of the expression regulation are in the same manner as seen in the expression of our control gene VEGF, that is proven to be regulated by the HIF-1-pathway; and (4) cytoglobin promoter region contains HRE sites

  20. Hypoxia Inducible Factors and Hypertension: Lessons from Sleep Apnea Syndrome

    Science.gov (United States)

    Nanduri, Jayasri; Peng, Ying-Jie; Yuan, Guoxiang; Kumar, Ganesh K.; Prabhakar, Nanduri R.

    2015-01-01

    Systemic hypertension is one of the most prevalent cardiovascular diseases. Sleep disordered breathing (SDB) with recurrent apnea is a major risk factor for developing essential hypertension. Chronic intermittent hypoxia (CIH) is a hallmark manifestation of recurrent apnea. Rodent models patterned after the O2 profiles seen with SDB patients showed that CIH is the major stimulus for causing systemic hypertension. This article reviews the physiological and molecular basis of CIH-induced hypertension. Physiological studies have identified that augmented carotid body chemosensory reflex and the resulting increase in sympathetic nerve activity is a major contributor to CIH-induced hypertension. Analysis of molecular mechanisms revealed that CIH activates hypoxia-inducible factor (HIF)-1 and suppresses HIF-2- mediated transcription. Dysregulation of HIF-1- and HIF-2- mediated transcription leads to imbalance of pro-oxidant and anti-oxidant enzyme gene expression resulting in increased reactive species (ROS) generation in the chemosensory reflex which is central for developing hypertension. PMID:25772710

  1. Hypoxia: From Placental Development to Fetal Programming.

    Science.gov (United States)

    Fajersztajn, Lais; Veras, Mariana Matera

    2017-10-16

    Hypoxia may influence normal and different pathological processes. Low oxygenation activates a variety of responses, many of them regulated by hypoxia-inducible factor 1 complex, which is mostly involved in cellular control of O 2 consumption and delivery, inhibition of growth and development, and promotion of anaerobic metabolism. Hypoxia plays a significant physiological role in fetal development; it is involved in different embryonic processes, for example, placentation, angiogenesis, and hematopoiesis. More recently, fetal hypoxia has been associated directly or indirectly with fetal programming of heart, brain, and kidney function and metabolism in adulthood. In this review, the role of hypoxia in fetal development, placentation, and fetal programming is summarized. Hypoxia is a basic mechanism involved in different pregnancy disorders and fetal health developmental complications. Although there are scientific data showing that hypoxia mediates changes in the growth trajectory of the fetus, modulates gene expression by epigenetic mechanisms, and determines the health status later in adulthood, more mechanistic studies are needed. Furthermore, if we consider that intrauterine hypoxia is not a rare event, and can be a consequence of unavoidable exposures to air pollution, nutritional deficiencies, obesity, and other very common conditions (drug addiction and stress), the health of future generations may be damaged and the incidence of some diseases will markedly increase as a consequence of disturbed fetal programming. Birth Defects Research 109:1377-1385, 2017.© 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  2. Genome-wide placental DNA methylation analysis of severely growth-discordant monochorionic twins reveals novel epigenetic targets for intrauterine growth restriction.

    Science.gov (United States)

    Roifman, Maian; Choufani, Sanaa; Turinsky, Andrei L; Drewlo, Sascha; Keating, Sarah; Brudno, Michael; Kingdom, John; Weksberg, Rosanna

    2016-01-01

    Intrauterine growth restriction (IUGR), which refers to reduced fetal growth in the context of placental insufficiency, is etiologically heterogeneous. IUGR is associated not only with perinatal morbidity and mortality but also with adult-onset disorders, such as cardiovascular disease and diabetes, posing a major health burden. Placental epigenetic dysregulation has been proposed as one mechanism that causes IUGR; however, the spectrum of epigenetic pathophysiological mechanisms leading to IUGR remains to be elucidated. Monozygotic monochorionic twins are particularly affected by IUGR, in the setting of severe discordant growth. Because monozygotic twins have the same genotype at conception and a shared maternal environment, they provide an ideal model system for studying epigenetic dysregulation of the placenta. We compared genome-wide placental DNA methylation patterns of severely growth-discordant twins to identify novel candidate genes for IUGR. Snap-frozen placental samples for eight severely growth-discordant monozygotic monochorionic twin pairs were obtained at delivery from each twin. A high-resolution DNA methylation array platform was used to identify methylation differences between IUGR and normal twins. Our analysis revealed differentially methylated regions in the promoters of eight genes: DECR1, ZNF300, DNAJA4, CCL28, LEPR, HSPA1A/L, GSTO1, and GNE. The largest methylation differences between the two groups were in the promoters of DECR1 and ZNF300. The significance of these group differences was independently validated by bisulfite pyrosequencing, implicating aberrations in fatty acid beta oxidation and transcriptional regulation, respectively. Further analysis of the array data identified methylation changes most prominently affecting the Wnt and cadherin pathways in the IUGR cohort. Our results suggest that IUGR in monozygotic twins is associated with impairments in lipid metabolism and transcriptional regulation as well as cadherin and Wnt

  3. Control of cardiorespiratory function in response to hypoxia in an air-breathing fish, the African sharptooth catfish, Clarias gariepinus.

    Science.gov (United States)

    Belão, T C; Zeraik, V M; Florindo, L H; Kalinin, A L; Leite, C A C; Rantin, F T

    2015-09-01

    We evaluated the role of the first pair of gill arches in the control of cardiorespiratory responses to normoxia and hypoxia in the air-breathing catfish, Clarias gariepinus. An intact group (IG) and an experimental group (EG, bilateral excision of first gill arch) were submitted to graded hypoxia, with and without access to air. The first pair of gill arches ablations reduced respiratory surface area and removed innervation by cranial nerve IX. In graded hypoxia without access to air, both groups displayed bradycardia and increased ventilatory stroke volume (VT), and the IG showed a significant increase in breathing frequency (fR). The EG exhibited very high fR in normoxia that did not increase further in hypoxia, this was linked to reduced O2 extraction from the ventilatory current (EO2) and a significantly higher critical O2 tension (PcO2) than the IG. In hypoxia with access to air, only the IG showed increased air-breathing, indicating that the first pair of gill arches excision severely attenuated air-breathing responses. Both groups exhibited bradycardia before and tachycardia after air-breaths. The fH and gill ventilation amplitude (VAMP) in the EG were overall higher than the IG. External and internal NaCN injections revealed that O2 chemoreceptors mediating ventilatory hypoxic responses (fR and VT) are internally oriented. The NaCN injections indicated that fR responses were mediated by receptors predominantly in the first pair of gill arches but VT responses by receptors on all gill arches. Receptors eliciting cardiac responses were both internally and externally oriented and distributed on all gill arches or extra-branchially. Air-breathing responses were predominantly mediated by receptors in the first pair of gill arches. In conclusion, the role of the first pair of gill arches is related to: (a) an elevated EO2 providing an adequate O2 uptake to maintain the aerobic metabolism during normoxia; (b) a significant bradycardia and increased fAB elicited

  4. Detrimental effects of hypoxia-specific expression of uracil DNA glycosylase (Ung) in Mycobacterium smegmatis.

    Science.gov (United States)

    Kurthkoti, Krishna; Varshney, Umesh

    2010-12-01

    Mycobacterium tuberculosis is known to reside latently in a significant fraction of the human population. Although the bacterium possesses an aerobic mode of metabolism, it adapts to persistence under hypoxic conditions such as those encountered in granulomas. While in mammalian systems hypoxia is a recognized DNA-damaging stress, aspects of DNA repair in mycobacteria under such conditions have not been studied. We subjected Mycobacterium smegmatis, a model organism, to the Wayne's protocol of hypoxia. Analysis of the mRNA of a key DNA repair enzyme, uracil DNA glycosylase (Ung), by real-time reverse transcriptase PCR (RT-PCR) revealed its downregulation during hypoxia. However, within an hour of recovery of the culture under normal oxygen levels, the Ung mRNA was restored. Analysis of Ung by immunoblotting and enzyme assays supported the RNA analysis results. To understand its physiological significance, we misexpressed Ung in M. smegmatis by using a hypoxia-responsive promoter of narK2 from M. tuberculosis. Although the misexpression of Ung during hypoxia decreased C-to-T mutations, it compromised bacterial survival upon recovery at normal oxygen levels. RT-PCR analysis of other base excision repair gene transcripts (UdgB and Fpg) suggested that these DNA repair functions also share with Ung the phenomenon of downregulation during hypoxia and recovery with return to normal oxygen conditions. We discuss the potential utility of this phenomenon in developing attenuated strains of mycobacteria.

  5. An Assessment of Exercise Tolerance in Normobaric Hypoxia of Patients with Diabetes Mellitus Type 1

    Directory of Open Access Journals (Sweden)

    Głuchowska Barbara

    2014-09-01

    Full Text Available Purpose. Physical activity is an integral part of the treatment of diabetes. The aim of the study was to assess aerobic capacity and cardiovascular-respiratory reactions to a single physical exercise with gradually increasing intensity in normobaric hypoxia in patients with Type 1 diabetes. Methods. The study was conducted on a sample of adults with Type 1 diabetes (GT1D, n = 13 and a randomly chosen healthy control (GK, n = 15. The study participants performed a progressive exercise test to exhaustion in normoxia (FiO2 ~ 20.90% and 7 days later in normobaric hypoxia (FiO2 ~ 15.14%. At rest, during exercise, and after completion of the test blood was drawn and physiological indicators were monitored. Results. Two-way ANOVA revealed a significant effect of hypoxia and physical exercise on blood glucose concentrations (F = 6.1 p < 0.01. In GT1D , lower glucose levels were observed in normobaric hypoxia compared with baseline and post-exercise levels in normoxia (p < 0.05. A tendency to increased maximal oxygen uptake and significantly higher minute pulmonary ventilation was observed in both groups in response to exercise and hypoxia. Conclusions. Physical activity and hypoxia may effectively control glucose homeostasis and increase cardiorespiratory adaptation to exercise in Type 1 diabetics.

  6. Molecular and biochemical responses of hypoxia exposure in Atlantic croaker collected from hypoxic regions in the northern Gulf of Mexico.

    Science.gov (United States)

    Rahman, Md Saydur; Thomas, Peter

    2017-01-01

    A major impact of global climate change has been the marked increase worldwide in the incidence of coastal hypoxia (dissolved oxygen, DOhypoxic waters as well as their molecular and physiological responses to environmental hypoxia exposure are largely unknown. A suite of potential hypoxia exposure biomarkers was evaluated in Atlantic croaker collected from hypoxic and normoxic regions in the northern Gulf of Mexico (nGOM), and in croaker after laboratory exposure to hypoxia (DO: 1.7 mg l-1). Expression of hypoxia-inducible factor-α, hif-α; neuronal nitric oxide synthase, nNOS; and insulin-like growth factor binding protein, igfbp mRNAs and protein carbonyl (PC, an oxidative stress indicator) content were elevated several-fold in brain and liver tissues of croaker collected from nGOM hypoxic sites. All of these molecular and biochemical biomarkers were also upregulated ~3-10-fold in croaker brain and liver tissues within 1-2 days of hypoxia exposure in controlled laboratory experiments. These results suggest that hif-αs, nNOS and igfbp-1 transcripts and PC contents are useful biomarkers of environmental hypoxia exposure and some of its physiological effects, making them important components for improved assessments of long-term impacts of environmental hypoxia on fish populations.

  7. Antioxidant responses of triangle sail mussel Hyriopsis cumingii exposed to harmful algae Microcystis aeruginosa and hypoxia.

    Science.gov (United States)

    Hu, Menghong; Wu, Fangli; Yuan, Mingzhe; Li, Qiongzhen; Gu, Yedan; Wang, Youji; Liu, Qigen

    2015-11-01

    Bloom forming algae and hypoxia are considered to be two main co-occurred stressors associated with eutrophication. The aim of this study was to evaluate the interactive effects of harmful algae Microcystis aeruginosa and hypoxia on an ecologically important mussel species inhabiting lakes and reservoirs, the triangle sail mussel Hyriopsis cumingii, which is generally considered as a bio-management tool for eutrophication. A set of antioxidant enzymes involved in immune defence mechanisms and detoxification processes, i.e. glutathione-S-transferases (GST), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), lysozyme (LZM) in mussel haemolymph were analyzed during 14days exposure along with 7days depuration duration period. GST, GSH, SOD, GPX and LZM were elevated by toxic M. aeruginosa exposure, while CAT activities were inhibited by such exposure. Hypoxia influenced the immune mechanisms through the activation of GSH and GPX, and the inhibition of SOD, CAT, and LZM activities. Meanwhile, some interactive effects of M. aeruginosa, hypoxia and time were observed. Independently of the presence or absence of hypoxia, toxic algal exposure generally increased the five tested enzyme activities of haemolymph, except CAT. Although half of microcystin could be eliminated after 7days depuration, toxic M. aeruginosa or hypoxia exposure history showed some latent effects on most parameters. These results revealed that toxic algae play an important role on haemolymph parameters alterations and its toxic effects could be affected by hypoxia. Although the microcystin depuration rate of H. cumingii is quick, toxic M. aeruginosa and/or hypoxia exposure history influenced its immunological mechanism recovery. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1975-01-01

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

  9. Expression of manganese superoxide dismutase in rat blood, heart and brain during induced systemic hypoxia

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    Septelia I. Wanandi

    2011-02-01

    Full Text Available Background: Hypoxia results in an increased generation of ROS. Until now, little is known about the role of MnSOD - a major endogenous antioxidant enzyme - on the cell adaptation response against hypoxia. The aim of this study was to  determine the MnSOD mRNA expression and levels of specific activity in blood, heart and brain of rats during induced systemic hypoxia.Methods: Twenty-five male Sprague Dawley rats were subjected to systemic hypoxia in an hypoxic chamber (at 8-10% O2 for 0, 1, 7, 14 and 21 days, respectively. The mRNA relative expression of MnSOD was analyzed using Real Time RT-PCR. MnSOD specific activity was determined using xanthine oxidase inhibition assay.Results: The MnSOD mRNA relative expression in rat blood and heart was decreased during early induced systemic hypoxia (day 1 and increased as hypoxia continued, whereas the mRNA expression in brain was increased since day 1 and reached its maximum level at day 7. The result of MnSOD specific activity during early systemic hypoxia was similar to the mRNA expression. Under very late hypoxic condition (day 21, MnSOD specific activity in blood, heart and brain was significantly decreased. We demonstrate a positive correlation between MnSOD mRNA expression and specific activity in these 3 tissues during day 0-14 of induced systemic hypoxia. Furthermore, mRNA expression and specific activity levels in heart strongly correlate with those in blood.Conclusion: The MnSOD expression at early and late phases of induced systemic hypoxia is distinctly regulated. The MnSOD expression in brain differs from that in blood and heart revealing that brain tissue can  possibly survive better from induced systemic hypoxia than heart and blood. The determination of MnSOD expression in blood can be used to describe its expression in heart under systemic hypoxic condition. (Med J Indones 2011; 20:27-33Keywords: MnSOD, mRNA expression, ROS, specific activity, systemic hypoxia

  10. The Clinical Importance of Assessing Tumor Hypoxia: Relationship of Tumor Hypoxia to Prognosis and Therapeutic Opportunities

    Science.gov (United States)

    Walsh, Joseph C.; Lebedev, Artem; Aten, Edward; Madsen, Kathleen; Marciano, Liane

    2014-01-01

    I. Introduction II. The Clinical Importance of Tumor Hypoxia A. Pathophysiology of hypoxia B. Hypoxia's negative impact on the effectiveness of curative treatment 1. Hypoxic tumors accumulate and propagate cancer stem cells 2. Hypoxia reduces the effectiveness of radiotherapy 3. Hypoxia increases metastasis risk and reduces the effectiveness of surgery 4. Hypoxic tumors are resistant to the effects of chemotherapy and chemoradiation C. Hypoxia is prognostic for poor patient outcomes III. Diagnosis of Tumor Hypoxia A. Direct methods 1. Oxygen electrode—direct pO2 measurement most used in cancer research 2. Phosphorescence quenching—alternative direct pO2 measurement 3. Electron paramagnetic resonance 4. 19F-magnetic resonance spectroscopy 5. Overhauser-enhanced MRI B. Endogenous markers of hypoxia 1. Hypoxia-inducible factor-1α 2. Carbonic anhydrase IX 3. Glucose transporter 1 4. Osteopontin 5. A combined IHC panel of protein markers for hypoxia 6. Comet assay C. Physiologic methods 1. Near-infrared spectroscopy/tomography—widely used for pulse oximetry 2. Photoacoustic tomography 3. Contrast-enhanced color duplex sonography 4. MRI-based measurements 5. Blood oxygen level-dependent MRI 6. Pimonidazole 7. EF5 (pentafluorinated etanidazole) 8. Hypoxia PET imaging—physiologic hypoxia measurement providing tomographic information a. 18F-fluoromisonidazole b. 18F-fluoroazomycinarabinofuranoside c. 18F-EF5 (pentafluorinated etanidazole) d. 18F-flortanidazole e. Copper (II) (diacetyl-bis (N4-methylthiosemicarbazone)) f. 18F-FDG imaging of hypoxia IV. Modifying Hypoxia to Improve Therapeutic Outcomes A. Use of hypoxia information in radiation therapy planning B. Use of hypoxia assessment for selection of patients responsive to nimorazole C. Use of hypoxia assessment for selection of patients responsive to tirapazamine D. Use of hypoxia assessment for selection of patients

  11. ENU mutagenesis reveals that Notchless homolog 1 (Drosophila affects Cdkn1a and several members of the Wnt pathway during murine pre-implantation development

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    Lossie Amy C

    2012-12-01

    Full Text Available Abstract Background Our interests lie in determining the genes and genetic pathways that are important for establishing and maintaining maternal-fetal interactions during pregnancy. Mutation analysis targeted to a 34 Mb domain flanked by Trp53 and Wnt3 demonstrates that this region of mouse chromosome 11 contains a large number of essential genes. Two mutant alleles (l11Jus1 and l11Jus4, which fall into the same complementation group, survive through implantation but fail prior to gastrulation. Results Through a positional cloning strategy, we discovered that these homozygous mutant alleles contain non-conservative missense mutations in the Notchless homolog 1 (Drosophila (Nle1 gene. NLE1 is a member of the large WD40-repeat protein family, and is thought to signal via the canonical NOTCH pathway in vertebrates. However, the phenotype of the Nle1 mutant mice is much more severe than single Notch receptor mutations or even in animals in which NOTCH signaling is blocked. To test the hypothesis that NLE1 functions in multiple signaling pathways during pre-implantation development, we examined expression of multiple Notch downstream target genes, as well as select members of the Wnt pathway in wild-type and mutant embryos. We did not detect altered expression of any primary members of the Notch pathway or in Notch downstream target genes. However, our data reveal that Cdkn1a, a NOTCH target, was upregulated in Nle1 mutants, while several members of the Wnt pathway are downregulated. In addition, we found that Nle1 mutant embryos undergo caspase-mediated apoptosis as hatched blastocysts, but not as morulae or blastocysts. Conclusions Taken together, these results uncover potential novel functions for NLE1 in the WNT and CDKN1A pathways during embryonic development in mammals.

  12. Dynamics and distribution of natural and human-caused hypoxia

    Directory of Open Access Journals (Sweden)

    N. N. Rabalais

    2010-02-01

    strengthened stratification alone, from increased surface water temperature as the global climate warms, is sufficient to worsen hypoxia where it currently exists and facilitate its formation in additional waters. Increased precipitation that increases freshwater discharge and flux of nutrients will result in increased primary production in the receiving waters up to a point. The interplay of increased nutrients and stratification where they occur will aggravate and accelerate hypoxia. Changes in wind fields may expand oxygen minimum zones onto more continental shelf areas. On the other hand, not all regions will experience increased precipitation, some oceanic water temperatures may decrease as currents shift, and frequency and severity of tropical storms may increase and temporarily disrupt hypoxia more often.

    The consequences of global warming and climate change are effectively uncontrollable at least in the near term. On the other hand, the consequences of eutrophication-induced hypoxia can be reversed if long-term, broad-scale, and persistent efforts to reduce substantial nutrient loads are developed and implemented. In the face of globally expanding hypoxia, there is a need for water and resource managers to act now to reduce nutrient loads to maintain, at least, the current status.

  13. Protective effects of intermittent hypoxia on brain and memory in a mouse model of apnea of prematurity

    OpenAIRE

    Bouslama, Myriam; Adle-Biassette, Homa; Ramanantsoa, Nelina; Bourgeois, Thomas; Bollen, Bieke; Brissaud, Olivier; Matrot, Boris; Gressens, Pierre; Gallego, Jorge

    2015-01-01

    Apnea of prematurity (AOP) is considered a risk factor for neurodevelopmental disorders in children based on epidemiological studies. This idea is supported by studies in newborn rodents in which exposure to intermittent hypoxia (IH) as a model of AOP significantly impairs development. However, the severe IH used in these studies may not fully reflect the broad spectrum of AOP severity. Considering that hypoxia appears neuroprotective under various conditions, we hypothesized that moderate IH...

  14. Ventilatory response of the newborn infant to mild hypoxia.

    Science.gov (United States)

    Cohen, G; Malcolm, G; Henderson-Smart, D

    1997-09-01

    The transition from an immature (biphasic) to a mature (sustained hyperpneic) response to a brief period of sustained hypoxia is believed to be well advanced by postnatal day 10 for newborn infants. However, a review of the supporting evidence convinced us that this issue warranted further, more systematic investigation. Seven healthy term infants aged 2 days to 8 weeks were studied. The ventilatory response (VR) elicited by 5 min breathing of 15% O2 was measured during quiet sleep. Arterial SaO2 (pulse oximeter) and minute ventilation (expressed as a change from control, delta V'i) were measured continuously. Infants were wrapped in their usual bedding and slept in open cots at room temperature (23 degrees-25 degrees). Infants aged 2-3 days exhibited predominantely a sustained hypopnea during the period of hypoxia (delta V'i = -2% at 1 min, -13% at 5 min). At 8 weeks of age, the mean response was typically biphasic (delta V'i = +9% at 1 min, -4% at 5 min). This age-related difference between responses was statistically significant (two-way ANOVA by time and age-group; interaction P < 0.05). These data reveal that term infants studied under ambient conditions during defined quiet sleep may exhibit an immature VR to mild, sustained hypoxia for at least 2 months after birth. This suggests that postnatal development of the O2 chemoreflex is slower than previously thought.

  15. Yak response to high-altitude hypoxic stress by altering mRNA expression and DNA methylation of hypoxia-inducible factors.

    Science.gov (United States)

    Xiong, Xianrong; Fu, Mei; Lan, Daoliang; Li, Jian; Zi, Xiangdong; Zhong, Jincheng

    2015-01-01

    Hypoxia-inducible factors (HIFs) are oxygen-dependent transcriptional activators, which play crucial roles in tumor angiogenesis and mammalian development, and regulate the transcription of genes involved in oxygen homeostasis in response to hypoxia. However, information on HIF-1α and HIF-2α in yak (Bos grunniens) is scarce. The complete coding region of yak HIF-2α was cloned, its mRNA expression in several tissues were determined, and the expression levels were compared with those of closely related low-altitude cattle (Bos taurus), and the methylation status of promoter regions were analyzed to better understand the roles of HIF-1α and HIF-2α in domesticated yak. The yak HIF-2α cDNA was cloned and sequenced in the present work reveals the evolutionary conservation through multiple sequence alignment, although 15 bases changed, resulting in 8 amino acid substitutions in the translated proteins in cattle. The tissue-specific expression results showed that HIF-1α is ubiquitously expressed, whereas HIF-2α expression is limited to endothelial tissues (kidney, heart, lung, spleen, and liver) and blood in yak. Both HIF-1α and HIF-2α expressions were higher in yak tissues than in cattle. The HIF-1α expression level is much higher in yak than cattle in these organs, except for the lung (P hypoxic stress response mechanism and may assist current medical research to understand hypoxia-related diseases.

  16. PlanHab study: assessment of psycho-neuroendocrine function in male subjects during 21 d of normobaric hypoxia and bed rest.

    Science.gov (United States)

    Strewe, C; Zeller, R; Feuerecker, M; Hoerl, M; Kumprej, I; Crispin, A; Johannes, B; Debevec, T; Mekjavic, I; Schelling, G; Choukèr, A

    2017-03-01

    Immobilization and hypoxemia are conditions often seen in patients suffering from severe heart insufficiency or primary pulmonary diseases (e.g. fibrosis, emphysema). In future planned long-duration and exploration class space missions (including habitats on the moon and Mars), healthy individuals will encounter such a combination of reduced physical activity and oxygen tension by way of technical reasons and the reduced gravitational forces. These overall unconventional extraterrestrial conditions can result in yet unknown consequences for the regulation of stress-permissive, psycho-neuroendocrine responses, which warrant appropriate measures in order to mitigate foreseeable risks. The Planetary Habitat Simulation Study (PlanHab) investigated these two space-related conditions: bed rest as model of reduced gravity and normobaric hypoxia, with the aim of examining their influence on psycho-neuroendocrine responses. We hypothesized that both conditions independently increase measures of psychological stress and enhance neuroendocrine markers of stress, and that these effects would be exacerbated by combined treatment. The cross-over study composed of three interventions (NBR, normobaric normoxic horizontal bed rest; HBR, normobaric hypoxic horizontal bed rest; HAMB, normobaric hypoxic ambulatory confinement) with 14 male subjects during three sequential campaigns separated by 4 months. The psychological state was determined through three questionnaires and principal neuroendocrine responses were evaluated by measuring cortisol in saliva, catecholamine in urine, and endocannabinoids in blood. The results revealed no effects after 3 weeks of normobaric hypoxia on psycho-neuroendocrine responses. Conversely, bed rest induced neuroendocrine alterations that were not influenced by hypoxia.

  17. Peak heart rate decreases with increasing severity of acute hypoxia

    DEFF Research Database (Denmark)

    Lundby, C; Araoz, M; Van Hall, Gerrit

    2001-01-01

    , 459, and 404 mmHg) in a hypobaric chamber and while breathing 9% O(2) in N(2). These conditions were equivalent to altitudes of 3300, 4300, 5300, and 6300 m above sea level, respectively. At 4300 m, maximal exercise was also repeated after 4 and 8 h. Peak heart rate (HR) decreased from 191 (182......-202) (mean and range) at sea level to 189 (179-200), 182 (172-189), 175 (166-183), and 165 (162-169) in the acute hypoxic conditions. Peak HR did not decrease further after 4 and 8 h at 4300 m compared to the acute exposure at this altitude. Between barometric pressures of 518 and 355 mmHg (approximately...... 3300 and 6300 m), peak HR decreased linearly: peak HR(hypobaria) = peak HR(sea level) - 0.135 x [hypobaria(3100) - hypobaria (mmHg)]; or peak HR(altitude) = peak HR(sea level) - 0.15 x (altitude - 3100 m). This corresponds to approximately 1-beat x min(-1) reduction in peak HR for every 7-mmHg decrease...

  18. Transcriptome sequencing of the naked mole rat (Heterocephalus glaber and identification of hypoxia tolerance genes

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    Bang Xiao

    2017-12-01

    Full Text Available The naked mole rat (NMR; Heterocephalus glaber is a small rodent species found in regions of Kenya, Ethiopia and Somalia. It has a high tolerance for hypoxia and is thus considered one of the most important natural models for studying hypoxia tolerance mechanisms. The various mechanisms underlying the NMR's hypoxia tolerance are beginning to be understood at different levels of organization, and next-generation sequencing methods promise to expand this understanding to the level of gene expression. In this study, we examined the sequence and transcript abundance data of the muscle transcriptome of NMRs exposed to hypoxia using the Illumina HiSeq 2500 system to clarify the possible genomic adaptive responses to the hypoxic underground surroundings. The RNA-seq raw FastQ data were mapped against the NMR genome. We identified 2337 differentially expressed genes (DEGs by comparison of the hypoxic and control groups. Functional annotation of the DEGs by gene ontology (GO analysis revealed enrichment of hypoxia stress-related GO categories, including ‘biological regulation’, ‘cellular process’, ‘ion transport’ and ‘cell-cell signaling’. Enrichment of DEGs in signaling pathways was analyzed against the Kyoto Encyclopedia of Genes and Genomes (KEGG database to identify possible interactions between DEGs. The results revealed significant enrichment of DEGs in focal adhesion, the mitogen-activated protein kinase (MAPK signaling pathway and the glycine, serine and threonine metabolism pathway. Furthermore, inhibition of DEGs (STMN1, MAPK8IP1 and MAPK10 expression induced apoptosis and arrested cell growth in NMR fibroblasts following hypoxia. Thus, this global transcriptome analysis of NMRs can provide an important genetic resource for the study of hypoxia tolerance in mammals. Furthermore, the identified DEGs may provide important molecular targets for biomedical research into therapeutic strategies for stroke and cardiovascular diseases.

  19. Hypoxia regulates the expression and localization of CCAAT/enhancer binding protein α by hypoxia inducible factor-1α in bladder transitional carcinoma cells.

    Science.gov (United States)

    Xue, Mei; Li, Xu; Chen, Wei

    2015-08-01

    Hypoxia inducible factor-1α (HIF-1α) is overexpressed in various types of solid tumor in humans, including bladder cancer. HIF-1α regulates the expression of a series of genes, which are involved in cell proliferation, differentiation, apoptosis, angiogenesis, migration and invasion and represents a potential therapeutic target for the treatment of human cancer. Despite extensive investigation of the effects of HIF-1α in the progression and metastasis of bladder cancer, the possible regulatory mechanisms underlying the effects of HIF-1α on bladder cancer cell proliferation and differentiation remain to be elucidated. It has been suggested that the transcription factor CCAAT/enhancer binding protein α (C/EBPα) acts as a tumor suppressor in several types of cancer cell, which are involved in regulating cell differentiation, proliferation and apoptosis. The present study confirmed that, in bladder cancer cells, the expression and localization of C/EBPα was regulated by hypoxia through an HIF-1α -dependent mechanism, which may be significant in bladder cancer cell proliferation and differentiation. The 5637 and T24 bladder cancer cell lines were incubated under normoxic and hypoxic conditions. The expression levels of HIF-1α and C/EBPα were detected by reverse transcription-quantitative polymerase chain reaction, western blotting and immunofluorescence analysis. The results revealed that, under hypoxic conditions, the protein expression levels of HIF-1α were markedly upregulated, but the mRNA levels were not altered. However, the mRNA and protein levels of C/EBPα were significantly reduced. The present study further analyzed the subcellular localization of C/EBPα, which was markedly decreased in the nuclei under hypoxic conditions. Following HIF-1α small interference RNA silencing of HIF-1α, downregulation of C/EBPα was prevented in the bladder cancer cells cultured under hypoxic conditions. In addition, groups of cells treated with 3-(5'-hydroxymethyl

  20. Effects of Acute Systemic Hypoxia and Hypercapnia on Brain Damage in a Rat Model of Hypoxia-Ischemia.

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    Wanchao Yang

    Full Text Available Therapeutic hypercapnia has the potential for neuroprotection after global cerebral ischemia. Here we further investigated the effects of different degrees of acute systemic hypoxia in combination with hypercapnia on brain damage in a rat model of hypoxia and ischemia. Adult wistar rats underwent unilateral common carotid artery (CCA ligation for 60 min followed by ventilation with normoxic or systemic hypoxic gas containing 11%O2,13%O2,15%O2 and 18%O2 (targeted to PaO2 30-39 mmHg, 40-49 mmHg, 50-59 mmHg, and 60-69 mmHg, respectively or systemic hypoxic gas containing 8% carbon dioxide (targeted to PaCO2 60-80 mmHg for 180 min. The mean artery pressure (MAP, blood gas, and cerebral blood flow (CBF were evaluated. The cortical vascular permeability and brain edema were examined. The ipsilateral cortex damage and the percentage of hippocampal apoptotic neurons were evaluated by Nissl staining and terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling (TUNEL assay as well as flow cytometry, respectively. Immunofluorescence and western blotting were performed to determine aquaporin-4 (AQP4 expression. In rats treated with severe hypoxia (PaO2 50 mmHg, hypercapnia protected against these pathophysiological changes. Moreover, hypercapnia treatment significantly reduced brain damage in the ischemic ipsilateral cortex and decreased the percentage of apoptotic neurons in the hippocampus after the CCA ligated rats were exposed to mild or moderate hypoxemia (PaO2 > 50 mmHg; especially under mild hypoxemia (PaO2 > 60 mmHg, hypercapnia significantly attenuated the expression of AQP4 protein with brain edema (p < 0.05. Hypercapnia exerts beneficial effects under mild to moderate hypoxemia and augments detrimental effects under severe hypoxemia on brain damage in a rat model of hypoxia-ischemia.

  1. Disturbance of recruitment success of mantis shrimp in Tokyo Bay associated with effects of hypoxia on the early life history.

    Science.gov (United States)

    Kodama, Keita; Tajima, Yoshihiro; Shimizu, Takamichi; Ohata, Satoshi; Shiraishi, Hiroaki; Horiguchi, Toshihiro

    2014-08-30

    We investigated effects of severe hypoxia (dissolved oxygen shrimp Oratosquilla oratoria in Tokyo Bay. Ten-year field surveys were conducted to examine quantitative relationships in annual mean densities of larvae and juveniles, and spatial distribution of juveniles and severe hypoxia. There was no significant correlation between annual mean densities of larvae and juveniles, suggesting that mortality during larval or juvenile stages varies among years, which might have regulated abundance of young-of-the-year juveniles. Juvenile density was low in the severely hypoxic area, implying that hypoxia could affect survivals and spatial distribution of juveniles. Meanwhile, there are yearly fluctuations in juvenile density in normoxic areas of both northern and southern part of the bay. This evidence suggests that abundance of post-settled juveniles might have been determined by not only effects of hypoxia, but also other factors influencing mortality during the early life stages. Copyright © 2014 Elsevier Ltd. All rights reserved.

  2. Translational control is a major contributor to hypoxia induced gene expression

    International Nuclear Information System (INIS)

    Beucken, Twan van den; Magagnin, Michael G.; Jutten, Barry; Seigneuric, Renaud; Lambin, Philippe; Koritzinsky, Marianne; Wouters, Bradly G.

    2011-01-01

    Background and purpose: Hypoxia is a common feature of solid tumors that is associated with an aggressive phenotype, resistance to therapy and poor prognosis. Major contributors to these adverse effects are the transcriptional program activated by the HIF family of transcription factors as well as the translational response mediated by PERK-dependent phosphorylation of eIF2α and inhibition of mTORC1 activity. In this study we determined the relative contribution of both transcriptional and translational responses to changes in hypoxia induced gene expression. Material and methods: Total and efficiently translated (polysomal) mRNA was isolated from DU145 prostate carcinoma cells that were exposed for up to 24 h of hypoxia ( 2 ). Changes in transcription and translation were assessed using affymetrix microarray technology. Results: Our data reveal an unexpectedly large contribution of translation control on both induced and repressed gene expression at all hypoxic time points, particularly during acute hypoxia (2-4 h). Gene ontology analysis revealed that gene classes like transcription and signal transduction are stimulated by translational control whereas expression of genes involved in cell growth and protein metabolism are repressed during hypoxic conditions by translational control. Conclusions: Our data indicate that translation influences gene expression during hypoxia on a scale comparable to that of transcription.

  3. The organ specificity in pathological damage of chronic intermittent hypoxia: an experimental study on rat with high-fat diet.

    Science.gov (United States)

    Wang, Hui; Tian, Jian-li; Feng, Shu-zhi; Sun, Ning; Chen, Bao-yuan; Zhang, Yun

    2013-09-01

    It is known today that sleep apnea hypopnea syndrome and its characteristic chronic intermittent hypoxia can cause damages to multiple organs, including the cardiovascular system, urinary system, and liver. It is still unclear, however, whether the damage caused by sleep apnea hypopnea syndrome and the severity of the damage are organ-specific. This research observed the pathological effects of chronic intermittent hypoxia on rat's thoracic aorta, myocardium, liver, and kidney, under the condition of lipid metabolism disturbance, through establishing the rat model of chronic intermittent hypoxia with high-fat diet by imitating the features of human sleep apnea hypopnea syndrome. In this model, 24 male Wistar rats were randomly divided into three groups: a control group fed by regular diet, a high-fat group fed by high-fat diet, and a high-fat plus intermittent hypoxia group fed by high-fat diet and treated with intermittent hypoxia 7 h a day. At the end of the ninth week, the pathological changes of rat's organs, including the thoracic aorta, myocardium, liver, and kidney are observed (under both optical microscopy and transmission electron microscopy). As the result of the experiment shows, while there was no abnormal effect observed on any organs of the control group, slight pathological changes were found in the organs of the high-fat group. For the high-fat plus intermittent hypoxia group, however, remarkably severer damages were found on all the organs. It also showed that the severity of the damage varies by organ in the high-fat plus intermittent hypoxia group, with the thoracic aorta being the worst, followed by the liver and myocardium, and the kidney being the slightest. Chronic intermittent hypoxia can lead to multiple-organ damage to rat with high-fat diet. Different organs appear to have different sensitivity to chronic intermittent hypoxia.

  4. Hypoxia-independent upregulation of placental hypoxia inducible factor-1α gene expression contributes to the pathogenesis of preeclampsia.

    Science.gov (United States)

    Iriyama, Takayuki; Wang, Wei; Parchim, Nicholas F; Song, Anren; Blackwell, Sean C; Sibai, Baha M; Kellems, Rodney E; Xia, Yang

    2015-06-01

    Accumulation of hypoxia inducible factor-1α (HIF-1α) is commonly an acute and beneficial response to hypoxia, whereas chronically elevated HIF-1α is associated with multiple disease conditions, including preeclampsia, a serious hypertensive disease of pregnancy. However, the molecular basis underlying the persistent elevation of placental HIF-1α in preeclampsia and its role in the pathogenesis of preeclampsia are poorly understood. Here we report that Hif-1α mRNA and HIF-1α protein were elevated in the placentas of pregnant mice infused with angiotensin II type I receptor agonistic autoantibody, a pathogenic factor in preeclampsia. Knockdown of placental Hif-1α mRNA by specific siRNA significantly attenuated hallmark features of preeclampsia induced by angiotensin II type I receptor agonistic autoantibody in pregnant mice, including hypertension, proteinuria, kidney damage, impaired placental vasculature, and elevated maternal circulating soluble fms-like tyrosine kinase-1 levels. Next, we discovered that Hif-1α mRNA levels and HIF-1α protein levels were induced in an independent preeclampsia model with infusion of the inflammatory cytokine tumor necrosis factor superfamily member 14 (LIGHT). SiRNA knockdown experiments also demonstrated that elevated HIF-1α contributed to LIGHT-induced preeclampsia features. Translational studies with human placentas showed that angiotensin II type I receptor agonistic autoantibody or LIGHT is capable of inducing HIF-1α in a hypoxia-independent manner. Moreover, increased HIF-1α was found to be responsible for angiotensin II type I receptor agonistic autoantibody or LIGHT-induced elevation of Flt-1 gene expression and production of soluble fms-like tyrosine kinase-1 in human villous explants. Overall, we demonstrated that hypoxia-independent stimulation of HIF-1α gene expression in the placenta is a common pathogenic mechanism promoting disease progression. Our findings reveal new insight to preeclampsia and highlight

  5. Gene expression analysis reveals early changes in several molecular pathways in cerebral malaria-susceptible mice versus cerebral malaria-resistant mice

    Directory of Open Access Journals (Sweden)

    Grau Georges E

    2007-12-01

    Full Text Available Abstract Background Microarray analyses allow the identification and assessment of molecular signatures in whole tissues undergoing pathological processes. To better understand cerebral malaria pathogenesis, we investigated intra-cerebral gene-expression profiles in well-defined genetically cerebral malaria-resistant (CM-R and CM-susceptible (CM-S mice, upon infection by Plasmodium berghei ANKA (PbA. We investigated mouse transcriptional responses at early and late stages of infection by use of cDNA microarrays. Results Through a rigorous statistical approach with multiple testing corrections, we showed that PbA significantly altered brain gene expression in CM-R (BALB/c, and in CM-S (CBA/J and C57BL/6 mice, and that 327 genes discriminated between early and late infection stages, between mouse strains, and between CM-R and CM-S mice. We further identified 104, 56, 84 genes with significant differential expression between CM-R and CM-S mice on days 2, 5, and 7 respectively. The analysis of their functional annotation indicates that genes involved in metabolic energy pathways, the inflammatory response, and the neuroprotection/neurotoxicity balance play a major role in cerebral malaria pathogenesis. In addition, our data suggest that cerebral malaria and Alzheimer's disease may share some common mechanisms of pathogenesis, as illustrated by the accumulation of β-amyloid proteins in brains of CM-S mice, but not of CM-R mice. Conclusion Our microarray analysis highlighted marked changes in several molecular pathways in CM-S compared to CM-R mice, particularly at early stages of infection. This study revealed some promising areas for exploration that may both provide new insight into the knowledge of CM pathogenesis and the development of novel therapeutic strategies.

  6. Guinea Pig as a Model to Study the Carotid Body Mediated Chronic Intermittent Hypoxia Effects.

    Science.gov (United States)

    Docio, Inmaculada; Olea, Elena; Prieto-LLoret, Jesus; Gallego-Martin, Teresa; Obeso, Ana; Gomez-Niño, Angela; Rocher, Asuncion

    2018-01-01

    Clinical and experimental evidence indicates a positive correlation between chronic intermittent hypoxia (CIH), increased carotid body (CB) chemosensitivity, enhanced sympatho-respiratory coupling and arterial hypertension and cardiovascular disease. Several groups have reported that both the afferent and efferent arms of the CB chemo-reflex are enhanced in CIH animal models through the oscillatory CB activation by recurrent hypoxia/reoxygenation episodes. Accordingly, CB ablation or denervation results in the reduction of these effects. To date, no studies have determined the effects of CIH treatment in chemo-reflex sensitization in guinea pig, a rodent with a hypofunctional CB and lacking ventilatory responses to hypoxia. We hypothesized that the lack of CB hypoxia response in guinea pig would suppress chemo-reflex sensitization and thereby would attenuate or eliminate respiratory, sympathetic and cardiovascular effects of CIH treatment. The main purpose of this study was to assess if guinea pig CB undergoes overactivation by CIH and to correlate CIH effects on CB chemoreceptors with cardiovascular and respiratory responses to hypoxia. We measured CB secretory activity, ventilatory parameters, systemic arterial pressure and sympathetic activity, basal and in response to acute hypoxia in two groups of animals: control and 30 days CIH exposed male guinea pigs. Our results indicated that CIH guinea pig CB lacks activity elicited by acute hypoxia measured as catecholamine (CA) secretory response or intracellular calcium transients. Plethysmography data showed that only severe hypoxia (7% O 2 ) and hypercapnia (5% CO 2 ) induced a significant increased ventilatory response in CIH animals, together with higher oxygen consumption. Therefore, CIH exposure blunted hyperventilation to hypoxia and hypercapnia normalized to oxygen consumption. Increase in plasma CA and superior cervical ganglion CA content was found, implying a CIH induced sympathetic hyperactivity. CIH

  7. Human erythropoietin response to hypocapnic hypoxia, normocapnic hypoxia, and hypocapnic normoxia

    DEFF Research Database (Denmark)

    Klausen, T; Christensen, H; Hansen, J M

    1996-01-01

    exposed to 2 h each of hypocapnic hypoxia, normocapnic hypoxia, hypocapnic normoxia, and normal breathing of room air (control experiment). During the control experiment, serum-EPO showed significant variations (ANOVA P = 0.047) with a 15% increase in mean values. The serum-EPO measured in the other...... (10% Co2 with 10% O2) to the hypoxic gas mixture. This elicited an increased ventilation, unaltered arterial pH and haemoglobin oxygen affinity, a lower degree of hypoxia than during hypocapnic hypoxia, and no significant changes in serum-EPO (ANOVA P > 0.05). Hypocapnic normoxia, produced...

  8. CD146+ human umbilical cord perivascular cells maintain stemness under hypoxia and as a cell source for skeletal regeneration.

    Directory of Open Access Journals (Sweden)

    Wing Pui Tsang

    Full Text Available The human umbilical cord perivascular cells (HUCPVCs have been considered as an alternative source of mesenchymal progenitors for cell based regenerative medicine. However, the biological properties of these cells remain to be well characterized. In the present study, HUCPVCs were isolated and sorted by CD146(+ pericyte marker. The purified CD146(+ HUCPVCs were induced to differentiate efficiently into osteoblast, chondrocyte and adipocyte lineages in vitro. Six weeks following subcutaneous transplantation of CD146(+ HUCPVCs-Gelfoam-alginate 3D complexes in severe combined immunodeficiency (SCID mice, newly formed bone matrix with embedded osteocytes of donor origin was observed. The functional engraftment of CD146(+ HUCPVCs in the new bone regenerates was further confirmed in a critical-sized bone defect model in SCID mice. Hypoxic conditions suppressed osteogenic differentiation while increased cell proliferation and colony-forming efficiency of CD146(+ HUCPVCs as compared to that under normoxic conditions. Re-oxygenation restored the multi-differentiation potential of the CD146(+ HUCPVCs. Western blot analysis revealed an upregulation of HIF-1α, HIF-2α, and OCT-4 protein expression in CD146(+ HUCPVCs under hypoxia, while there was no remarkable change in SOX2 and NANOG expression. The gene expression profiles of stem cell transcription factors between cells treated by normoxia and hypoxic conditions were compared by PCR array analysis. Intriguingly, PPAR-γ was dramatically downregulated (20-fold in mRNA expression under hypoxia, and was revealed to possess a putative binding site in the Hif-2α gene promoter region. Chromatin immunoprecipitation assays confirmed the binding of PPAR-γ protein to the Hif-2α promoter and the binding was suppressed by hypoxia treatment. Luciferase reporter assay showed that the Hif-2α promoter activity was suppressed by PPAR expression. Thus, PPAR-γ may involve in the regulation of HIF-2α for stemness

  9. In vitro downregulated hypoxia transcriptome is associated with poor prognosis in breast cancer.

    Science.gov (United States)

    Abu-Jamous, Basel; Buffa, Francesca M; Harris, Adrian L; Nandi, Asoke K

    2017-06-15

    hypoxia signatures. We present a clustering approach suitable to integrate data from diverse experimental set-ups. Its application to breast cancer cell line datasets reveals new hypoxia-regulated signatures of genes which behave differently when in vitro (cell-line) data is compared with in vivo (clinical) data, and are of a prognostic value comparable or exceeding the state-of-the-art hypoxia signatures.

  10. Hypoxia and the heart of poikilotherms

    Czech Academy of Sciences Publication Activity Database

    Ošťádal, Bohuslav

    2014-01-01

    Roč. 1, č. 1 (2014), s. 28-32 Institutional support: RVO:67985823 Keywords : blood supply heart * poikilotherms * tolerance to hypoxia Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery

  11. Hypoxia, HIF-1 Regulation and Cancer Therapy

    NARCIS (Netherlands)

    Groot, A.J.

    2008-01-01

    Oxygen insufficiency (hypoxia) is a common feature of human cancer and associated with tumor aggressiveness and poor clinical outcome. Furthermore, hypoxic tumors are more resistant to ionizing radiation and chemotherapy contributing to their unfavorable prognosis. The oxygen sensing pathway is

  12. 2007 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  13. 2004 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  14. 2005 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  15. 2002 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  16. 2003 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  17. 2001 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  18. Cognition Effects of Low-Grade Hypoxia

    Science.gov (United States)

    2016-07-01

    human short-term memory . Br J Anaesth. 1971; 43(6):548–552. 3. Crow TJ, Kelman GR. Psychological effects of mild acute hypoxia. Br J Anaesth. 1973; 45...Journal Article 3. DATES COVERED (From – To) Jan 2003 – Sep 2005 4. TITLE AND SUBTITLE Cognition Effects of Low-Grade Hypoxia 5a. CONTRACT NUMBER... cognitive function are reported in this paper. The study compared cognitive function during short exposures at four different altitudes. Ninety-one

  19. Transcriptomic and proteomic analyses of the Aspergillus fumigatus hypoxia response using an oxygen-controlled fermenter

    Science.gov (United States)

    2012-01-01

    Background Aspergillus fumigatus is a mold responsible for the majority of cases of aspergillosis in humans. To survive in the human body, A. fumigatus must adapt to microenvironments that are often characterized by low nutrient and oxygen availability. Recent research suggests that the ability of A. fumigatus and other pathogenic fungi to adapt to hypoxia contributes to their virulence. However, molecular mechanisms of A. fumigatus hypoxia adaptation are poorly understood. Thus, to better understand how A. fumigatus adapts to hypoxic microenvironments found in vivo during human fungal pathogenesis, the dynamic changes of the fungal transcriptome and proteome in hypoxia were investigated over a period of 24 hours utilizing an oxygen-controlled fermenter system. Results Significant increases in transcripts associated with iron and sterol metabolism, the cell wall, the GABA shunt, and transcriptional regulators were observed in response to hypoxia. A concomitant reduction in transcripts was observed with ribosome and terpenoid backbone biosynthesis, TCA cycle, amino acid metabolism and RNA degradation. Analysis of changes in transcription factor mRNA abundance shows that hypoxia induces significant positive and negative changes that may be important for regulating the hypoxia response in this pathogenic mold. Growth in hypoxia resulted in changes in the protein levels of several glycolytic enzymes, but these changes were not always reflected by the corresponding transcriptional profiling data. However, a good correlation overall (R2 = 0.2, p proteomics datasets for all time points. The lack of correlation between some transcript levels and their subsequent protein levels suggests another regulatory layer of the hypoxia response in A. fumigatus. Conclusions Taken together, our data suggest a robust cellular response that is likely regulated both at the transcriptional and post-transcriptional level in response to hypoxia by the human pathogenic mold A. fumigatus. As

  20. Acute hypoxia stress induced abundant differential expression genes and alternative splicing events in heart of tilapia.

    Science.gov (United States)

    Xia, Jun Hong; Li, Hong Lian; Li, Bi Jun; Gu, Xiao Hui; Lin, Hao Ran

    2018-01-10

    Hypoxia is one of the critical environmental stressors for fish in aquatic environments. Although accumulating evidences indicate that gene expression is regulated by hypoxia stress in fish, how genes undergoing differential gene expression and/or alternative splicing (AS) in response to hypoxia stress in heart are not well understood. Using RNA-seq, we surveyed and detected 289 differential expressed genes (DEG) and 103 genes that undergo differential usage of exons and splice junctions events (DUES) in heart of a hypoxia tolerant fish, Nile tilapia, Oreochromis niloticus following 12h hypoxic treatment. The spatio-temporal expression analysis validated the significant association of differential exon usages in two randomly selected DUES genes (fam162a and ndrg2) in 5 tissues (heart, liver, brain, gill and spleen) sampled at three time points (6h, 12h, and 24h) under acute hypoxia treatment. Functional analysis significantly associated the differential expressed genes with the categories related to energy conservation, protein synthesis and immune response. Different enrichment categories were found between the DEG and DUES dataset. The Isomerase activity, Oxidoreductase activity, Glycolysis and Oxidative stress process were significantly enriched for the DEG gene dataset, but the Structural constituent of ribosome and Structural molecule activity, Ribosomal protein and RNA binding protein were significantly enriched only for the DUES genes. Our comparative transcriptomic analysis reveals abundant stress responsive genes and their differential regulation function in the heart tissues of Nile tilapia under acute hypoxia stress. Our findings will facilitate future investigation on transcriptome complexity and AS regulation during hypoxia stress in fish. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in mice

    Directory of Open Access Journals (Sweden)

    Izziki Mohamed

    2009-01-01

    Full Text Available Abstract Background Inflammation may contribute to the pathogenesis of various forms of pulmonary hypertension (PH. Recent studies in patients with idiopathic PH or PH associated with underlying diseases suggest a role for interleukin-6 (IL-6. Methods To determine whether endogenous IL-6 contributes to mediate hypoxic PH and lung inflammation, we studied IL-6-deficient (IL-6-/- and wild-type (IL-6+/+ mice exposed to hypoxia for 2 weeks. Results Right ventricular systolic pressure, right ventricle hypertrophy, and the number and media thickness of muscular pulmonary vessels were decreased in IL-6-/- mice compared to wild-type controls after 2 weeks' hypoxia, although the pressure response to acute hypoxia was similar in IL-6+/+ and IL-6-/- mice. Hypoxia exposure of IL-6+/+ mice led to marked increases in IL-6 mRNA and protein levels within the first week, with positive IL-6 immunostaining in the pulmonary vessel walls. Lung IL-6 receptor and gp 130 (the IL-6 signal transducer mRNA levels increased after 1 and 2 weeks' hypoxia. In vitro studies of cultured human pulmonary-artery smooth-muscle-cells (PA-SMCs and microvascular endothelial cells revealed prominent synthesis of IL-6 by PA-SMCs, with further stimulation by hypoxia. IL-6 also markedly stimulated PA-SMC migration without affecting proliferation. Hypoxic IL-6-/- mice showed less inflammatory cell recruitment in the lungs, compared to hypoxic wild-type mice, as assessed by lung protein levels and immunostaining for the specific macrophage marker F4/80, with no difference in lung expression of adhesion molecules or cytokines. Conclusion These data suggest that IL-6 may be actively involved in hypoxia-induced lung inflammation and pulmonary vascular remodeling in mice.

  2. Epigenetic control of hypoxia inducible factor-1α-dependent expression of placental growth factor in hypoxic conditions.

    Science.gov (United States)

    Tudisco, Laura; Della Ragione, Floriana; Tarallo, Valeria; Apicella, Ivana; D'Esposito, Maurizio; Matarazzo, Maria Rosaria; De Falco, Sandro

    2014-04-01

    Hypoxia plays a crucial role in the angiogenic switch, modulating a large set of genes mainly through the activation of hypoxia-inducible factor (HIF) transcriptional complex. Endothelial cells play a central role in new vessels formation and express placental growth factor (PlGF), a member of vascular endothelial growth factor (VEGF) family, mainly involved in pathological angiogenesis. Despite several observations suggest a hypoxia-mediated positive modulation of PlGF, the molecular mechanism governing this regulation has not been fully elucidated. We decided to investigate if epigenetic modifications are involved in hypoxia-induced PlGF expression. We report that PlGF expression was induced in cultured human and mouse endothelial cells exposed to hypoxia (1% O 2), although DNA methylation at the Plgf CpG-island remains unchanged. Remarkably, robust hyperacetylation of histones H3 and H4 was observed in the second intron of Plgf, where hypoxia responsive elements (HREs), never described before, are located. HIF-1α, but not HIF-2α, binds to identified HREs. Noteworthy, only HIF-1α silencing fully inhibited PlGF upregulation. These results formally demonstrate a direct involvement of HIF-1α in the upregulation of PlGF expression in hypoxia through chromatin remodeling of HREs sites. Therefore, PlGF may be considered one of the putative targets of anti-HIF therapeutic applications.

  3. Hypoxia in Korean Coastal Waters: A Case Study of the Natural Jinhae Bay and Artificial Shihwa Bay

    Directory of Open Access Journals (Sweden)

    Jiyoung Lee

    2018-03-01

    Full Text Available Several coastal regions in Korea have suffered from hypoxia since the 1970s. We present the first review of Korean coastal hypoxia, focusing on its spatiotemporal variation, controlling factors, and effects on marine ecosystems. The review considers the two hotspots of the natural Jinhae Bay (JB and artificial Shihwa Bay (SB, which are referred to as “Korean dead zones.” The hypoxia in the JB is attributed to eutrophication due to domestic and land-used waste input and thermal stratification based on the naturally sluggish water circulation, whereas the hypoxia in the SB is due to eutrophication resulting from domestic, land-used, and industrial waste input and haline stratification as a consequence of the artificially created water stagnation. The bottom-water hypoxia and stratification has led to an imbalance in nitrogen:phosphorus ratio between surface and bottom waters. Hypoxia has also created undesirable benthic community changes in the both bays: (1 mass mortality of large species and recolonization with elevated abundances of opportunists in JB, and (2 decrease of the number of species, abundance, and diversity of benthic communities in SB. Therefore, it behooves us to pay attention to these environmental changes. This review will be helpful in determining the direction of future studies of Korean coastal hypoxia.

  4. Evaluation of current and new biomarkers in severe preeclampsia: a microarray approach reveals the VSIG4 gene as a potential blood biomarker.

    Directory of Open Access Journals (Sweden)

    Julien Textoris

    Full Text Available Preeclampsia is a placental disease characterized by hypertension and proteinuria in pregnant women, and it is associated with a high maternal and neonatal morbidity. However, circulating biomarkers that are able to predict the prognosis of preeclampsia are lacking. Thirty-eight women were included in the current study. They consisted of 19 patients with preeclampsia (13 with severe preeclampsia and 6 with non-severe preeclampsia and 19 gestational age-matched women with normal pregnancies as controls. We measured circulating factors that are associated with the coagulation pathway (including fibrinogen, fibronectin, factor VIII, antithrombin, protein S and protein C, endothelial activation (such as soluble endoglin and CD146, and the release of total and platelet-derived microparticles. These markers enabled us to discriminate the preeclampsia condition from a normal pregnancy but were not sufficient to distinguish severe from non-severe preeclampsia. We then used a microarray to study the transcriptional signature of blood samples. Preeclampsia patients exhibited a specific transcriptional program distinct from that of the control group of women. Interestingly, we also identified a severity-related transcriptional signature. Functional annotation of the upmodulated signature in severe preeclampsia highlighted two main functions related to "ribosome" and "complement". Finally, we identified 8 genes that were specifically upmodulated in severe preeclampsia compared with non-severe preeclampsia and the normotensive controls. Among these genes, we identified VSIG4 as a potential diagnostic marker of severe preeclampsia. The determination of this gene may improve the prognostic assessment of severe preeclampsia.

  5. Cerebral hypoxia and ischemia in preterm infants

    Directory of Open Access Journals (Sweden)

    Alberto Ravarino

    2014-06-01

    Full Text Available Premature birth is a major public health issue internationally affecting 13 million babies worldwide. Hypoxia and ischemia is probably the commonest type of acquired brain damage in preterm infants. The clinical manifestations of hypoxic-ischemic injury in survivors of premature birth include a spectrum of cerebral palsy and intellectual disabilities. Until recently, the extensive brain abnormalities in preterm neonates appeared to be related mostly to destructive processes that lead to substantial deletion of neurons, axons, and glia from necrotic lesions in the developing brain. Advances in neonatal care coincide with a growing body of evidence that the preterm gray and white matter frequently sustain less severe insults, where tissue destruction is the minor component. Periventricular leukomalacia (PVL is the major form of white matter injury and consists classically of focal necrotic lesions, with subsequent cyst formation, and a less severe but more diffuse injury to cerebral white mater, with prominent astrogliosis and microgliosis but without overt necrosis. With PVL a concomitant injury occurs to subplate neurons, located in the subcortical white matter. Severe hypoxic-ischemic insults that trigger significant white matter necrosis are accompanied by neuronal degeneration in cerebral gray and white matter. This review aims to illustrate signs of cerebral embryology of the second half of fetal life and correlate hypoxic-ischemic brain injury in the premature infant. This should help us better understand the symptoms early and late and facilitate new therapeutic strategies. Proceedings of the International Course on Perinatal Pathology (part of the 10th International Workshop on Neonatology · October 22nd-25th, 2014 · Cagliari (Italy · October 25th, 2014 · The role of the clinical pathological dialogue in problem solving Guest Editors: Gavino Faa, Vassilios Fanos, Peter Van Eyken

  6. Systemic Hypoxia Changes the Organ-Specific Distribution of Vascular Endothelial Growth Factor and Its Receptors

    Science.gov (United States)

    Marti, Hugo H.; Risau, Werner

    1998-12-01

    Vascular endothelial growth factor (VEGF) plays a key role in physiological blood vessel formation and pathological angiogenesis such as tumor growth and ischemic diseases. Hypoxia is a potent inducer of VEGF in vitro. Here we demonstrate that VEGF is induced in vivo by exposing mice to systemic hypoxia. VEGF induction was highest in brain, but also occurred in kidney, testis, lung, heart, and liver. In situ hybridization analysis revealed that a distinct subset of cells within a given organ, such as glial cells and neurons in brain, tubular cells in kidney, and Sertoli cells in testis, responded to the hypoxic stimulus with an increase in VEGF expression. Surprisingly, however, other cells at sites of constitutive VEGF expression in normal adult tissues, such as epithelial cells in the choroid plexus and kidney glomeruli, decreased VEGF expression in response to the hypoxic stimulus. Furthermore, in addition to VEGF itself, expression of VEGF receptor-1 (VEGFR-1), but not VEGFR-2, was induced by hypoxia in endothelial cells of lung, heart, brain, kidney, and liver. VEGF itself was never found to be up-regulated in endothelial cells under hypoxic conditions, consistent with its paracrine action during normoxia. Our results show that the response to hypoxia in vivo is differentially regulated at the level of specific cell types or layers in certain organs. In these tissues, up- or down-regulation of VEGF and VEGFR-1 during hypoxia may influence their oxygenation after angiogenesis or modulate vascular permeability.

  7. Endogenous adenosine produced during hypoxia attenuates neutrophil accumulation: coordination by extracellular nucleotide metabolism.

    Science.gov (United States)

    Eltzschig, Holger K; Thompson, Linda F; Karhausen, Jorn; Cotta, Richard J; Ibla, Juan C; Robson, Simon C; Colgan, Sean P

    2004-12-15

    Hypoxia is a well-documented inflammatory stimulus and results in tissue polymorphonuclear leukocyte (PMN) accumulation. Likewise, increased tissue adenosine levels are commonly associated with hypoxia, and given the anti-inflammatory properties of adenosine, we hypothesized that adenosine production via adenine nucleotide metabolism at the vascular surface triggers an endogenous anti-inflammatory response during hypoxia. Initial in vitro studies indicated that endogenously generated adenosine, through activation of PMN adenosine A(2A) and A(2B) receptors, functions as an antiadhesive signal for PMN binding to microvascular endothelia. Intravascular nucleotides released by inflammatory cells undergo phosphohydrolysis via hypoxia-induced CD39 ectoapyrase (CD39 converts adenosine triphosphate/adenosine diphosphate [ATP/ADP] to adenosine monophosphate [AMP]) and CD73 ecto-5'-nucleotidase (CD73 converts AMP to adenosine). Extensions of our in vitro findings using cd39- and cd73-null animals revealed that extracellular adenosine produced through adenine nucleotide metabolism during hypoxia is a potent anti-inflammatory signal for PMNs in vivo. These findings identify CD39 and CD73 as critical control points for endogenous adenosine generation and implicate this pathway as an innate mechanism to attenuate excessive tissue PMN accumulation.

  8. Hypoxia inhibits the growth, differentiation and bone-forming capacity of rat osteoblasts

    International Nuclear Information System (INIS)

    Utting, J.C.; Robins, S.P.; Brandao-Burch, A.; Orriss, I.R.; Behar, J.; Arnett, T.R.

    2006-01-01

    We investigated the effect of hypoxia on rat osteoblast function in long-term primary cultures. Reduction of pO 2 from 20% to 5% and 2% decreased formation of mineralized bone nodules 1.7-fold and 11-fold, respectively. When pO 2 was reduced further to 0.2%, bone nodule formation was almost abolished. The inhibitory effect of hypoxia on bone formation was partly due to decreased osteoblast proliferation, as measured by 3 H-thymidine incorporation. Hypoxia also sharply reduced osteoblast alkaline phosphatase (ALP) activity and expression of mRNAs for ALP and osteocalcin, suggesting inhibition of differentiation to the osteogenic phenotype. Hypoxia did not increase the apoptosis of osteoblasts but induced a reversible state of quiescence. Transmission electron microscopy revealed that collagen fibrils deposited by osteoblasts cultured in 2% O 2 were less organized and much less abundant than in 20% O 2 cultures. Furthermore, collagen produced by hypoxic osteoblasts contained a lower percentage of hydroxylysine residues and exhibited an increased sensitivity to pepsin degradation. These data demonstrate the absolute oxygen requirement of osteoblasts for successful bone formation and emphasize the importance of the vasculature in maintaining bone health. We recently showed that hypoxia also acts in a reciprocal manner as a powerful stimulator of osteoclast formation. Considered together, our results help to explain the bone loss that occurs at the sites of fracture, tumors, inflammation and infection, and in individuals with vascular disease or anemia

  9. Apelin Protects Primary Rat Retinal Pericytes from Chemical Hypoxia-Induced Apoptosis

    Directory of Open Access Journals (Sweden)

    Li Chen

    2015-01-01

    Full Text Available Pericytes are a population of cells that participate in normal vessel architecture and regulate permeability. Apelin, as the endogenous ligand of G protein-coupled receptor APJ, participates in a number of physiological and pathological processes. To date, the effect of apelin on pericyte is not clear. Our study aimed to investigate the potential protection mechanisms of apelin, with regard to primary rat retinal pericytes under hypoxia. Immunofluorescence staining revealed that pericytes colocalized with APJ in the fibrovascular membranes dissected from proliferative diabetic retinopathy patients. In the in vitro studies, we first demonstrated that the expression of apelin/APJ was upregulated in pericytes under hypoxia, and apelin increased pericytes proliferation and migration. Moreover, knockdown of apelin in pericyte was achieved via lentivirus-mediated RNA interference. After the inhibition of apelin, pericytes proliferation was inhibited significantly in hypoxia culture condition. Furthermore, exogenous recombinant apelin effectively prevented hypoxia-induced apoptosis through downregulating active-caspase 3 expression and increasing the ratio of B cell lymphoma-2 (Bcl-2/Bcl-2 associated X protein (Bax in pericytes. These results suggest that apelin suppressed hypoxia-induced pericytes injury, which indicated that apelin could be a potential therapeutic target for retinal angiogenic diseases.

  10. Postoperative hypoxia and length of intensive care unit stay after cardiac surgery: the underweight paradox?

    Directory of Open Access Journals (Sweden)

    Marco Ranucci

    Full Text Available Cardiac operations with cardiopulmonary bypass can be associated with postoperative lung dysfunction. The present study investigates the incidence of postoperative hypoxia after cardiac surgery, its relationship with the length of intensive care unit stay, and the role of body mass index in determining postoperative hypoxia and intensive care unit length of stay.Single-center, retrospective study.University Hospital. Patients. Adult patients (N = 5,023 who underwent cardiac surgery with CPB.None.According to the body mass index, patients were attributed to six classes, and obesity was defined as a body mass index >30. POH was defined as a PaO2/FiO2 ratio <200 at the arrival in the intensive care unit. Postoperative hypoxia was detected in 1,536 patients (30.6%. Obesity was an independent risk factor for postoperative hypoxia (odds ratio 2.4, 95% confidence interval 2.05-2.78, P = 0.001 and postoperative hypoxia was a determinant of intensive care unit length of stay. There is a significant inverse correlation between body mass index and PaO2/FiO2 ratio, with the risk of postoperative hypoxia increasing by 1.7 folds per each incremental body mass index class. The relationship between body mass index and intensive care unit length of stay is U-shaped, with longer intensive care unit stay in underweight patients and moderate-morbid obese patients.Obese patients are at higher risk for postoperative hypoxia, but this leads to a prolonged intensive care unit stay only for moderate-morbid obese patients. Obese patients are partially protected against the deleterious effects of hemodilution and transfusions. Underweight patients present the "paradox" of a better lung gas exchange but a longer intensive care unit stay. This is probably due to a higher severity of their cardiac disease.

  11. Hippocampal mitogen-activated protein kinase activation is associated with intermittent hypoxia in a rat model of obstructive sleep apnea syndrome.

    Science.gov (United States)

    Zhao, Ya-Ning; Wang, Hong-Yang; Li, Jian-Min; Chen, Bao-Yuan; Xia, Guo; Zhang, Pan-Pan; Ge, Yan-Lei

    2016-01-01

    generally increased at the late stages under continued hypoxia, but increased at all time-points under the intermittent hypoxia conditions. The two types of hypoxia induced an increase in the MDA content, but a decrease in SOD activity. Marked changes in these two parameters coupled with markedly reduced surviving cells in the hippocampus in a time‑dependent manner were observed in the intermittent hypoxia group in comparison with the continued hypoxia group. OSAS‑induced intermittent hypoxia markedly activated the MAPK signaling pathways, which were triggered by oxidative stress, leading to abnormal expression of downstream Bcl‑2 and Bax, and a severe loss of neural cells in the hippocampus.

  12. Tumor Hypoxia: Causative Mechanisms, Microregional Heterogeneities, and the Role of Tissue-Based Hypoxia Markers.

    Science.gov (United States)

    Vaupel, Peter; Mayer, Arnulf

    Tumor hypoxia is a hallmark of solid malignant tumor growth, profoundly influences malignant progression and contributes to the development of therapeutic resistance. Pathogenesis of tumor hypoxia is multifactorial, with contributions from both acute and chronic factors. Spatial distribution of hypoxia within tumors is markedly heterogeneous and often changes over time, e.g., during a course of radiotherapy. Substantial changes in the oxygenation status can occur within the distance of a few cell layers, explaining the inability of currently used molecular imaging techniques to adequately assess this crucial trait. Due to the possible importance of tumor hypoxia for clinical decision-making, there is a great demand for molecular tools which may provide the necessary resolution down to the single cell level. Exogenous and endogenous markers of tumor hypoxia have been investigated for this purpose. Their potential use may be greatly enhanced by multiparametric in situ methods in experimental and human tumor tissue.

  13. The Plasmodium falciparum transcriptome in severe malaria reveals altered expression of genes involved in important processes including surface antigen–encoding var genes

    Science.gov (United States)

    Tonkin-Hill, Gerry Q.; Trianty, Leily; Noviyanti, Rintis; Nguyen, Hanh H. T.; Sebayang, Boni F.; Lampah, Daniel A.; Marfurt, Jutta; Cobbold, Simon A.; Rambhatla, Janavi S.; McConville, Malcolm J.; Rogerson, Stephen J.; Brown, Graham V.; Day, Karen P.; Price, Ric N.; Anstey, Nicholas M.

    2018-01-01

    Within the human host, the malaria parasite Plasmodium falciparum is exposed to multiple selection pressures. The host environment changes dramatically in severe malaria, but the extent to which the parasite responds to—or is selected by—this environment remains unclear. From previous studies, the parasites that cause severe malaria appear to increase expression of a restricted but poorly defined subset of the PfEMP1 variant, surface antigens. PfEMP1s are major targets of protective immunity. Here, we used RNA sequencing (RNAseq) to analyse gene expression in 44 parasite isolates that caused severe and uncomplicated malaria in Papuan patients. The transcriptomes of 19 parasite isolates associated with severe malaria indicated that these parasites had decreased glycolysis without activation of compensatory pathways; altered chromatin structure and probably transcriptional regulation through decreased histone methylation; reduced surface expression of PfEMP1; and down-regulated expression of multiple chaperone proteins. Our RNAseq also identified novel associations between disease severity and PfEMP1 transcripts, domains, and smaller sequence segments and also confirmed all previously reported associations between expressed PfEMP1 sequences and severe disease. These findings will inform efforts to identify vaccine targets for severe malaria and also indicate how parasites adapt to—or are selected by—the host environment in severe malaria. PMID:29529020

  14. Gill and lung ventilation responses to steady-state aquatic hypoxia and hyperoxia in the bullfrog tadpole.

    Science.gov (United States)

    West, N H; Burggren, W W

    1982-02-01

    Gill ventilation frequency (fG), the pressure amplitude (PBC) and stroke volume (VS) of buccal ventilation cycles, the frequency of air breaths (fL), water flow over the gills (VW), gill oxygen uptake (MGO2), oxygen utilization (U), and heart frequency (fH) have been measured in unanaesthetized, air breathing Rana catesbeiana tadpoles (stage XVI-XIX). The animals were unrestrained except for ECG leads or cannulae, and were able to surface voluntarily for air breathing. They were subjected to aquatic normoxia, hyperoxia and three levels of aquatic hypoxia, and their respiratory responses recorded in the steady state. The experiments were performed at 20 +/- 0.5 degrees C. In hyperoxia there was an absence of air breathing, and fG, PBC and VW fell from the normoxic values, while U increased, resulting in no significant change in MGO2. Animals in normoxia showed a very low fL which increased in progressively more hypoxic states. VW increased from the normoxic value in mild hypoxia (PO2 = 96 +/- 2 mm Hg), but fell, associated with a reduction in PBC, in moderate (PO2 = 41 +/- 1 mm Hg) and severe (PO2 = 21 +/- 3 mm Hg) hypoxia in the presence of lung ventilation. Gill MGO2 was not significantly different from the normoxic value in mild hypoxia but fell in moderate hypoxia, while in severe hypoxia oxygen was lost to the ventilating water from the blood perfusing the gills. There was no significant change in fH from the normoxic value in either hypoxia or hyperoxia. These data indicate, that in the bimodally breathing bullfrog tadpole, aquatic PO2 exerts a strong control over both gill and lung ventilation. Furthermore, there is an interaction between gill and lung ventilation such that the onset of a high frequency of lung ventilation in moderate and severe hypoxia promotes a suppression of gill ventilation cycles.

  15. Effect of hypoxia on specific dynamic action and postprandial cardiovascular physiology in rainbow trout (Oncorhynchus mykiss).

    Science.gov (United States)

    Eliason, Erika J; Farrell, Anthony P

    2014-05-01

    Fish routinely encounter hypoxic environments, which may have detrimental effects on digestion and performance. The present study measured oxygen consumption (MO2), gastrointestinal blood flow (GBF), cardiac output (Vb) and heart rate (f(H)) in rainbow trout Oncorhynchus mykiss at 10°C-11.5°C while exposed to a 1.5-h step-wise hypoxia treatment (80%, 60% and 40% saturation=16.7, 12.6 and 8.4 kPa, respectively), which began 4 h after being fed 1% of their body mass. GBF and f(H) significantly decreased by 41 and 25%-29%, respectively, at the most severe hypoxia step (40% saturation), while MO2 and Vb were maintained throughout the entire hypoxia exposure. Thus, GBF and f(H) were more sensitive to hypoxia than MO2 or Vb in digesting rainbow trout. Subsequent to the hypoxic exposure, the fish were returned to normoxia and monitored for a total of 50h after feeding. While the magnitude of SDA was unaffected, peak postprandial MO2 was reduced by 17%, and the duration of specific dynamic action (SDA) was prolonged by 6h in hypoxia-treated fish when compared to control fish. In conclusion, digestive performance was compromised both during and after the hypoxic exposure, which could lead to negative effects on growth. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. Regulation of Cited2 expression provides a functional link between translational and transcriptional responses during hypoxia

    International Nuclear Information System (INIS)

    Beucken, Twan van den; Magagnin, Michael G.; Savelkouls, Kim; Lambin, Philippe; Koritzinsky, Marianne; Wouters, Bradly G.

    2007-01-01

    Background and purpose: Protein synthesis rates are greatly reduced under hypoxic conditions as a consequence of an overall inhibition of mRNA translation. Certain specific mRNA species have the ability to escape this general translational repression. At the cellular level this results in differential protein expression during hypoxic conditions. The objective of this study was to characterize the translational regulation of the postulated HIF-1α antagonist Cited2. Materials and methods: DU145 prostate carcinoma cells and mouse embryonic fibroblasts with a homozygous knock-in mutation for eIF2α (S51A) or wild-type eIF2α were exposed to severe hypoxia after which both total mRNA and efficiently translated mRNA were isolated. Quantitative RT-PCR was used to measure and compare changes in transcription (total mRNA) with changes in translation (efficiently translated mRNA fraction). Results: We show using HIF-1α null MEF cells that transcriptional induction of Cited2 during hypoxia is dependent on HIF-1α. Although global mRNA translation is inhibited during hypoxia Cited2 mRNA remains efficiently translated. An evolutionary conserved upstream open reading frame (uORF) in the 5'UTR of Cited2 did not stimulate translation in an eIF2α dependent manner during hypoxia. Conclusions: Selective translation Cited2 by an eIF2α independent mechanism establishes a link between translation and HIF-1 dependent transcription during hypoxia

  17. The More Extreme Nature of North American Monsoon Precipitation in the Southwestern United States as Revealed by a Historical Climatology of Simulated Severe Weather Events

    KAUST Repository

    Luong, Thang M.; Castro, Christopher L.; Chang, Hsin-I; Lahmers, Timothy; Adams, David K.; Ochoa-Moya, Carlos A.

    2017-01-01

    Long-term changes in North American monsoon (NAM) precipitation intensity in the southwestern United States are evaluated through the use of convective-permitting model simulations of objectively identified severe weather events during

  18. The More Extreme Nature of North American Monsoon Precipitation in the Southwestern United States as Revealed by a Historical Climatology of Simulated Severe Weather Events

    KAUST Repository

    Luong, Thang M.

    2017-07-03

    Long-term changes in North American monsoon (NAM) precipitation intensity in the southwestern United States are evaluated through the use of convective-permitting model simulations of objectively identified severe weather events during

  19. Hypoxia Downregulates MAPK/ERK but Not STAT3 Signaling in ROS-Dependent and HIF-1-Independent Manners in Mouse Embryonic Stem Cells

    Directory of Open Access Journals (Sweden)

    Jan Kučera

    2017-01-01

    Full Text Available Hypoxia is involved in the regulation of stem cell fate, and hypoxia-inducible factor 1 (HIF-1 is the master regulator of hypoxic response. Here, we focus on the effect of hypoxia on intracellular signaling pathways responsible for mouse embryonic stem (ES cell maintenance. We employed wild-type and HIF-1α-deficient ES cells to investigate hypoxic response in the ERK, Akt, and STAT3 pathways. Cultivation in 1% O2 for 24 h resulted in the strong dephosphorylation of ERK and its upstream kinases and to a lesser extent of Akt in an HIF-1-independent manner, while STAT3 phosphorylation remained unaffected. Downregulation of ERK could not be mimicked either by pharmacologically induced hypoxia or by the overexpression. Dual-specificity phosphatases (DUSP 1, 5, and 6 are hypoxia-sensitive MAPK-specific phosphatases involved in ERK downregulation, and protein phosphatase 2A (PP2A regulates both ERK and Akt. However, combining multiple approaches, we revealed the limited significance of DUSPs and PP2A in the hypoxia-mediated attenuation of ERK signaling. Interestingly, we observed a decreased reactive oxygen species (ROS level in hypoxia and a similar phosphorylation pattern for ERK when the cells were supplemented with glutathione. Therefore, we suggest a potential role for the ROS-dependent attenuation of ERK signaling in hypoxia, without the involvement of HIF-1.

  20. Complex Evaluation Oxygen Status and Lipid Metabolism Indexes in Newborns with Perinatal Hypoxia and Hypovolemic Shock

    Directory of Open Access Journals (Sweden)

    Svetlana A. Perepelitsa

    2017-01-01

    Full Text Available Aim. To asses of metabolism, lipid metabolism and oxygen status parameters in newborns with perinatal hypoxia.Materials and Methods. 53 newborn babies born with signs of severe hypoxia and low Apgar scoring equal to 2 at the 1st minute of life were enrolled in the study. Newborns were divided into 2 groups depending on the presence of the clinical presentation of shock: Group 1 «Shock» and Group 2 «Acute intranatal hypoxia» (AIH. All newborns underwent testing for blood gas and acid-base balance, lactate level. Cholesterol and triglyceride levels in the central venous blood were also tested immediately after the birth and on the 5th day of life. Mechanical ventilation mode and parameters were registered. The mean airway pressure (MAP and the oxygen saturation index (OSI were calculated.Results. Severe decompensated metabolic lactic acidosis was diagnosed in a «Shock» group newborns at birth, thus indicating severe perinatal hypoxia which had triggered the development of shock. As for the «AIH» group newborns, they had hyperlactatemia alone. The most severe hypoxemia at birth was diagnosed in newborns of the «Shock» group; the OSI value in these infants was significantly higher than that in «AIH» infants (P<0.01. Despite the treatment and mechanical ventilation, during the posthypoxic period, newborns from the «Shock» group were characterized by increased OSI values over 12 hours after birth. Significantly high levels of OSI persisted for 48 hours after the delivery. Severe hypotriglyceridemia and hypocholesterolemia were found in both group newborns.Conclusion. The study demonstrated that there was intranatal complex metabolism impairment in the case of perinatal hypoxia; at birth, it manifested by metabolic acidosis of various degrees of severity and imbalance of triglycerides and cholesterol levels. The longer and more severe hypoxia is, the more severe acid-base balance and blood lactate level impairment at birth become

  1. Body temperature depression and peripheral heat loss accompany the metabolic and ventilatory responses to hypoxia in low and high altitude birds.

    Science.gov (United States)

    Scott, Graham R; Cadena, Viviana; Tattersall, Glenn J; Milsom, William K

    2008-04-01

    The objectives of this study were to compare the thermoregulatory, metabolic and ventilatory responses to hypoxia of the high altitude bar-headed goose with low altitude waterfowl. All birds were found to reduce body temperature (T(b)) during hypoxia, by up to 1-1.5 degrees C in severe hypoxia. During prolonged hypoxia, T(b) stabilized at a new lower temperature. A regulated increase in heat loss contributed to T(b) depression as reflected by increases in bill surface temperatures (up to 5 degrees C) during hypoxia. Bill warming required peripheral chemoreceptor inputs, since vagotomy abolished this response to hypoxia. T(b) depression could still occur without bill warming, however, because vagotomized birds reduced T(b) as much as intact birds. Compared to both greylag geese and pekin ducks, bar-headed geese required more severe hypoxia to initiate T(b) depression and heat loss from the bill. However, when T(b) depression or bill warming were expressed relative to arterial O(2) concentration (rather than inspired O(2)) all species were similar; this suggests that enhanced O(2) loading, rather than differences in thermoregulatory control centres, reduces T(b) depression during hypoxia in bar-headed geese. Correspondingly, bar-headed geese maintained higher rates of metabolism during severe hypoxia (7% inspired O(2)), but this was only partly due to differences in T(b). Time domains of the hypoxic ventilatory response also appeared to differ between bar-headed geese and low altitude species. Overall, our results suggest that birds can adjust peripheral heat dissipation to facilitate T(b) depression during hypoxia, and that bar-headed geese minimize T(b) and metabolic depression as a result of evolutionary adaptations that enhance O(2) transport.

  2. Inflammation and hypoxia in the kidney: friends or foes?

    Science.gov (United States)

    Haase, Volker H

    2015-08-01

    Hypoxic injury is commonly associated with inflammatory-cell infiltration, and inflammation frequently leads to the activation of cellular hypoxia response pathways. The molecular mechanisms underlying this cross-talk during kidney injury are incompletely understood. Yamaguchi and colleagues identify CCAAT/enhancer-binding protein δ as a cytokine- and hypoxia-regulated transcription factor that fine-tunes hypoxia-inducible factor-1 signaling in renal epithelial cells and thus provide a novel molecular link between hypoxia and inflammation in kidney injury.

  3. Overexpression of Hypoxia-Inducible Factor-1α Exacerbates Endothelial Barrier Dysfunction Induced by Hypoxia

    Directory of Open Access Journals (Sweden)

    Pei Wang

    2013-09-01

    Full Text Available Background/Aims: The mechanisms involved in endothelial barrier dysfunction induced by hypoxia are incompletely understood. There is debate about the role of hypoxia-inducible factor-1α (HIF-1α in endothelial barrier disruption. The aim of this study was to investigate the effect of genetic overexpression of HIF-1α on barrier function and the underlying mechanisms in hypoxic endothelial cells. Methods: The plasmid pcDNA3.1/V5-His-HIF-1α was stably transfected into human endothelial cells. The cells were exposed to normoxia or hypoxia. The mRNA and protein expressions of HIF-1α were detected by RT-PCR and Western blot respectively. The barrier function was assessed by measuring the transendothelial electrical resistance (TER. The Western blot analysis was used to determine the protein expression of glucose transporter-1 (GLUT-1, zonular occludens-1 (ZO-1, occludin, and myosin light chain kinase (MLCK in endothelial cells. The mRNA expression of proinflammatory cytokines was detected by qRT-PCR. Results: Genetic overexpression of HIF-1α significantly increased the mRNA and protein expression of HIF-1α in endothelial cells. The overexpression of HIF-1α enhanced the hypoxia-induced increase of HIF-1α and GLUT-1 protein expression. HIF-1α overexpression not only exacerbated hypoxia-induced endothelial barrier dysfunction but also augmented hypoxia-induced up-regulation of MLCK protein expression. HIF-1α overexpression also enhanced IL-1β, IL-6 and TNF-α mRNA expression. Conclusion: We provide evidence that genetic overexpression of HIF-1α aggravates the hypoxia-induced endothelial barrier dysfunction via enhancing the up-regulation of MLCK protein expression caused by hypoxia, suggesting a potential role for HIF-1α in the pathogenesis of endothelial barrier dysfunction in hypoxia.

  4. Analysis of hypoxia and hypoxia-like states through metabolite profiling.

    Directory of Open Access Journals (Sweden)

    Julie E Gleason

    Full Text Available In diverse organisms, adaptation to low oxygen (hypoxia is mediated through complex gene expression changes that can, in part, be mimicked by exposure to metals such as cobalt. Although much is known about the transcriptional response to hypoxia and cobalt, little is known about the all-important cell metabolism effects that trigger these responses.Herein we use a low molecular weight metabolome profiling approach to identify classes of metabolites in yeast cells that are altered as a consequence of hypoxia or cobalt exposures. Key findings on metabolites were followed-up by measuring expression of relevant proteins and enzyme activities. We find that both hypoxia and cobalt result in a loss of essential sterols and unsaturated fatty acids, but the basis for these changes are disparate. While hypoxia can affect a variety of enzymatic steps requiring oxygen and heme, cobalt specifically interferes with diiron-oxo enzymatic steps for sterol synthesis and fatty acid desaturation. In addition to diiron-oxo enzymes, cobalt but not hypoxia results in loss of labile 4Fe-4S dehydratases in the mitochondria, but has no effect on homologous 4Fe-4S dehydratases in the cytosol. Most striking, hypoxia but not cobalt affected cellular pools of amino acids. Amino acids such as aromatics were elevated whereas leucine and methionine, essential to the strain used here, dramatically decreased due to hypoxia induced down-regulation of amino acid permeases.These studies underscore the notion that cobalt targets a specific class of iron proteins and provide the first evidence for hypoxia effects on amino acid regulation. This research illustrates the power of metabolite profiling for uncovering new adaptations to environmental stress.

  5. Effects of intermittent hypoxia on running economy.

    Science.gov (United States)

    Burtscher, M; Gatterer, H; Faulhaber, M; Gerstgrasser, W; Schenk, K

    2010-09-01

    We investigated the effects of two 5-wk periods of intermittent hypoxia on running economy (RE). 11 male and female middle-distance runners were randomly assigned to the intermittent hypoxia group (IHG) or to the control group (CG). All athletes trained for a 13-wk period starting at pre-season until the competition season. The IHG spent additionally 2 h at rest on 3 days/wk for the first and the last 5 weeks in normobaric hypoxia (15-11% FiO2). RE, haematological parameters and body composition were determined at low altitude (600 m) at baseline, after the 5 (th), the 8 (th) and the 13 (th) week of training. RE, determined by the relative oxygen consumption during submaximal running, (-2.3+/-1.2 vs. -0.3+/-0.7 ml/min/kg, Ptraining phase. Georg Thieme Verlag KG Stuttgart . New York.

  6. Inhibition of the H3K9 methyltransferase G9A attenuates oncogenicity and activates the hypoxia signaling pathway

    Science.gov (United States)

    Ho, Jolene Caifeng; Abdullah, Lissa Nurrul; Pang, Qing You; Jha, Sudhakar; Chow, Edward Kai-Hua; Yang, Henry; Kato, Hiroyuki; Ueda, Jun

    2017-01-01

    Epigenetic mechanisms play important roles in the regulation of tumorigenesis, and hypoxia-induced epigenetic changes may be critical for the adaptation of cancer cells to the hypoxic microenvironment of solid tumors. Previously, we showed that loss-of-function of the hypoxia-regulated H3K9 methyltransferase G9A attenuates tumor growth. However, the mechanisms by which blockade of G9A leads to a tumor suppressive effect remain poorly understood. We show that G9A is highly expressed in breast cancer and is associated with poor patient prognosis, where it may function as a potent oncogenic driver. In agreement with this, G9A inhibition by the small molecule inhibitor, BIX-01294, leads to increased cell death and impaired cell migration, cell cycle and anchorage-independent growth. Interestingly, whole transcriptome analysis revealed that genes involved in diverse cancer cell functions become hypoxia-responsive upon G9A inhibition. This was accompanied by the upregulation of the hypoxia inducible factors HIF1α and HIF2α during BIX-01294 treatment even in normoxia that may facilitate the tumor suppressive effects of BIX-01294. HIF inhibition was able to reverse some of the transcriptional changes induced by BIX-01294 in hypoxia, indicating that the HIFs may be important drivers of these derepressed target genes. Therefore, we show that G9A is a key mediator of oncogenic processes in breast cancer cells and G9A inhibition by BIX-01294 can successfully attenuate oncogenicity even in hypoxia. PMID:29145444

  7. Hypoxia-induced secretion of TGF-β1 in mesenchymal stem cell promotes breast cancer cell progression.

    Science.gov (United States)

    Hung, Shun-Pei; Yang, Muh-Hwa; Tseng, Kuo-Fung; Lee, Oscar K

    2013-01-01

    In solid tumors, a decreased oxygen and nutrient supply creates a hypoxic microenvironment in the central region. This hypoxic condition induces molecular responses of normal and cancer cells in the local area, including angiogenesis, metabolic changes, and metastasis. In addition, other cells including mesenchymal stem cells (MSCs) have been reported to be recruited into the hypoxic area of solid tumors. In our previous study, we found that hypoxic condition induces the secretion of growth factors and cytokines in MSCs, and here we demonstrate that elevated secretion of transforming growth factor-β1 (TGF-β1) by MSCs under hypoxia promotes the growth, motility, and invasive ability of breast cancer cells. It was found that TGF-β1 promoter activity was regulated by hypoxia, and the major hypoxia-regulated element was located between bp -1030 to -666 in front of the TGF-β1 promoter region. In ChIP assay, the results revealed that HIF-1 was bound to the hypoxia response element (HRE) of TGF-β1 promoter. Collectively, the results indicate that hypoxia microenvironment can enhance cancer cell growth through the paracrine effects of the MSCs by driving their TGF-β1 gene expression and secretion. Therefore, extra caution has to be exercised when considering hypoxia pretreatment of MSCs before cell transplantation into patients for therapeutic purposes, particularly in patients susceptible to tumor growth.

  8. The impact of hypoxia on oncolytic virotherapy

    Directory of Open Access Journals (Sweden)

    Guo ZS

    2011-11-01

    Full Text Available Z Sheng GuoUniversity of Pittsburgh Cancer Institute and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USAAbstract: The hypoxic tumor microenvironment plays significant roles in tumor cell metabolism and survival, tumor growth, and progression. Hypoxia modulates target genes in target cells mainly through an oxygen-sensing signaling pathway mediated by hypoxia-inducible factor of transcription factors. As a result, hypoxic tumor cells are resistant to conventional therapeutics such as radiation and chemotherapy. Oncolytic virotherapy may be a promising novel therapeutic for hypoxic cancer. Some oncolytic viruses are better adapted than others to the hypoxic tumor environment. Replication of adenoviruses from both groups B and C is inhibited, yet replication of herpes simplex virus is enhanced. Hypoxia seems to exert little or no effect on the replication of other oncolytic viruses. Vaccinia virus displayed increased cytotoxicity in some hypoxic cancer cells even though viral protein synthesis and transgene expression were not affected. Vesicular stomatitis virus replicated to similar levels in both hypoxic and normoxic conditions, and is effective for killing hypoxic cancer cells. However, vesicular stomatitis virus and reovirus, but not encephalomyocarditis virus, are sensitive to elevated levels of hypoxia-inducible factor-1α in renal cancer cells with the loss of von Hippel–Lindau tumor suppressor protein, because elevated hypoxia-inducible factor activity confers dramatically enhanced resistance to cytotoxicity mediated by vesicular stomatitis virus or reovirus. A variety of hypoxia-selective and tumor-type-specific oncolytic adenoviruses, generated by incorporating hypoxia-responsive elements into synthetic promoters to control essential genes for viral replication or therapeutic genes, have been shown to be safe and efficacious. Hypoxic tumor-homing macrophages can function effectively as carrier

  9. Late gestational hypoxia and a postnatal high salt diet programs endothelial dysfunction and arterial stiffness in adult mouse offspring.

    Science.gov (United States)

    Walton, Sarah L; Singh, Reetu R; Tan, Tiffany; Paravicini, Tamara M; Moritz, Karen M

    2016-03-01

    Gestational hypoxia and high dietary salt intake have both been associated with impaired vascular function in adulthood. Using a mouse model of prenatal hypoxia, we examined whether a chronic high salt diet had an additive effect in promoting vascular dysfunction in offspring. Pregnant CD1 dams were placed in a hypoxic chamber (12% O2) or housed under normal conditions (21% O2) from embryonic day 14.5 until birth. Gestational hypoxia resulted in a reduced body weight for both male and female offspring at birth. This restriction in body weight persisted until weaning, after which the animals underwent catch-up growth. At 10 weeks of age, a subset of offspring was placed on a high salt diet (5% NaCl). Pressurized myography of mesenteric resistance arteries at 12 months of age showed that both male and female offspring exposed to maternal hypoxia had significantly impaired endothelial function, as demonstrated by impaired vasodilatation to ACh but not sodium nitroprusside. Endothelial dysfunction caused by prenatal hypoxia was not exacerbated by postnatal consumption of a high salt diet. Prenatal hypoxia increased microvascular stiffness in male offspring. The combination of prenatal hypoxia and a postnatal high salt diet caused a leftward shift in the stress-strain relationship in both sexes. Histopathological analysis of aortic sections revealed a loss of elastin integrity and increased collagen, consistent with increased vascular stiffness. These results demonstrate that prenatal hypoxia programs endothelial dysfunction in both sexes. A chronic high salt diet in postnatal life had an additive deleterious effect on vascular mechanics and structural characteristics in both sexes. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

  10. Cellular effects of the microtubule-targeting agent peloruside A in hypoxia-conditioned colorectal carcinoma cells.

    Science.gov (United States)

    Řehulka, Jiří; Annadurai, Narendran; Frydrych, Ivo; Znojek, Pawel; Džubák, Petr; Northcote, Peter; Miller, John H; Hajdúch, Marián; Das, Viswanath

    2017-07-01

    Hypoxia is a prominent feature of solid tumors, dramatically remodeling microtubule structures and cellular pathways and contributing to paclitaxel resistance. Peloruside A (PLA), a microtubule-targeting agent, has shown promising anti-tumor effects in preclinical studies. Although it has a similar mode of action to paclitaxel, it binds to a distinct site on β-tubulin that differs from the classical taxane site. In this study, we examined the unexplored effects of PLA in hypoxia-conditioned colorectal HCT116 cancer cells. Cytotoxicity of PLA was determined by cell proliferation assay. The effects of a pre-exposure to hypoxia on PLA-induced cell cycle alterations and apoptosis were examined by flow cytometry, time-lapse imaging, and western blot analysis of selected markers. The hypoxia effect on stabilization of microtubules by PLA was monitored by an intracellular tubulin polymerization assay. Our findings show that the cytotoxicity of PLA is not altered in hypoxia-conditioned cells compared to paclitaxel and vincristine. Furthermore, hypoxia does not alter PLA-induced microtubule stabilization nor the multinucleation of cells. PLA causes cyclin B1 and G2/M accumulation followed by apoptosis. The cellular and molecular effects of PLA have been determined in normoxic conditions, but there are no reports of PLA effects in hypoxic cells. Our findings reveal that hypoxia preconditioning does not alter the sensitivity of HCT116 to PLA. These data report on the cellular and molecular effects of PLA in hypoxia-conditioned cells for the first time, and will encourage further exploration of PLA as a promising anti-tumor agent. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Hypoxia-inducible factor 1-mediated human GATA1 induction promotes erythroid differentiation under hypoxic conditions.

    Science.gov (United States)

    Zhang, Feng-Lin; Shen, Guo-Min; Liu, Xiao-Ling; Wang, Fang; Zhao, Ying-Ze; Zhang, Jun-Wu

    2012-08-01

    Hypoxia-inducible factor promotes erythropoiesis through coordinated cell type-specific hypoxia responses. GATA1 is essential to normal erythropoiesis and plays a crucial role in erythroid differentiation. In this study, we show that hypoxia-induced GATA1 expression is mediated by HIF1 in erythroid cells. Under hypoxic conditions, significantly increased GATA1 mRNA and protein levels were detected in K562 cells and erythroid induction cultures of CD34(+) haematopoietic stem/progenitor cells. Enforced HIF1α expression increased GATA1 expression, while HIF1α knockdown by RNA interference decreased GATA1 expression. In silico analysis revealed one potential hypoxia response element (HRE). The results from reporter gene and mutation analysis suggested that this element is necessary for hypoxic response. Chromatin immunoprecipitation (ChIP)-PCR showed that the putative HRE was recognized and bound by HIF1 in vivo. These results demonstrate that the up-regulation of GATA1 during hypoxia is directly mediated by HIF1.The mRNA expression of some erythroid differentiation markers was increased under hypoxic conditions, but decreased with RNA interference of HIF1α or GATA1. Flow cytometry analysis also indicated that hypoxia, desferrioxamine or CoCl(2) induced expression of erythroid surface markers CD71 and CD235a, while expression repression of HIF1α or GATA1 by RNA interference led to a decreased expression of CD235a. These results suggested that HIF1-mediated GATA1 up-regulation promotes erythropoiesis in order to satisfy the needs of an organism under hypoxic conditions. © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

  12. The radiosensitivity of glioblastoma cell lines after hypoxia-induced Bax expression

    International Nuclear Information System (INIS)

    Chen, J.K.; Hu, L.J.; Kong, E.L.; Lamborn, K.R.; Deen, D.F.

    2003-01-01

    Full text: Radiation therapy is the most effective treatment after surgery for patients with malignant gliomas. However, the hypoxic cells exclusive to tumor tissue have proven resistant to both radiotherapy and many forms of chemotherapy. In order to specifically target these hypoxic cells, U-251 MG and U-87 MG human glioblastoma cells were stably transfected with constructs containing the suicide gene Bax under the regulation of nine copies of hypoxia-responsive elements (HREs). During hypoxia, the transcriptional complex hypoxia-inducible-factor 1 (HIF-1) binds to HRE and facilitates the transcription of downstream genes. Previously, hypoxia-induced Bax expression in transfected U-251 and U-87 clone cells has been shown to increase cell killing. The benefits of the gene therapy could be further expanded if Bax also acted to increase the sensitivity of these clone cells to radiation. To determine whether this was the case, parent and clone cells were irradiated with graded doses of X-rays under hypoxic conditions. These cells were then left hypoxic for varying durations of time, after which they were incubated for two weeks under aerated conditions to assay for clonogenic cell survival. After less than an hour under hypoxia, both U-251 and U-87 clone cells appeared significantly more sensitive to radiation than their respective parent cells. However, after longer amounts of time under anoxia, higher surviving fractions were found in each clone that were consistent with those of their respective parent cell line, showing that potentially lethal damage repair (PLDR) had occurred in the clone cells. Parent cells did not exhibit PLDR. Results are inconclusive at this point in time. Western blot analyses detailing the amount of Bax expression at each time point as well as further research exploring different durations of hypoxia will be necessary to reveal the nature of the correlation between Bax expression and radiosensitivity. Supported by NS-42927 and CA-85356

  13. Prostate cancer cell lines under hypoxia exhibit greater stem-like properties.

    Directory of Open Access Journals (Sweden)

    Yuanyuan Ma

    Full Text Available Hypoxia is an important environmental change in many cancers. Hypoxic niches can be occupied by cancer stem/progenitor-like cells that are associated with tumor progression and resistance to radiotherapy and chemotherapy. However, it has not yet been fully elucidated how hypoxia influences the stem-like properties of prostate cancer cells. In this report, we investigated the effects of hypoxia on human prostate cancer cell lines, PC-3 and DU145. In comparison to normoxia (20% O(2, 7% O(2 induced higher expressions of HIF-1α and HIF-2α, which were associated with upregulation of Oct3/4 and Nanog; 1% O(2 induced even greater levels of these factors. The upregulated NANOG mRNA expression in hypoxia was confirmed to be predominantly retrogene NANOGP8. Similar growth rates were observed for cells cultivated under hypoxic and normoxic conditions for 48 hours; however, the colony formation assay revealed that 48 hours of hypoxic pretreatment resulted in the formation of more colonies. Treatment with 1% O(2 also extended the G(0/G(1 stage, resulting in more side population cells, and induced CD44 and ABCG2 expressions. Hypoxia also increased the number of cells positive for ABCG2 expression, which were predominantly found to be CD44(bright cells. Correspondingly, the sorted CD44(bright cells expressed higher levels of ABCG2, Oct3/4, and Nanog than CD44(dim cells, and hypoxic pretreatment significantly increased the expressions of these factors. CD44(bright cells under normoxia formed significantly more colonies and spheres compared with the CD44(dim cells, and hypoxic pretreatment even increased this effect. Our data indicate that prostate cancer cells under hypoxia possess greater stem-like properties.

  14. The tell-tale: what do heart rate; skin temperature and skin conductance reveal about emotions of people with severe and profound intellectual disabilities?

    Science.gov (United States)

    Vos, Pieter; De Cock, Paul; Munde, Vera; Petry, Katja; Van Den Noortgate, Wim; Maes, Bea

    2012-01-01

    Identifying emotions in people with severe and profound intellectual disabilities is a difficult challenge. Since self-reports are not available, behaviour is the most used source of information. Given the limitations and caveats associated with using behaviour as the sole source of information about their emotions, it is important to supplement behavioural information with information from another source. As it is accepted that emotions consist of language, behaviour and physiology, in this article we investigated if physiology could give information about the emotions of people with severe and profound intellectual disabilities. To this aim we tested hypotheses derived from the motivational model of Bradley, Codispoti, Cuthbert, and Lang (2001) about the relation between heart rate and the valence of emotions and between heart rate, skin conductance and skin temperature and behavioural expressions of emotions of people with severe and profound intellectual disability. We presented 27 participants with 4 staff-selected negative and 4 staff-selected positive stimuli. The situations were videotaped and their heart rate, skin conductance and skin temperature was measured. Each behaviour of the participant was coded using the observational method developed by Petry and Maes (2006). As hypothesized, we found a lower heart rate when participants were presented with negative stimuli than when they were presented with positive stimuli in the first 6s of stimuli presentation. Their skin temperature was higher for the expression of low intensity negative emotions compared to the expression of low intensity positive emotions. The results suggest that, as with people without disability, heart rate and skin temperature can give information about the emotions of persons with severe and profound ID. Copyright © 2012 Elsevier Ltd. All rights reserved.

  15. In vivo Identification and Specificity assessment of mRNA markers of hypoxia in human and mouse tumors

    International Nuclear Information System (INIS)

    Busk, Morten; Toustrup, Kasper; Sørensen, Brita S; Alsner, Jan; Horsman, Michael R; Jakobsen, Steen; Overgaard, Jens

    2011-01-01

    Tumor hypoxia is linked to poor prognosis, but identification and quantification of tissue hypoxia remains a challenge. The hypoxia-specificity of HIF-1α target genes in vivo has been questioned due to the confounding influence of other microenvironmental abnormalities known to affect gene expression (e.g., low pH). Here we describe a new technique that by exploiting intratumoral oxygenation heterogeneity allows us to identify and objectively rank the most robust mRNA hypoxia biomarkers. Mice carrying human (FaDu dd ) or murine (SCCVII) tumors were injected with the PET hypoxia tracer FAZA. Four hours post-injection tumors were removed, frozen, and crushed into milligram-sized fragments, which were transferred individually to pre-weighed tubes containing RNAlater and then weighed. For each fragment radioactivity per tissue mass and expression patterns of selected mRNA biomarkers were analyzed and compared. In both tumour models, fragmentation into pieces weighing 10 to 60 mg resulted in tissue fragments with highly variable relative content of hypoxic cells as evidenced by an up to 13-fold variation in FAZA radioactivity per mass of tissue. Linear regression analysis comparing FAZA retention with patterns of gene expression in individual tissue fragments revealed that CA9, GLUT1 and LOX mRNA levels were equally and strongly correlated to hypoxic extent in FaDu dd . The same link between hypoxia and gene expression profile was observed for CA9 and GLUT1, but not LOX, in SCCVII tumors. Apparent in vivo hypoxia-specificity for other putative molecular markers of tissue hypoxia was considerably weaker. The portrayed technique allows multiple pairwise measurements of mRNA transcript levels and extent of hypoxia in individual tumors at a smallest possible volumetric scale which (by limiting averaging effects inherent to whole-tumor analysis) strengthen the conclusiveness on true hypoxia-specificity of candidate genes while limiting the required number of tumors. Among

  16. In vivo Identification and Specificity assessment of mRNA markers of hypoxia in human and mouse tumors

    Directory of Open Access Journals (Sweden)

    Horsman Michael R

    2011-02-01

    Full Text Available Abstract Background Tumor hypoxia is linked to poor prognosis, but identification and quantification of tissue hypoxia remains a challenge. The hypoxia-specificity of HIF-1α target genes in vivo has been questioned due to the confounding influence of other microenvironmental abnormalities known to affect gene expression (e.g., low pH. Here we describe a new technique that by exploiting intratumoral oxygenation heterogeneity allows us to identify and objectively rank the most robust mRNA hypoxia biomarkers. Methods Mice carrying human (FaDudd or murine (SCCVII tumors were injected with the PET hypoxia tracer FAZA. Four hours post-injection tumors were removed, frozen, and crushed into milligram-sized fragments, which were transferred individually to pre-weighed tubes containing RNAlater and then weighed. For each fragment radioactivity per tissue mass and expression patterns of selected mRNA biomarkers were analyzed and compared. Results In both tumour models, fragmentation into pieces weighing 10 to 60 mg resulted in tissue fragments with highly variable relative content of hypoxic cells as evidenced by an up to 13-fold variation in FAZA radioactivity per mass of tissue. Linear regression analysis comparing FAZA retention with patterns of gene expression in individual tissue fragments revealed that CA9, GLUT1 and LOX mRNA levels were equally and strongly correlated to hypoxic extent in FaDudd. The same link between hypoxia and gene expression profile was observed for CA9 and GLUT1, but not LOX, in SCCVII tumors. Apparent in vivo hypoxia-specificity for other putative molecular markers of tissue hypoxia was considerably weaker. Conclusions The portrayed technique allows multiple pairwise measurements of mRNA transcript levels and extent of hypoxia in individual tumors at a smallest possible volumetric scale which (by limiting averaging effects inherent to whole-tumor analysis strengthen the conclusiveness on true hypoxia-specificity of candidate

  17. Toward a quantitative reconstruction of hypoxia from varve records in the large perialpin Lake Bourget over the last 150 years

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    Jenny, J.-P.; Arnaud, F.; Dorioz, J. M.; Giguet Covex, C.; Frossard, V.; Sabatier, P.; Millet, L.; Reyss, J. L.; Tachikawa, K.; Romeyer, O.; Pignol, C.; Mallet, E.; Perga, M. E.

    2012-04-01

    Hypoxia -defined as dissolved oxygen ≤2 mg/l- is a severe detrimental factor for aquatic environments. In lakes, despit the importance for management, it is generally still hard to estimate hypoxia because of the lack of appropriate proxies or restricted number of sample cores. In this study, by using (40) sediment core data from chosen depths, we propose to go a step further toward a quantitative reconstruction of hypoxia integrating the extension of hypoxic water layer, both through space (volume) and time (yearly value). For that we went a step further in using an existing proxy: varve preservation. It is generally well-adapted for hypoxia detection, but not yet developed for small scale time and space variations through a complete large lake basin. Varves preservation is the consequence of the death of most of benthic macro-organisms that normally mix-up first millimetres of sediments, due to oxygen depletion. In Lake Bourget recent laminated sediments correspond to biochemical varves. We assume that their preservation results from a threshold in dissolved oxygen concentrations induced by seasonal hypoxia. Chironomids, organic matter and Mn/Fe ratio (XRF) were used as complementary proxies of hypoxia to validate our assumptions concerning varves. Our results show that volume of hypoxia can be annually estimated according to varve records through lake. Volumes of hypoxia varied through time in the Lake Bourget. Sediments recorded first the onset of severe hypoxia in the deepest part of the basin (-140m) in AD 1935±1, corresponding to 11.103m3 of hypoxic waters. Then hypoxic surface progressively extended on the slope until reaching a maximum at -90m in AD 1960, leading to 306.103m3 of hypoxic waters. After a retreat dated to AD 1980, hypoxia seemed to re-extend until today. Those fluctuations over the "oscillating zone" of hypoxia (-90 to -133m) were compared with potential forcing factors. The onset of hypolimnetic hypoxia is commonly attributed to

  18. Transcriptomic and proteomic approach to identify differentially expressed genes and proteins in Arabidopsis thaliana mutants lacking chloroplastic 1 and cytosolic FBPases reveals several levels of metabolic regulation.

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    Soto-Suárez, Mauricio; Serrato, Antonio J; Rojas-González, José A; Bautista, Rocío; Sahrawy, Mariam

    2016-12-01

    During the photosynthesis, two isoforms of the fructose-1,6-bisphosphatase (FBPase), the chloroplastidial (cFBP1) and the cytosolic (cyFBP), catalyse the first irreversible step during the conversion of triose phosphates (TP) to starch or sucrose, respectively. Deficiency in cyFBP and cFBP1 isoforms provokes an imbalance of the starch/sucrose ratio, causing a dramatic effect on plant development when the plastidial enzyme is lacking. We study the correlation between the transcriptome and proteome profile in rosettes and roots when cFBP1 or cyFBP genes are disrupted in Arabidopsis thaliana knock-out mutants. By using a 70-mer oligonucleotide microarray representing the genome of Arabidopsis we were able to identify 1067 and 1243 genes whose expressions are altered in the rosettes and roots of the cfbp1 mutant respectively; whilst in rosettes and roots of cyfbp mutant 1068 and 1079 genes are being up- or down-regulated respectively. Quantitative real-time PCR validated 100% of a set of 14 selected genes differentially expressed according to our microarray analysis. Two-dimensional (2-D) gel electrophoresis-based proteomic analysis revealed quantitative differences in 36 and 26 proteins regulated in rosettes and roots of cfbp1, respectively, whereas the 18 and 48 others were regulated in rosettes and roots of cyfbp mutant, respectively. The genes differentially expressed and the proteins more or less abundant revealed changes in protein metabolism, RNA regulation, cell signalling and organization, carbon metabolism, redox regulation, and transport together with biotic and abiotic stress. Notably, a significant set (25%) of the proteins identified were also found to be regulated at a transcriptional level. This transcriptomic and proteomic analysis is the first comprehensive and comparative study of the gene/protein re-adjustment that occurs in photosynthetic and non-photosynthetic organs of Arabidopsis mutants lacking FBPase isoforms.

  19. Inhibition of Hypoxia Inducible Factor Alpha and Astrocyte-Elevated Gene-1 Mediates Cryptotanshinone Exerted Antitumor Activity in Hypoxic PC-3 Cells

    Directory of Open Access Journals (Sweden)

    Hyo-Jeong Lee

    2012-01-01

    Full Text Available Although cryptotanshinone (CT was known to exert antitumor activity in several cancers, its molecular mechanism under hypoxia still remains unclear. Here, the roles of AEG-1 and HIF-1α in CT-induced antitumor activity were investigated in hypoxic PC-3 cells. CT exerted cytotoxicity against prostate cancer cells and suppressed HIF-1α accumulation and AEG-1 expression in hypoxic PC-3 cells. Also, AEG-1 was overexpressed in prostate cancer cells. Interestingly, HIF-1α siRNA transfection enhanced the cleavages of caspase-9,3, and PAPR and decreased expression of Bcl-2 and AEG1 induced by CT in hypoxic PC-3 cells. Of note, DMOG enhanced the stability of AEG-1 and HIF-1α during hypoxia. Additionally, CT significantly reduced cellular level of VEGF in PC-3 cells and disturbed tube formation of HUVECs. Consistently, ChIP assay revealed that CT inhibited the binding of HIF-1α to VEGF promoter. Furthermore, CT at 10 mg/kg suppressed the growth of PC-3 cells in BALB/c athymic nude mice by 46.4% compared to untreated control. Consistently, immunohistochemistry revealed decreased expression of Ki-67, CD34, VEGF, carbonic anhydrase IX, and AEG-1 indices in CT-treated group compared to untreated control. Overall, our findings suggest that CT exerts antitumor activity via inhibition of HIF-1α, AEG1, and VEGF as a potent chemotherapeutic agent.

  20. Neutralizing S1P inhibits intratumoral hypoxia, induces vascular remodelling and sensitizes to chemotherapy in prostate cancer

    Science.gov (United States)

    Ader, Isabelle; Golzio, Muriel; Andrieu, Guillaume; Zalvidea, Santiago; Richard, Sylvain; Sabbadini, Roger A.; Malavaud, Bernard; Cuvillier, Olivier

    2015-01-01

    Hypoxia promotes neovascularization, increased tumor growth, and therapeutic resistance. The transcription factor, hypoxia-inducible factor 1α (HIF-1α), has been reported as the master driver of adaptation to hypoxia. We previously identified the sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) pathway as a new modulator of HIF-1α under hypoxia. Taking advantage of a monoclonal antibody neutralizing extracellular S1P (sphingomab), we report that inhibition of S1P extracellular signaling blocks HIF-1α accumulation and activity in several cancer cell models exposed to hypoxia. In an orthotopic xenograft model of prostate cancer, we show that sphingomab reduces hypoxia and modifies vessel architecture within 5 days of treatment, leading to increased intratumoral blood perfusion. Supporting the notion that a transient vascular normalization of tumor vessels is the mechanism by which sphingomab exerts its effects, we demonstrate that administration of the antibody for 5 days before chemotherapy is more effective at local tumor control and metastatic dissemination than any other treatment scheduling. These findings validate sphingomab as a potential new normalization agent that could contribute to successful sensitization of hypoxic tumors to chemotherapy. PMID:25915662

  1. Role of hypoxia and hypoxia inducible factor in physiological and pathological conditions

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    Mozhgan Jahani

    2017-11-01

    Full Text Available Introduction: Organisms are exposed to oxygen deprivation (Hypoxia in various physiological and pathological conditions. There are different conserve evolutionary responses to counterview with this stress that primary transcriptional response to stress related to hypoxia is interceded by hypoxia-inducible factor (HIF-1 in mammals. This factor can regulate different genes that have essential roles in adaptation to this condition. In this review, the role of this factor in physiological and pathological conditions under hypoxic condition has been evaluated after examining structural features and regulation characteristics of HIF-1. Methods: First, articles related to the keywords of hypoxia and HIF-1 (from 1991-2016 were searched from valid databases such as Springer Link, Google Scholar, PubMed and Science direct. Then, the articles correlated with hypoxia, HIF-1 and their roles in physiological and pathological conditions (120 articles were searched and just 64 articles were selected for this study. Result: According to studies, there are different genes in cells and organs that can be regulated by HIF-1. Activation of genes expression by this protein occurs through its linkage to cis-acting of 50 base pair hypoxia response element (HRE region located in their promotor and enhancer. Depending on circumstances, activation of these genes can be beneficial or harmful. Conclusion: Activation of different genes in hypoxia by HIF-1 has different effects on physiological and pathological conditions. Therefore, HIF-1, as a hypoxia-inducible factor in hypoxic conditions, plays an essential role in the adaptation of cells and organs to changes related to the presence of oxygen.

  2. Hypoxia and cyanobacteria blooms - are they really natural features of the late Holocene history of the Baltic Sea?

    Directory of Open Access Journals (Sweden)

    L. Zillén

    2010-08-01

    Full Text Available During the last century (1900s industrialized forms of agriculture and human activities have caused eutrophication of Baltic Sea waters. As a consequence, the hypoxic zone in the Baltic Sea has increased, especially during the last 50 years, and has caused severe ecosystem disturbance. Climate forcing has been proposed to be responsible for the reported trends in hypoxia (< 2 mg/l O2 both during the last c. 100 years (since c. 1900 AD and the Medieval Period. By contrast, investigations of the degree of anthropogenic forcing on the ecosystem on long time-scales (millennial and greater have not been thoroughly addressed. This paper examines evidence for anthropogenic disturbance of the marine environment beyond the last century through the analysis of the human population growth, technological development and land-use changes in the drainage area. Natural environmental changes, i.e. changes in the morphology and depths of the Baltic basin and the sills, were probably the main driver for large-scale hypoxia during the early Holocene (8000–4000 cal yr BP. We show that hypoxia during the last two millennia has followed the general expansion and contraction trends in Europe and that human perturbation has been an important driver for hypoxia during that time. Hypoxia occurring during the Medieval Period coincides with a doubling of the population (from c. 4.6 to 9.5 million in the Baltic Sea watershed, a massive reclamation of land in both established and marginal cultivated areas and significant increases in soil nutrient release. The role of climate forcing on hypoxia in the Baltic Sea has yet to be demonstrated convincingly, although it could have helped to sustain hypoxia through enhanced salt water inflows or through changes in hydrological inputs. In addition, cyanobacteria blooms are not natural features of the Baltic Sea as previously deduced, but are a consequence of enhanced phosphorus release from the seabed that occurs during

  3. Intermittent Hypoxia Impairs Glucose Homeostasis in C57BL6/J Mice: Partial Improvement with Cessation of the Exposure

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    Polak, Jan; Shimoda, Larissa A.; Drager, Luciano F.; Undem, Clark; McHugh, Holly; Polotsky, Vsevolod Y.; Punjabi, Naresh M.

    2013-01-01

    Objectives: Obstructive sleep apnea is associated with insulin resistance, glucose intolerance, and type 2 diabetes mellitus. Although several studies have suggested that intermittent hypoxia in obstructive sleep apnea may induce abnormalities in glucose homeostasis, it remains to be determined whether these abnormalities improve after discontinuation of the exposure. The objective of this study was to delineate the effects of intermittent hypoxia on glucose homeostasis, beta cell function, and liver glucose metabolism and to investigate whether the impairments improve after the hypoxic exposure is discontinued. Interventions: C57BL6/J mice were exposed to 14 days of intermittent hypoxia, 14 days of intermittent air, or 7 days of intermittent hypoxia followed by 7 days of intermittent air (recovery paradigm). Glucose and insulin tolerance tests were performed to estimate whole-body insulin sensitivity and calculate measures of beta cell function. Oxidative stress in pancreatic tissue and glucose output from isolated hepatocytes were also assessed. Results: Intermittent hypoxia increased fasting glucose levels and worsened glucose tolerance by 67% and 27%, respectively. Furthermore, intermittent hypoxia exposure was associated with impairments in insulin sensitivity and beta cell function, an increase in liver glycogen, higher hepatocyte glucose output, and an increase in oxidative stress in the pancreas. While fasting glucose levels and hepatic glucose output normalized after discontinuation of the hypoxic exposure, glucose intolerance, insulin resistance, and impairments in beta cell function persisted. Conclusions: Intermittent hypoxia induces insulin resistance, impairs beta cell function, enhances hepatocyte glucose output, and increases oxidative stress in the pancreas. Cessation of the hypoxic exposure does not fully reverse the observed changes in glucose metabolism. Citation: Polak J; Shimoda LA; Drager LF; Undem C; McHugh H; Polotsky VY; Punjabi NM

  4. Combined Use of Systematic Conservation Planning, Species Distribution Modelling, and Connectivity Analysis Reveals Severe Conservation Gaps in a Megadiverse Country (Peru)

    Science.gov (United States)

    Fajardo, Javier; Lessmann, Janeth; Bonaccorso, Elisa; Devenish, Christian; Muñoz, Jesús

    2014-01-01

    Conservation planning is crucial for megadiverse countries where biodiversity is coupled with incomplete reserve systems and limited resources to invest in conservation. Using Peru as an example of a megadiverse country, we asked whether the national system of protected areas satisfies biodiversity conservation needs. Further, to complement the existing reserve system, we identified and prioritized potential conservation areas using a combination of species distribution modeling, conservation planning and connectivity analysis. Based on a set of 2,869 species, including mammals, birds, amphibians, reptiles, butterflies, and plants, we used species distribution models to represent species' geographic ranges to reduce the effect of biased sampling and partial knowledge about species' distributions. A site-selection algorithm then searched for efficient and complementary proposals, based on the above distributions, for a more representative system of protection. Finally, we incorporated connectivity among areas in an innovative post-hoc analysis to prioritize those areas maximizing connectivity within the system. Our results highlight severe conservation gaps in the Coastal and Andean regions, and we propose several areas, which are not currently covered by the existing network of protected areas. Our approach helps to find areas that contribute to creating a more representative, connected and efficient network. PMID:25479411

  5. Microenvironmental oxygen partial pressure in acute myeloid leukemia: Is there really a role for hypoxia?

    Science.gov (United States)

    Rieger, Christina T; Fiegl, Michael

    2016-07-01

    Reduced oxygen partial pressure (pO2) has been recognized as being relevant in hematopoiesis and the pathophysiology of malignant diseases. Although hypoxic (meaning insufficient supply of oxygen) and anoxic areas are present and of pathophysiologic importance (by hypoxia-induced pathways such as HiF1α) in solid tumors, this may not be true for (malignant) hematologic cells. Hematopoiesis occurs in the stem cell niche, which is characterized, among other things, by extremely low pO2. However, in contrast to solid tumors, in this context, the low pO2 is physiological and this feature, among others, is shared by the malignant stem cell niche harboring leukemia-initiating cells. Upon differentiation, hematopoietic cells are constantly exposed to changes in pO2 as they travel throughout the human body and encounter arterial and venous blood and migrate into oxygen-carrier-free tissue with low pO2. Hematologic malignancies such as acute myeloid leukemia (AML) make little difference in this respect and, whereas low oxygen is the usual environment of AML cells, recent evidence suggests no role for real hypoxia. Although there is no evidence that AML pathophysiology is related to hypoxia, leukemic blasts still show several distinct biological features when exposed to reduced pO2: they down- or upregulate membrane receptors such as CXCR4 or FLT3, activate or inhibit intracellular signaling pathways such as PI3K, and specifically secrete cytokines (IL-8). In summary, reduced pO2 should not be mistaken for hypoxia (nor should it be so called), and it does not automatically induce hypoxia-response mechanisms; therefore, a strict distinction should be made between physiologically low pO2 (physoxia) and hypoxia. Copyright © 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

  6. Chronic intermittent hypoxia induces atherosclerosis via activation of adipose angiopoietin-like 4.

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    Drager, Luciano F; Yao, Qiaoling; Hernandez, Karen L; Shin, Mi-Kyung; Bevans-Fonti, Shannon; Gay, Jason; Sussan, Thomas E; Jun, Jonathan C; Myers, Allen C; Olivecrona, Gunilla; Schwartz, Alan R; Halberg, Nils; Scherer, Philipp E; Semenza, Gregg L; Powell, David R; Polotsky, Vsevolod Y

    2013-07-15

    Obstructive sleep apnea is a risk factor for dyslipidemia and atherosclerosis, which have been attributed to chronic intermittent hypoxia (CIH). Intermittent hypoxia inhibits a key enzyme of lipoprotein clearance, lipoprotein lipase, and up-regulates a lipoprotein lipase inhibitor, angiopoietin-like 4 (Angptl4), in adipose tissue. The effects and mechanisms of Angptl4 up-regulation in sleep apnea are unknown. To examine whether CIH induces dyslipidemia and atherosclerosis by increasing adipose Angptl4 via hypoxia-inducible factor-1 (HIF-1). ApoE(-/-) mice were exposed to intermittent hypoxia or air for 4 weeks while being treated with Angptl4-neutralizing antibody or vehicle. In vehicle-treated mice, hypoxia increased adipose Angptl4 levels, inhibited adipose lipoprotein lipase, increased fasting levels of plasma triglycerides and very low density lipoprotein cholesterol, and increased the size of atherosclerotic plaques. The effects of CIH were abolished by the antibody. Hypoxia-induced increases in plasma fasting triglycerides and adipose Angptl4 were not observed in mice with germline heterozygosity for a HIF-1α knockout allele. Transgenic overexpression of HIF-1α in adipose tissue led to dyslipidemia and increased levels of adipose Angptl4. In cultured adipocytes, constitutive expression of HIF-1α increased Angptl4 levels, which was abolished by siRNA. Finally, in obese patients undergoing bariatric surgery, the severity of nocturnal hypoxemia predicted Angptl4 levels in subcutaneous adipose tissue. HIF-1-mediated increase in adipose Angptl4 and the ensuing lipoprotein lipase inactivation may contribute to atherosclerosis in patients with sleep apnea.

  7. Aberrant methylation and associated transcriptional mobilization of Alu elements contributes to genomic instability in hypoxia.

    Science.gov (United States)

    Pal, Arnab; Srivastava, Tapasya; Sharma, Manish K; Mehndiratta, Mohit; Das, Prerna; Sinha, Subrata; Chattopadhyay, Parthaprasad

    2010-11-01

    Hypoxia is an integral part of tumorigenesis and contributes extensively to the neoplastic phenotype including drug resistance and genomic instability. It has also been reported that hypoxia results in global demethylation. Because a majority of the cytosine-phosphate-guanine (CpG) islands are found within the repeat elements of DNA, and are usually methylated under normoxic conditions, we suggested that retrotransposable Alu or short interspersed nuclear elements (SINEs) which show altered methylation and associated changes of gene expression during hypoxia, could be associated with genomic instability. U87MG glioblastoma cells were cultured in 0.1% O₂ for 6 weeks and compared with cells cultured in 21% O₂ for the same duration. Real-time PCR analysis showed a significant increase in SINE and reverse transcriptase coding long interspersed nuclear element (LINE) transcripts during hypoxia. Sequencing of bisulphite treated DNA as well as the Combined Bisulfite Restriction Analysis (COBRA) assay showed that the SINE loci studied underwent significant hypomethylation though there was patchy hypermethylation at a few sites. The inter-alu PCR profile of DNA from cells cultured under 6-week hypoxia, its 4-week revert back to normoxia and 6-week normoxia showed several changes in the band pattern indicating increased alu mediated genomic alteration. Our results show that aberrant methylation leading to increased transcription of SINE and reverse transcriptase associated LINE elements could lead to increased genomic instability in hypoxia. This might be a cause of genetic heterogeneity in tumours especially in variegated hypoxic environment and lead to a development of foci of more aggressive tumour cells. © 2009 The Authors Journal compilation © 2010 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

  8. Obstructive sleep apnea and intermittent hypoxia increase expression of dual specificity phosphatase 1.

    Science.gov (United States)

    Hoffmann, Michal S; Singh, Prachi; Wolk, Robert; Narkiewicz, Krzysztof; Somers, Virend K

    2013-12-01

    Dual specificity phosphatase 1 (DUSP1) inhibits mitogen activated protein kinase activity, and is activated by several stimuli such as sustained hypoxia, oxidative stress, and hormones. However, the effect of intermittent hypoxia is not known. The aim of this study was to evaluate the role of intermittent hypoxia on DUSP1 expression, and to validate its role in a human model of intermittent hypoxia, as seen in obstructive sleep apnea (OSA). OSA is characterized by recurrent episodes of hypoxemia/reoxygenation and is a known risk factor for cardiovascular morbidity. In-vitro studies using human coronary artery endothelial cells (HCAEC) and ex-vivo studies using white blood cells isolated from healthy and OSA subjects. Intermittent hypoxia induced DUSP1 expression in human coronary artery endothelial cells (HCAEC), and in granulocytes isolated from healthy human subjects. Functionally, DUSP1 increased the expression and activity of manganese superoxide dismutase (MnSOD) in HCAEC. Further, significant increases in DUSP1 mRNA from total blood, and in DUSP1 protein in mononuclear cells and granulocytes isolated from OSA subjects, were observed in the early morning hours after one night of intermittent hypoxemia due to untreated OSA. This early-morning OSA-induced augmentation of DUSP1 gene expression was attenuated by continuous positive airway pressure (CPAP) treatment of OSA. Intermittent hypoxia increases MnSOD activity via increased DUSP1 expression in HCAEC. Similarly, overnight intermittent hypoxemia in patients with OSA induces expression of DUSP1, which may mediate increases of MnSOD expression and activity. This may contribute significantly to neutralizing the effects of reactive oxygen species, a consequence of the intermittent hypoxemia/reperfusion elicited by OSA. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  9. Impact of age on intermittent hypoxia in obstructive sleep apnea: a propensity-matched analysis.

    Science.gov (United States)

    Bostanci, Asli; Bozkurt, Selen; Turhan, Murat

    2018-05-01

    To determine independent relationship of aging with chronic intermittent hypoxia, we compared hypoxia-related polysomnographic variables of geriatric patients (aged ≥ 65 years) with an apnea-hypopnea index (AHI)-, gender-, body mass index (BMI)-, and neck circumference-matched cohort of non-geriatric patients. The study was conducted using clinical and polysomnographic data of 1280 consecutive patients who underwent complete polysomnographic evaluation for suspected sleep-disordered breathing (SDB) at a single sleep disorder center. A propensity score-matched analysis was performed to obtain matched cohorts of geriatric and non-geriatric patients, which resulted in successful matching of 168 patients from each group. Study groups were comparable for gender (P = 0.999), BMI (P = 0.940), neck circumference (P = 0.969), AHI (P = 0.935), and severity of SDB (P = 0.089). The oximetric variables representing the duration of chronic intermittent hypoxia such as mean (P = 0.001), the longest (P = 0.001) and total apnea durations (P = 0.003), mean (P = 0.001) and the longest hypopnea durations (P = 0.001), and total sleep time with oxygen saturation below 90% (P = 0.008) were significantly higher in the geriatric patients as compared with younger adults. Geriatric patients had significantly lower minimum (P = 0.013) and mean oxygen saturation (P = 0.001) than non-geriatric patients. The study provides evidence that elderly patients exhibit more severe and deeper nocturnal intermittent hypoxia than the younger adults, independent of severity of obstructive sleep apnea, BMI, gender, and neck circumference. Hypoxia-related polysomnographic variables in geriatric patients may in fact reflect a physiological aging process rather than the severity of a SDB.

  10. Metabolic Plasticity Enables Circadian Adaptation to Acute Hypoxia in Zebrafish Cells.

    Science.gov (United States)

    Sandbichler, Adolf M; Jansen, Bianca; Peer, Bettina A; Paulitsch, Monika; Pelster, Bernd; Egg, Margit

    2018-01-01

    Reduced oxygen availability, hypoxia, is frequently encountered by organisms, tissues and cells, in aquatic environments as well as in high altitude or under pathological conditions such as infarct, stroke or cancer. The hypoxic signaling pathway was found to be mutually intertwined with circadian timekeeping in vertebrates and, as reported recently, also in mammals. However, the impact of hypoxia on intracellular metabolic oscillations is still unknown. For determination of metabolites we used Multilabel Reader based fluorescence and luminescence assays, circadian levels of Hypoxia Inducible Factor 1 alpha and oxidized peroxiredoxins were semi quantified by Western blotting and ratiometric quantification of cytosolic and mitochondrial H2O2 was achieved with stable transfections of a redox sensitive green fluorescent protein sensor into zebrafish fibroblasts. Circadian oscillations of core clock gene mRNA´s were assessed using realtime qPCR with subsequent cosine wave fit analysis. Here we show that under normoxia primary metabolic activity of cells predominately occurs during day time and that after acute hypoxia of two hours, administrated immediately before each sampling point, steady state concentrations of glycolytic key metabolites such as glucose and lactate reveal to be highly rhythmic, following a circadian pattern with highest levels during the night periods and reflecting the circadian variation of the cellular response to hypoxia. Remarkably, rhythms in glycolysis are transferred to cellular energy states under normoxic conditions, so that ADP/ATP ratios oscillate as well, which is the first evidence for cycling ADP/ATP pools in a metazoan cell line to our knowledge. Furthermore, the hypoxia induced alterations in rhythms of glycolysis lead to the alignment of three major cellular redox systems, namely the circadian oscillations of NAD+/NADH and NADP+/NADPH ratios and of increased nocturnal levels of oxidized peroxiredoxins, resulting in a highly

  11. Metabolic Plasticity Enables Circadian Adaptation to Acute Hypoxia in Zebrafish Cells

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    Adolf M. Sandbichler

    2018-04-01

    Full Text Available Background/Aims: Reduced oxygen availability, hypoxia, is frequently encountered by organisms, tissues and cells, in aquatic environments as well as in high altitude or under pathological conditions such as infarct, stroke or cancer. The hypoxic signaling pathway was found to be mutually intertwined with circadian timekeeping in vertebrates and, as reported recently, also in mammals. However, the impact of hypoxia on intracellular metabolic oscillations is still unknown. Methods: For determination of metabolites we used Multilabel Reader based fluorescence and luminescence assays, circadian levels of Hypoxia Inducible Factor 1 alpha and oxidized peroxiredoxins were semi quantified by Western blotting and ratiometric quantification of cytosolic and mitochondrial H2O2 was achieved with stable transfections of a redox sensitive green fluorescent protein sensor into zebrafish fibroblasts. Circadian oscillations of core clock gene mRNA´s were assessed using realtime qPCR with subsequent cosine wave fit analysis. Results: Here we show that under normoxia primary metabolic activity of cells predominately occurs during day time and that after acute hypoxia of two hours, administrated immediately before each sampling point, steady state concentrations of glycolytic key metabolites such as glucose and lactate reveal to be highly rhythmic, following a circadian pattern with highest levels during the night periods and reflecting the circadian variation of the cellular response to hypoxia. Remarkably, rhythms in glycolysis are transferred to cellular energy states under normoxic conditions, so that ADP/ATP ratios oscillate as well, which is the first evidence for cycling ADP/ATP pools in a metazoan cell line to our knowledge. Furthermore, the hypoxia induced alterations in rhythms of glycolysis lead to the alignment of three major cellular redox systems, namely the circadian oscillations of NAD+/NADH and NADP+/NADPH ratios and of increased nocturnal levels

  12. Frequently asked questions in hypoxia research

    Directory of Open Access Journals (Sweden)

    Wenger RH

    2015-09-01

    Full Text Available Roland H Wenger,1,2 Vartan Kurtcuoglu,1,2 Carsten C Scholz,1,2 Hugo H Marti,3 David Hoogewijs1,2,4 1Institute of Physiology and Zurich Center for Human Physiology (ZIHP, University of Zurich, 2National Center of Competence in Research “Kidney.CH”, Zurich, Switzerland; 3Institute of Physiology and Pathophysiology, University of Heidelberg, Heidelberg, 4Institute of Physiology, University of Duisburg-Essen, Essen, Germany Abstract: “What is the O2 concentration in a normoxic cell culture incubator?” This and other frequently asked questions in hypoxia research will be answered in this review. Our intention is to give a simple introduction to the physics of gases that would be helpful for newcomers to the field of hypoxia research. We will provide background knowledge about questions often asked, but without straightforward answers. What is O2 concentration, and what is O2 partial pressure? What is normoxia, and what is hypoxia? How much O2 is experienced by a cell residing in a culture dish in vitro vs in a tissue in vivo? By the way, the O2 concentration in a normoxic incubator is 18.6%, rather than 20.9% or 20%, as commonly stated in research publications. And this is strictly only valid for incubators at sea level. Keywords: gas laws, hypoxia-inducible factor, Krogh tissue cylinder, oxygen diffusion, partial pressure, tissue oxygen levels

  13. Hypoxanthine as a measurement of hypoxia.

    Science.gov (United States)

    Saugstad, O D

    1975-04-01

    The hypoxanthine concentration in plasma was found to be a sensitive parameter of hypoxia of the fetus and the newborn infant. The plasma level of hypoxanthine in the umbilical cord in 29 newborn infants with normal delivery varied between 0 and 11.0 mumol/liter with a mean of 5.8 mumol/liter, SD 3.0 mumol/liter. Compared with this reference group the hypoxanthine concentration in plasma of the umbilical cord in 10 newborn infants with clinical signs of intrauterine hypoxia during labor was found to be significantly higher, with a range of 11.0-61.5 mumol/liter, with a mean of 25.0 mumol/liter, SD 18.0 mumol/liter. The plasma level of hypoxanthine in two premature babies developing an idiopathic respiratory distress syndrome was monitored. The metabolite was found to be considerably increased, in one of them more than 24 hr after a period of hypoxia necessitating artificial ventilation. The hypoxanthine level in plasma of umbilical arterial blood was followed about 2 hr postpartum in three newborn infants with clinical signs of intrauterine hypoxia. The decrease of the plasma concentration of the metabolite seemed to be with a constant velocity, as it was about 10 mumol/liter/hr in these cases. A new method was used for the determination of hypoxanthine in plasma, based on the principle that PO2 decreased when hypoxanthine is oxidized to uric acid.

  14. Hypoxia and Angiogenesis in Endometrioid Endometrial Carcinogenesis

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    Nicole Horrée

    2007-01-01

    Full Text Available Background: Hypoxia-inducible factor 1α (HIF-1α plays an essential role in the adaptive response of cells to hypoxia, triggering biologic events associated with aggressive tumor behavior. Methods: Expression of HIF-1α and proteins in the HIF-1α pathway (Glut-1, CAIX, VEGF in paraffin-embedded specimens of normal (n = 17, premalignant (n = 17 and endometrioid endometrial carcinoma (n = 39 was explored by immunohistochemistry, in relation to microvessel density (MVD. Results: HIF-1α overexpression was absent in inactive endometrium but present in hyperplasia (61% and carcinoma (87%, with increasing expression in a perinecrotic fashion pointing to underlying hypoxia. No membranous expression of Glut-1 and CAIX was noticed in inactive endometrium, in contrast with expression in hyperplasia (Glut-1 0%, CAIX 61%, only focal and diffuse and carcinoma (Glut-1 94.6%, CAIX 92%, both mostly perinecrotically. Diffuse HIF-1α was accompanied by activation of downstream targets. VEGF was significantly higher expressed in hyperplasias and carcinomas compared to inactive endometrium. MVD was higher in hyperplasias and carcinomas than in normal endometrium (p < 0.001. Conclusion: HIF-1α and its downstream genes are increasingly expressed from normal through premalignant to endometrioid adenocarcinoma of the endometrium, paralleled by activation of its downstream genes and increased angiogenesis. This underlines the potential importance of hypoxia and its key regulator HIF-1α in endometrial carcinogenesis.

  15. Intermittent hypoxia in obese Zucker rats: cardiometabolic and inflammatory effects.

    Science.gov (United States)

    Briançon-Marjollet, Anne; Monneret, Denis; Henri, Marion; Joyeux-Faure, Marie; Totoson, Perle; Cachot, Sandrine; Faure, Patrice; Godin-Ribuot, Diane

    2016-11-01

    What is the central question of this study? This study addresses the relative impact of obesity and intermittent hypoxia in the pathophysiological process of obstructive sleep apnoea by investigating the metabolic, inflammatory and cardiovascular consequences of intermittent hypoxia in lean and obese Zucker rats. What is the main finding and its importance? We found that obesity and intermittent hypoxia have mainly distinct consequences on the investigated inflammatory and cardiometabolic parameters in Zucker rats. This suggests that, for a given severity of sleep apnea, the association of obesity and obstructive sleep apnoea may not necessarily be deleterious. Obstructive sleep apnoea is associated with obesity with a high prevalence, and both co-morbidities are independent cardiovascular risk factors. Intermittent hypoxia (IH) is thought to be the main factor responsible for the obstructive sleep apnoea-related cardiometabolic alterations. The aim of this study was to assess the respective impact of obesity and IH on the inflammatory and cardiometabolic state in rats. Lean and obese Zucker rats were exposed to normoxia or chronic IH, and we assessed metabolic and inflammatory parameters, such as plasma lipids and glucose, serum leptin and adiponectin, liver cytokines, nuclear factor-κB activity and cardiac endothelin-1 levels. Myocardial infarct size was also evaluated following in vitro ischaemia-reperfusion. Circulating lipids, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), leptin and adiponectin levels were higher in obese versus lean rats. Chronic IH did not have a significant impact on metabolic parameters in lean rats. In obese rats, IH increased glycaemia and HOMA-IR. Liver interleukin-6 and tumour necrosis factor-α levels were elevated in lean rats exposed to IH; obesity prevented the increase in interleukin-6 but not in tumour necrosis factor-α. Finally, IH exposure enhanced myocardial sensitivity to infarction in both lean and

  16. Seasonal dynamics and long-term trend of hypoxia in the coastal zone of Emilia Romagna (NW Adriatic Sea, Italy).

    Science.gov (United States)

    Alvisi, Francesca; Cozzi, Stefano

    2016-01-15

    Long-term series of meteorological, hydrological and oceanographic data were compared with hypoxia occurrence, in order to define characteristics and trends of this phenomenon in the Emilia Romagna Coastal Zone (ERCZ) in 1977-2008. During this period, hypoxia was recorded at all sampling stations, up to 20 km offshore. In winter, spring and late autumn, hypoxia appearance was matched to significant positive anomalies of air and surface seawater temperatures (up to +3.6 °C), whereas this effect was less pronounced in August-October. Hypoxia generally occurred with scarce precipitation (0-2 dm(3)m(2)d(-1)) and low wind velocity (0-2 ms(-1)), suggesting the importance of stable meteo-marine conditions for the onset of this phenomenon. Nevertheless, wind direction emerged as an indicator of hydrodynamic seasonal changes in the area and is thus a hypoxia regulator. In winter, spring and autumn, hypoxia was favored by large increases of biomass induced by river freshets. In contrast, summer hypoxia occurred during periods of low runoff, suggesting that pronounced stratification and weak circulation of coastal waters were more important in this season. Since the 1990s, a shift from widespread summer hypoxia to local hypoxia irregularly distributed across the year has occurred. This process was concomitant to long-term increases of air temperature (+0.14 °C yr(-1)), wind speed (+0.03 ms(-1) yr(-1)) and salinity (+0.09 yr(-1)), and decreases of Po River flow (-0.54 km(3) yr(-1)), oxygen saturation (-0.2% yr(-1)) and PO4(3-) (-0.004 μmol P L(-1) yr(-1)) and NH4(+) (-0.04 μmol N L(-1) yr(-1)) concentrations in surface coastal waters. Despite that several of these changes suggest an ERCZ trophic level positive reduction, similar to that reported for the N Adriatic, the concomitant climate warming might further exacerbate hypoxia in particularly shallow shelf locations. Therefore, in order to avoid hypoxia development a further mitigation of anthropogenic pressure is still

  17. Hepcidin: A Critical Regulator of Iron Metabolism during Hypoxia

    Directory of Open Access Journals (Sweden)

    Korry J. Hintze

    2011-01-01

    Full Text Available Iron status affects cognitive and physical performance in humans. Recent evidence indicates that iron balance is a tightly regulated process affected by a series of factors other than diet, to include hypoxia. Hypoxia has profound effects on iron absorption and results in increased iron acquisition and erythropoiesis when humans move from sea level to altitude. The effects of hypoxia on iron balance have been attributed to hepcidin, a central regulator of iron homeostasis. This paper will focus on the molecular mechanisms by which hypoxia affects hepcidin expression, to include a review of the hypoxia inducible factor (HIF/hypoxia response element (HRE system, as well as recent evidence indicating that localized adipose hypoxia due to obesity may affect hepcidin signaling and organismal iron metabolism.

  18. Analysis of cagA in Helicobacter pylori strains from Colombian populations with contrasting gastric cancer risk reveals a biomarker for disease severity

    Science.gov (United States)

    Loh, John T.; Shaffer, Carrie L.; Piazuelo, M. Blanca; Bravo, Luis E.; McClain, Mark S.; Correa, Pelayo; Cover, Timothy L.

    2011-01-01

    BACKGROUND Helicobacter pylori infection is a risk factor for the development of gastric cancer, and the bacterial oncoprotein CagA contributes to gastric carcinogenesis. METHODS We analyzed H. pylori isolates from persons in Colombia and observed that there was marked variation among strains in levels of CagA expression. To elucidate the basis for this variation, we analyzed sequences upstream from the CagA translational initiation site in each strain. RESULTS A DNA motif (AATAAGATA) upstream of the translational initiation site of CagA was associated with high levels of CagA expression. Experimental studies showed that this motif was necessary but not sufficient for high-level CagA expression. H. pylori strains from a region of Colombia with high gastric cancer rates expressed higher levels of CagA than did strains from a region with lower gastric cancer rates, and Colombian strains of European phylogeographic origin expressed higher levels of CagA than did strains of African origin. Histopathological analysis of gastric biopsy specimens revealed that strains expressing high levels of CagA or containing the AATAAGATA motif were associated with more advanced precancerous lesions than those found in persons infected with strains expressing low levels of CagA or lacking the AATAAGATA motif. CONCLUSIONS CagA expression varies greatly among H. pylori strains. The DNA motif identified in this study is associated with high levels of CagA expression, and may be a useful biomarker to predict gastric cancer risk. IMPACT These findings help to explain why some persons infected with cagA-positive H. pylori develop gastric cancer and others do not. PMID:21859954

  19. Regulation of mRNA translation influences hypoxia tolerance

    International Nuclear Information System (INIS)

    Koritzinsky, M.; Wouters, B.G.; Koumenis, C.

    2003-01-01

    Hypoxia is a heterogenous but common characteristic of human tumours and poor oxygenation is associated with poor prognosis. We believe that the presence of viable hypoxic tumor cells reflects in part an adaptation and tolerance of these cells to oxygen deficiency. Since oxidative phosphorylation is compromized during hypoxia, adaptation may involve both the upregulation of glycolysis as well as downregulation of energy consumption. mRNA translation is one of the most energy costly cellular processes, and we and others have shown that global mRNA translation is rapidly inhibited during hypoxia. However, some mRNAs, including those coding for HIF-1 α and VEGF, remain efficiently translated during hypoxia. Clearly, the mechanisms responsible for the overall inhibition of translation during hypoxia does not compromize the translation of certain hypoxia-induced mRNA species. We therefore hypothesize that the inhibition of mRNA translation serves to promote hypoxia tolerance in two ways: i) through conservation of energy and ii) through differential gene expression involved in hypoxia adaptation. We have recently identified two pathways that are responsible for the global inhibition of translation during hypoxia. The phosphorylation of the eukaryotic initiation factor eIF2 α by the ER resident kinase PERK results in down-regulation of protein synthesis shortly after the onset of hypoxia. In addition, the initiation complex eIF4F is disrupted during long lasting hypoxic conditions. The identification of the molecular pathways responsible for the inhibition of overall translation during hypoxia has rendered it possible to investigate their importance for hypoxia tolerance. We have found that mouse embryo fibroblasts that are knockout for PERK and therefore not able to inhibit protein synthesis efficiently during oxygen deficiency are significantly less tolerant to hypoxia than their wildtype counterparts. We are currently also investigating the functional significance

  20. Recurrent symptomatic ischemic stroke in a 46-year-old African male revealing Angio-Behçet with severe cardiovascular involvement.

    Science.gov (United States)

    Marie, Ba Djibril; Aminata, Diack; Cherif, Mboup Mouhamed; Daouda, Fall Moussa

    2017-03-01

    Behçet'sdisease (BD) is a chronic, multisystem vasculitis. It is categorized under variable vessel vasculitis in the new Chapel Hill nomenclature as it involves blood vessels of any type and size. It is characterized by relapsing aphthous ulcers commonly occurring in the oral mucosa and genitalia with ocular involvement. Other organ systems may be involved any time throughout the course of the disease. The exact cause is unknown. However, combination of genetic and environmental factors is likely to play a role. Cardiac involvement may occur in the form of intracardiac thrombus, endocarditis, myocarditis, pericarditis, endomyocardial fibrosis, coronary arteritis, myocardial infarction, and valvular disease. We present a case of Angio-Behçet in a 46-year-old African male with severe cardiovascular involvement including pulmonary artery hypertension (PAH), right ventricular failure and left ventricular diastolic dysfunction diagnosed after 2 episodes of symptomatic ischemic stroke resulting from complete occlusion of the right internal carotid artery (ICA) up to its intracranial portion. Immunosuppressive and anticoagulant therapies have induced improvement in cardiac manifestations. Nevertheless, prompt recognition of the primarily vascular manifestation of BD without mucocutaneous manifestations was responsible for considerable delay that did not afford surgical therapy for the carotid occlusion.

  1. Label-free Proteomic Reveals that Cowpea Severe Mosaic Virus Transiently Suppresses the Host Leaf Protein Accumulation During the Compatible Interaction with Cowpea (Vigna unguiculata [L.] Walp.).

    Science.gov (United States)

    Paiva, Ana L S; Oliveira, Jose T A; de Souza, Gustavo A; Vasconcelos, Ilka M

    2016-12-02

    Viruses are important plant pathogens that threaten diverse crops worldwide. Diseases caused by Cowpea severe mosaic virus (CPSMV) have drawn attention because of the serious damages they cause to economically important crops including cowpea. This work was undertaken to quantify and identify the responsive proteins of a susceptible cowpea genotype infected with CPSMV, in comparison with mock-inoculated controls, using label-free quantitative proteomics and databanks, aiming at providing insights on the molecular basis of this compatible interaction. Cowpea leaves were mock- or CPSMV-inoculated and 2 and 6 days later proteins were extracted and analyzed. More than 3000 proteins were identified (data available via ProteomeXchange, identifier PXD005025) and 75 and 55 of them differentially accumulated in response to CPSMV, at 2 and 6 DAI, respectively. At 2 DAI, 76% of the proteins decreased in amount and 24% increased. However, at 6 DAI, 100% of the identified proteins increased. Thus, CPSMV transiently suppresses the synthesis of proteins involved particularly in the redox homeostasis, protein synthesis, defense, stress, RNA/DNA metabolism, signaling, and other functions, allowing viral invasion and spread in cowpea tissues.

  2. Comparison Between Several Integrase-defective Lentiviral Vectors Reveals Increased Integration of an HIV Vector Bearing a D167H Mutant

    Directory of Open Access Journals (Sweden)

    Muhammad Qamar Saeed

    2014-01-01

    Full Text Available HIV-1 derived vectors are among the most efficient for gene transduction in mammalian tissues. As the parent virus, they carry out vector genome insertion into the host cell chromatin. Consequently, their preferential integration in transcribed genes raises several conceptual and safety issues. To address part of these questions, HIV-derived vectors have been engineered to be nonintegrating. This was mainly achieved by mutating HIV-1 integrase at functional hotspots of the enzyme enabling the development of streamlined nuclear DNA circles functional for transgene expression. Few integrase mutant vectors have been successfully tested so far for gene transfer. They are cleared with time in mitotic cells, but stable within nondividing retina cells or neurons. Here, we compared six HIV vectors carrying different integrases, either wild type or with different mutations (D64V, D167H, Q168A, K186Q+Q214L+Q216L, and RRK262-264AAH shown to modify integrase enzymatic activity, oligomerization, or interaction with key cellular cofactor of HIV DNA integration as LEDGF/p75 or TNPO3. We show that these mutations differently affect the transduction efficiency as well as rates and patterns of integration of HIV-derived vectors suggesting their different processing in the nucleus. Surprisingly and most interestingly, we report that an integrase carrying the D167H substitution improves vector transduction efficiency and integration in both HEK-293T and primary CD34+ cells.

  3. Proteomic analysis of a model unicellular green alga, Chlamydomonas reinhardtii, during short-term exposure to irradiance stress reveals significant down regulation of several heat-shock proteins.

    Science.gov (United States)

    Mahong, Bancha; Roytrakul, Suttiruk; Phaonaklop, Narumon; Wongratana, Janewit; Yokthongwattana, Kittisak

    2012-03-01

    Oxygenic photosynthetic organisms often suffer from excessive irradiance, which cause harmful effects to the chloroplast proteins and lipids. Photoprotection and the photosystem II repair processes are the mechanisms that plants deploy to counteract the drastic effects from irradiance stress. Although the protective and repair mechanisms seemed to be similar in most plants, many species do confer different level of tolerance toward high light. Such diversity may originate from differences at the molecular level, i.e., perception of the light stress, signal transduction and expression of stress responsive genes. Comprehensive analysis of overall changes in the total pool of proteins in an organism can be performed using a proteomic approach. In this study, we employed 2-DE/LC-MS/MS-based comparative proteomic approach to analyze total proteins of the light sensitive model unicellular green alga Chlamydomonas reinhardtii in response to excessive irradiance. Results showed that among all the differentially expressed proteins, several heat-shock proteins and molecular chaperones were surprisingly down-regulated after 3-6 h of high light exposure. Discussions were made on the possible involvement of such down regulation and the light sensitive nature of this model alga.

  4. Metabolomic Dynamic Analysis of Hypoxia in MDA-MB-231 and the Comparison with Inferred Metabolites from Transcriptomics Data

    Directory of Open Access Journals (Sweden)

    Yufeng Jane Tseng

    2013-05-01

    Full Text Available Hypoxia affects the tumor microenvironment and is considered important to metastasis progression and therapy resistance. Thus far, the majority of global analyses of tumor hypoxia responses have been limited to just a single omics level. Combining multiple omics data can broaden our understanding of tumor hypoxia. Here, we investigate the temporal change of the metabolite composition with gene expression data from literature to provide a more comprehensive insight into the system level in response to hypoxia. Nuclear magnetic resonance spectroscopy was used to perform metabolomic profiling on the MDA-MB-231 breast cancer cell line under hypoxic conditions. Multivariate statistical analysis revealed that the metabolic difference between hypoxia and normoxia was similar over 24 h, but became distinct over 48 h. Time dependent microarray data from the same cell line in the literature displayed different gene expressions under hypoxic and normoxic conditions mostly at 12 h or earlier. The direct metabolomic profiles show a large overlap with theoretical metabolic profiles deduced from previous transcriptomic studies. Consistent pathways are glycolysis/gluconeogenesis, pyruvate, purine and arginine and proline metabolism. Ten metabolic pathways revealed by metabolomics were not covered by the downstream of the known transcriptomic profiles, suggesting new metabolic phenotypes. These results confirm previous transcriptomics understanding and expand the knowledge from existing models on correlation and co-regulation between transcriptomic and metabolomics profiles, which demonstrates the power of integrated omics analysis.

  5. Metabolomic Dynamic Analysis of Hypoxia in MDA-MB-231 and the Comparison with Inferred Metabolites from Transcriptomics Data

    Energy Technology Data Exchange (ETDEWEB)

    Tsai, I-Lin [Department of Pharmacy, National Taiwan University, No. 1, Jen-Ai Road, Section 1 Taipei 10051, Taiwan (China); The Metabolomics Group, National Taiwan University, Taipei 106, Taiwan (China); Center for Genomic Medicine, National Taiwan University, Taipei 10051, Taiwan (China); Kuo, Tien-Chueh [The Metabolomics Group, National Taiwan University, Taipei 106, Taiwan (China); Graduate Institute of Biomedical Electronic and Bioinformatics, National Taiwan University, Room 410 BL Building, No. 1, Roosevelt Road, Sec. 4, Taipei 106, Taiwan (China); Ho, Tsung-Jung [The Metabolomics Group, National Taiwan University, Taipei 106, Taiwan (China); Department of Computer Science and Information Engineering, National Taiwan University, No. 1, Sec. 4, Roosevelt Rd., Taipei 10617, Taiwan (China); Harn, Yeu-Chern [The Metabolomics Group, National Taiwan University, Taipei 106, Taiwan (China); Graduate Institute of Networking and Multimedia, National Taiwan University, No. 1, Sec. 4, Roosevelt Rd., Taipei 10617, Taiwan (China); Wang, San-Yuan [The Metabolomics Group, National Taiwan University, Taipei 106, Taiwan (China); Department of Computer Science and Information Engineering, National Taiwan University, No. 1, Sec. 4, Roosevelt Rd., Taipei 10617, Taiwan (China); Fu, Wen-Mei [Department of Pharmacology, National Taiwan University, 11 F No. 1 Sec. 1, Ren-ai Rd., Taipei 10051, Taiwan (China); Kuo, Ching-Hua, E-mail: kuoch@ntu.edu.tw [Department of Pharmacy, National Taiwan University, No. 1, Jen-Ai Road, Section 1 Taipei 10051, Taiwan (China); The Metabolomics Group, National Taiwan University, Taipei 106, Taiwan (China); Center for Genomic Medicine, National Taiwan University, Taipei 10051, Taiwan (China); Tseng, Yufeng Jane, E-mail: kuoch@ntu.edu.tw [Department of Pharmacy, National Taiwan University, No. 1, Jen-Ai Road, Section 1 Taipei 10051, Taiwan (China); The Metabolomics Group, National Taiwan University, Taipei 106, Taiwan (China); Center for Genomic Medicine, National Taiwan University, Taipei 10051, Taiwan (China); Graduate Institute of Biomedical Electronic and Bioinformatics, National Taiwan University, Room 410 BL Building, No. 1, Roosevelt Road, Sec. 4, Taipei 106, Taiwan (China); Department of Computer Science and Information Engineering, National Taiwan University, No. 1, Sec. 4, Roosevelt Rd., Taipei 10617, Taiwan (China)

    2013-05-03

    Hypoxia affects the tumor microenvironment and is considered important to metastasis progression and therapy resistance. Thus far, the majority of global analyses of tumor hypoxia responses have been limited to just a single omics level. Combining multiple omics data can broaden our understanding of tumor hypoxia. Here, we investigate the temporal change of the metabolite composition with gene expression data from literature to provide a more comprehensive insight into the system level in response to hypoxia. Nuclear magnetic resonance spectroscopy was used to perform metabolomic profiling on the MDA-MB-231 breast cancer cell line under hypoxic conditions. Multivariate statistical analysis revealed that the metabolic difference between hypoxia and normoxia was similar over 24 h, but became distinct over 48 h. Time dependent microarray data from the same cell line in the literature displayed different gene expressions under hypoxic and normoxic conditions mostly at 12 h or earlier. The direct metabolomic profiles show a large overlap with theoretical metabolic profiles deduced from previous transcriptomic studies. Consistent pathways are glycolysis/gluconeogenesis, pyruvate, purine and arginine and proline metabolism. Ten metabolic pathways revealed by metabolomics were not covered by the downstream of the known transcriptomic profiles, suggesting new metabolic phenotypes. These results confirm previous transcriptomics understanding and expand the knowledge from existing models on correlation and co-regulation between transcriptomic and metabolomics profiles, which demonstrates the power of integrated omics analysis.

  6. Metabolomic Dynamic Analysis of Hypoxia in MDA-MB-231 and the Comparison with Inferred Metabolites from Transcriptomics Data

    International Nuclear Information System (INIS)

    Tsai, I-Lin; Kuo, Tien-Chueh; Ho, Tsung-Jung; Harn, Yeu-Chern; Wang, San-Yuan; Fu, Wen-Mei; Kuo, Ching-Hua; Tseng, Yufeng Jane

    2013-01-01

    Hypoxia affects the tumor microenvironment and is considered important to metastasis progression and therapy resistance. Thus far, the majority of global analyses of tumor hypoxia responses have been limited to just a single omics level. Combining multiple omics data can broaden our understanding of tumor hypoxia. Here, we investigate the temporal change of the metabolite composition with gene expression data from literature to provide a more comprehensive insight into the system level in response to hypoxia. Nuclear magnetic resonance spectroscopy was used to perform metabolomic profiling on the MDA-MB-231 breast cancer cell line under hypoxic conditions. Multivariate statistical analysis revealed that the metabolic difference between hypoxia and normoxia was similar over 24 h, but became distinct over 48 h. Time dependent microarray data from the same cell line in the literature displayed different gene expressions under hypoxic and normoxic conditions mostly at 12 h or earlier. The direct metabolomic profiles show a large overlap with theoretical metabolic profiles deduced from previous transcriptomic studies. Consistent pathways are glycolysis/gluconeogenesis, pyruvate, purine and arginine and proline metabolism. Ten metabolic pathways revealed by metabolomics were not covered by the downstream of the known transcriptomic profiles, suggesting new metabolic phenotypes. These results confirm previous transcriptomics understanding and expand the knowledge from existing models on correlation and co-regulation between transcriptomic and metabolomics profiles, which demonstrates the power of integrated omics analysis

  7. Systematic Identification, Evolution and Expression Analysis of the Zea mays PHT1 Gene Family Reveals Several New Members Involved in Root Colonization by Arbuscular Mycorrhizal Fungi.

    Science.gov (United States)

    Liu, Fang; Xu, Yunjian; Jiang, Huanhuan; Jiang, Chaosheng; Du, Yibin; Gong, Cheng; Wang, Wei; Zhu, Suwen; Han, Guomin; Cheng, Beijiu

    2016-06-13

    The Phosphate Transporter1 (PHT1) family of genes plays pivotal roles in the uptake of inorganic phosphate from soils. However, there is no comprehensive report on the PHT1 family in Zea mays based on the whole genome. In the present study, a total of 13 putative PHT1 genes (ZmPHT1;1 to 13) were identified in the inbred line B73 genome by bioinformatics methods. Then, their function was investigated by a yeast PHO84 mutant complementary experiment and qRT-PCR. Thirteen ZmPHT1 genes distributed on six chromosomes (1, 2, 5, 7, 8 and 10) were divided into two paralogues (Class A and Class B). ZmPHT1;1/ZmPHT1;9 and ZmPHT1;9/ZmPHT1;13 are produced from recent segmental duplication events. ZmPHT1;1/ZmPHT1;13 and ZmPHT1;8/ZmPHT1;10 are produced from early segmental duplication events. All 13 putative ZmPHT1s can completely or partly complement the yeast Pi-uptake mutant, and they were obviously induced in maize under low Pi conditions, except for ZmPHT1;1 (p < 0.01), indicating that the overwhelming majority of ZmPHT1 genes can respond to a low Pi condition. ZmPHT1;2, ZmPHT1;4, ZmPHT1;6, ZmPHT1;7, ZmPHT1;9 and ZmPHT1;11 were up-regulated by arbuscular mycorrhizal fungi (AMF), implying that these genes might participate in mediating Pi absorption and/or transport. Analysis of the promoters revealed that the MYCS and P1BS element are widely distributed on the region of different AMF-inducible ZmPHT1 promoters. In light of the above results, five of 13 ZmPHT1 genes were newly-identified AMF-inducible high-affinity phosphate transporters in the maize genome. Our results will lay a foundation for better understanding the PHT1 family evolution and the molecular mechanisms of inorganic phosphate transport under AMF inoculation.

  8. [Study on intermittent hypoxia in children sleep apnea hypopnea syndrome model and insulin-like growth factor-1 and insulin-like growth factor binding protein-3 levels in serum].

    Science.gov (United States)

    Hou, Jin; Yan, Jing; Kang, Quan-qing

    2012-03-01

    Using rats fed in intermittent hypoxia environment to study the relationship between sleep apnea hypopnea syndrome (SAHS) of children and growth retardation. The hypoxic chamber was designed and manufactured, the control of intermittent hypoxia was achieved. Twenty-four rats were randomly divided into three groups: mild and severe hypoxia group, and control group. In control group, the animals were normally fed, without interruption. The animals in other two groups were kept in the cabin, simulated mild and severe intermittent hypoxia conditions 8-hour a day, a total of 35 days. According to the results of preliminary experiments, the concentration of intermittent hypoxia and frequency were determined. The animals with mild hypoxia events occurred nearly six times per hour, the average minimum oxygen saturation dropped to 0.853, the animals with severe hypoxia events occurred nearly 24 times per hour, the average minimum oxygen saturation dropped to 0.776. Body mass and length were measured before and after experiment. The serum insulin-like growth factor (IGF)-1 and insulin-like growth factor binding protein (IGFBP)-3 expression were tested from venous blood by enzyme-linked immunosorbent assay (ELISA). The length and body mass of rats in three groups before and after experiment were not statistically different (P>0.05). Before the experiment the serum IGF-1 and IGFBP-3 levels were not significantly different (P>0.05). 35 d after the experiment, the serum IGF-1 (x±s, the same below) in the control group, mild hypoxia and severe hypoxia were (60.0±18.5) ng/ml, (40.6±9.9) ng/ml and (13.1±8.6) ng/ml, F=25.840, Phypoxia increased (Papnea hypopnea syndrome, the intermittent hypoxia in young rats does not show physical growth retardation, but the serum IGF-1, IGFBP-3 levels decreased with the increase of hypoxia and decline of oxygen saturation.

  9. Detailed assessment of gene activation levels by multiple hypoxia-responsive elements under various hypoxic conditions.

    Science.gov (United States)

    Takeuchi, Yasuto; Inubushi, Masayuki; Jin, Yong-Nan; Murai, Chika; Tsuji, Atsushi B; Hata, Hironobu; Kitagawa, Yoshimasa; Saga, Tsuneo

    2014-12-01

    HIF-1/HRE pathway is a promising target for the imaging and the treatment of intractable malignancy (HIF-1; hypoxia-inducible factor 1, HRE; hypoxia-responsive element). The purposes of our study are: (1) to assess the gene activation levels resulting from various numbers of HREs under various hypoxic conditions, (2) to evaluate the bidirectional activity of multiple HREs, and (3) to confirm whether multiple HREs can induce gene expression in vivo. Human colon carcinoma HCT116 cells were transiently transfected by the constructs containing a firefly luciferase reporter gene and various numbers (2, 4, 6, 8, 10, and 12) of HREs (nHRE+, nHRE-). The relative luciferase activities were measured under various durations of hypoxia (6, 12, 18, and 24 h), O2 concentrations (1, 2, 4, 8, and 16 %), and various concentrations of deferoxamine mesylate (20, 40, 80, 160, and 320 µg/mL growth medium). The bidirectional gene activation levels by HREs were examined in the constructs (dual-luc-nHREs) containing firefly and Renilla luciferase reporter genes at each side of nHREs. Finally, to test whether the construct containing 12HRE and the NIS reporter gene (12HRE-NIS) can induce gene expression in vivo, SPECT imaging was performed in a mouse xenograft model. (1) gene activation levels by HREs tended to increase with increasing HRE copy number, but a saturation effect was observed in constructs with more than 6 or 8 copies of an HRE, (2) gene activation levels by HREs increased remarkably during 6-12 h of hypoxia, but not beyond 12 h, (3) gene activation levels by HREs decreased with increasing O2 concentrations, but could be detected even under mild hypoxia at 16 % O2, (4) the bidirectionally proportional activity of the HRE was confirmed regardless of the hypoxic severity, and (5) NIS expression driven by 12 tandem copies of an HRE in response to hypoxia could be visualized on in vivo SPECT imaging. The results of this study will help in the understanding and assessment of

  10. Molecular analysis of serum and bronchoalveolar lavage in a mouse model of influenza reveals markers of disease severity that can be clinically useful in humans.

    Directory of Open Access Journals (Sweden)

    Yadunanda Kumar

    Full Text Available BACKGROUND: Management of influenza, a major contributor to the worldwide disease burden, is complicated by lack of reliable methods for early identification of susceptible individuals. Identification of molecular markers that can augment existing diagnostic tools for prediction of severity can be expected to greatly improve disease management capabilities. METHODOLOGY/PRINCIPAL FINDINGS: We have analyzed cytokines, proteome flux and protein adducts in bronchoalveolar lavage (BAL and sera from mice infected with influenza A virus (PR8 strain using a previously established non-lethal model of influenza infection. Through detailed cytokine and protein adduct measurements of murine BAL, we first established the temporal profile of innate and adaptive responses as well as macrophage and neutrophil activities in response to influenza infection. A similar analysis was also performed with sera from a longitudinal cohort of influenza patients. We then used an iTRAQ-based, comparative serum proteome analysis to catalog the proteome flux in the murine BAL during the stages correlating with "peak viremia," "inflammatory damage," as well as the "recovery phase." In addition to activation of acute phase responses, a distinct class of lung proteins including surfactant proteins was found to be depleted from the BAL coincident with their "appearance" in the serum, presumably due to leakage of the protein following loss of the integrity of the lung/epithelial barrier. Serum levels of at least two of these proteins were elevated in influenza patients during the febrile phase of infection compared to healthy controls or to the same patients at convalescence. CONCLUSIONS/SIGNIFICANCE: The findings from this study provide a molecular description of disease progression in a mouse model of influenza and demonstrate its potential for translation into a novel class of markers for measurement of acute lung injury and improved case management.

  11. Eye Tracking Reveals Abnormal Visual Preference for Geometric Images as an Early Biomarker of an Autism Spectrum Disorder Subtype Associated With Increased Symptom Severity.

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    Pierce, Karen; Marinero, Steven; Hazin, Roxana; McKenna, Benjamin; Barnes, Cynthia Carter; Malige, Ajith

    2016-04-15

    Clinically and biologically, autism spectrum disorder (ASD) is heterogeneous. Unusual patterns of visual preference as indexed by eye tracking are hallmarks; however, whether they can be used to define an early biomarker of ASD as a whole or leveraged to define a subtype is unclear. To begin to examine this issue, large cohorts are required. A sample of 334 toddlers from six distinct groups (115 toddlers with ASD, 20 toddlers with ASD features, 57 toddlers with developmental delay, 53 toddlers with other conditions [e.g., premature birth, prenatal drug exposure], 64 toddlers with typical development, and 25 unaffected toddlers with siblings with ASD) was studied. Toddlers watched a movie containing geometric and social images. Fixation duration and number of saccades within each area of interest and validation statistics for this independent sample were computed. Next, to maximize power, data from our previous study (n = 110) were added for a total of 444 subjects. A subset of toddlers repeated the eye-tracking procedure. As in the original study, a subset of toddlers with ASD fixated on geometric images >69% of the time. Using this cutoff, sensitivity for ASD was 21%, specificity was 98%, and positive predictive value was 86%. Toddlers with ASD who strongly preferred geometric images had 1) worse cognitive, language, and social skills relative to toddlers with ASD who strongly preferred social images and 2) fewer saccades when viewing geometric images. Unaffected siblings of ASD probands did not show evidence of heightened preference for geometric images. Test-retest reliability was good. Examination of age effects suggested that this test may not be appropriate with children >4 years old. Enhanced visual preference for geometric repetition may be an early developmental biomarker of an ASD subtype with more severe symptoms. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  12. Eye-tracking Reveals Abnormal Visual Preference for Geometric Images as an Early Biomarker of an ASD Subtype Associated with Increased Symptom Severity

    Science.gov (United States)

    Pierce, Karen; Marinero, Steven; Hazin, Roxana; McKenna, Benjamin; Barnes, Cynthia Carter; Malige, Ajith

    2015-01-01

    Background Clinically and biologically, ASD is heterogeneous. Unusual patterns of visual preference as indexed by eye-tracking are hallmarks, yet whether they can be used to define an early biomarker of ASD as a whole, or leveraged to define a subtype is unclear. To begin to examine this issue, large cohorts are required. Methods A sample of 334 toddlers from 6 distinct groups (115 ASD, 20 ASD-Features, 57 DD, 53 Other, 64 TD, and 25 Typ SIB) participated. Toddlers watched a movie containing both geometric and social images. Fixation duration and number of saccades within each AOI and validation statistics for this independent sample computed. Next, to maximize power, data from our previous study (N=110) was added totaling 444 subjects. A subset of toddlers repeated the eye-tracking procedure. Results As in the original study, a subset of toddlers with ASD fixated on geometric images greater than 69%. Using this cutoff, sensitivity for ASD was 21%, specificity 98%, and PPV 86%. Toddlers with ASD who strongly preferred geometric images had (a) worse cognitive, language, and social skills relative to toddlers with ASD who strongly preferred social images and (b) fewer saccades when viewing geometric images. Unaffected siblings of ASD probands did not show evidence of heightened preference for geometric images. Test-retest reliability was good. Examination of age effects suggest that this test may not be appropriate with children > 4 years. Conclusions Enhanced visual preference for geometric repetition may be an early developmental biomarker of an ASD subtype with more severe symptoms. PMID:25981170

  13. Human SOD1 ALS Mutations in a Drosophila Knock-In Model Cause Severe Phenotypes and Reveal Dosage-Sensitive Gain- and Loss-of-Function Components.

    Science.gov (United States)

    Şahin, Aslı; Held, Aaron; Bredvik, Kirsten; Major, Paxton; Achilli, Toni-Marie; Kerson, Abigail G; Wharton, Kristi; Stilwell, Geoff; Reenan, Robert

    2017-02-01

    Amyotrophic Lateral Sclerosis (ALS) is the most common adult-onset motor neuron disease and familial forms can be caused by numerous dominant mutations of the copper-zinc superoxide dismutase 1 (SOD1) gene. Substantial efforts have been invested in studying SOD1-ALS transgenic animal models; yet, the molecular mechanisms by which ALS-mutant SOD1 protein acquires toxicity are not well understood. ALS-like phenotypes in animal models are highly dependent on transgene dosage. Thus, issues of whether the ALS-like phenotypes of these models stem from overexpression of mutant alleles or from aspects of the SOD1 mutation itself are not easily deconvolved. To address concerns about levels of mutant SOD1 in disease pathogenesis, we have genetically engineered four human ALS-causing SOD1 point mutations (G37R, H48R, H71Y, and G85R) into the endogenous locus of Drosophila SOD1 (dsod) via ends-out homologous recombination and analyzed the resulting molecular, biochemical, and behavioral phenotypes. Contrary to previous transgenic models, we have recapitulated ALS-like phenotypes without overexpression of the mutant protein. Drosophila carrying homozygous mutations rendering SOD1 protein enzymatically inactive (G85R, H48R, and H71Y) exhibited neurodegeneration, locomotor deficits, and shortened life span. The mutation retaining enzymatic activity (G37R) was phenotypically indistinguishable from controls. While the observed mutant dsod phenotypes were recessive, a gain-of-function component was uncovered through dosage studies and comparisons with age-matched dsod null animals, which failed to show severe locomotor defects or nerve degeneration. We conclude that the Drosophila knock-in model captures important aspects of human SOD1-based ALS and provides a powerful and useful tool for further genetic studies. Copyright © 2017 by the Genetics Society of America.

  14. Normobaric hypoxia training: the effects of breathing-gas flow rate on symptoms.

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    Artino, Anthony R; Folga, Richard V; Vacchiano, Charles

    2009-06-01

    The U.S. Navy has replaced segments of refresher low-pressure chamber instruction with normobaric hypoxia training using a reduced oxygen breathing device (ROBD). A previous training evaluation revealed that this alternative instructional paradigm is a preferred means of training experienced jet aviators to recognize and recover from hypoxia. However, findings from this earlier work also indicated that air hunger was the most commonly reported symptom during ROBD training. This finding raised concern that air hunger could have resulted from a training artifact caused by the lower breathing-gas flow rate produced by the ROBD when compared to more familiar jet aircraft breathing systems. In an effort to address this issue, a software change was made that increased ROBD mask flow from 30 to 50 L x min(-1) (LPM). The purpose of this retrospective study was to determine if there are differences in the hypoxia symptoms reported by aviators trained on the ROBD upgrade (ROBD-50) compared to those trained on the original device (ROBD-30). Hypoxia training was provided to 156 aviators using the ROBD-50, and survey results were compared to those obtained from 121 aviators trained on the ROBD-30. There was a significant decrease in the number of aviators who reported experiencing air hunger while training on the ROBD-50 (44.2%) as compared to the ROBD-30 (59.4%) [Pearson chi2 (1) = 5.45, P hunger and, therefore, may impact training fidelity.

  15. Moderate hypoxia influences potassium outward currents in adipose-derived stem cells.

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    Mayuri Prasad

    Full Text Available Moderate hypoxic preconditioning of adipose-derived stem cells (ASCs enhances properties such as proliferation and secretion of growth factors, representing a valuable strategy to increase the efficiency of cell-based therapies. In a wide variety of cells potassium (K+ channels are key elements involved in the cellular responses to hypoxia, suggesting that ASCs cultured under low oxygen conditions may display altered electrophysiological properties. Here, the effects of moderate hypoxic culture on proliferation, whole-cell currents, and ion channel expression were investigated using human ASCs cultured at 5% and 20% oxygen. Although cell proliferation was greatly enhanced, the dose-dependent growth inhibition by the K+ channel blocker tetraethylammonium (TEA was not significantly affected by hypoxia. Under both normoxic and hypoxic conditions, ASCs displayed outward K+ currents composed by Ca2+-activated, delayed rectifier, and transient components. Hypoxic culture reduced the slope of the current-voltage curves and caused a negative shift in the voltage activation threshold of the whole-cell currents. However, the TEA-mediated shift of voltage activation threshold was not affected by hypoxia. Semiquantitative real-time RT-PCR revealed that expression of genes encoding for various ion channels subunits related to oxygen sensing and proliferation remained unchanged after hypoxic culture. In conclusion, outward currents are influenced by moderate hypoxia in ASCs through a mechanism that is not likely the result of modulation of TEA-sensitive K+ channels.

  16. p53 and telomerase control rat myocardial tissue response to hypoxia and ageing

    Directory of Open Access Journals (Sweden)

    A. Cataldi

    2009-12-01

    Full Text Available Cellular senescence implies loss of proliferative and tissue regenerative capability. Also hypoxia, producing Reactive Oxygen Species (ROS, can damage cellular components through the oxidation of DNA, proteins and lipids, thus influencing the shortening of telomeres. Since ribonucleoprotein Telomerase (TERT, catalyzing the replication of the ends of eukaryotic chromosomes, promotes cardiac muscle cell proliferation, hypertrophy and survival, here we investigated its role in the events regulating apoptosis occurrence and life span in hearts deriving from young and old rats exposed to hypoxia. TUNEL (terminal-deoxinucleotidyl -transferase- mediated dUTP nick end-labeling analysis reveals an increased apoptotic cell number in both samples after hypoxia exposure, mainly in the young with respect to the old. TERT expression lowers either in the hypoxic young, either in the old in both experimental conditions, with respect to the normoxic young. These events are paralleled by p53 and HIF-1 ? expression dramatic increase and by p53/ HIF-1 ? co-immunoprecipitation in the hypoxic young, evidencing the young subject as the most stressed by such challenge. These effects could be explained by induction of damage to genomic DNA by ROS that accelerates cell senescence through p53 activation. Moreover, by preventing TERT enzyme down-regulation, cell cycle exit and apoptosis occurrence could be delayed and new possibilities for intervention against cell ageing and hypoxia could be opened.

  17. The endogenous hallucinogen and trace amine N,N-dimethyltryptamine (DMT displays potent protective effects against hypoxia via sigma-1 receptor activation in human primary iPSC-derived cortical neurons and microglia-like immune cells

    Directory of Open Access Journals (Sweden)

    Attila Szabo

    2016-09-01

    Full Text Available N,N-dimethyltryptamine (DMT is a potent endogenous hallucinogen present in the brain of humans and other mammals. Despite extensive research, its physiological role remains largely unknown. Recently, DMT has been found to activate the sigma-1 receptor (Sig-1R, an intracellular chaperone fulfilling an interface role between the endoplasmic reticulum (ER and mitochondria. It ensures the correct transmission of ER stress into the nucleus resulting in the enhanced production of antistress and antioxidant proteins. Due to this function, the activation of Sig-1R can mitigate the outcome of hypoxia or oxidative stress. In this paper we aimed to test the hypothesis that DMT plays a neuroprotective role in the brain by activating the Sig-1R. We tested whether DMT can mitigate hypoxic stress in in vitro cultured human cortical neurons (derived from induced pluripotent stem cells, and in monocyte-derived macrophages and dendritic cells. Here we report that DMT robustly increases the survival of these cell types in severe hypoxia (0.5% O2 through the Sig-1R. Furthermore, this phenomenon is associated with the decreased expression and function of the alpha subunit of the hypoxia-inducible factor 1 (HIF-1 suggesting that DMT-mediated Sig-1R activation may alleviate hypoxia-induced cellular stress and increase survival in a HIF-1-independent manner. Our results reveal a novel and important role of DMT in human cellular physiology. We postulate that this compound may be endogenously generated in situations of stress, ameliorating the adverse effects of hypoxic/ischemic insult to the brain.

  18. The Endogenous Hallucinogen and Trace Amine N,N-Dimethyltryptamine (DMT) Displays Potent Protective Effects against Hypoxia via Sigma-1 Receptor Activation in Human Primary iPSC-Derived Cortical Neurons and Microglia-Like Immune Cells.

    Science.gov (United States)

    Szabo, Attila; Kovacs, Attila; Riba, Jordi; Djurovic, Srdjan; Rajnavolgyi, Eva; Frecska, Ede

    2016-01-01

    N,N-dimethyltryptamine (DMT) is a potent endogenous hallucinogen present in the brain of humans and other mammals. Despite extensive research, its physiological role remains largely unknown. Recently, DMT has been found to activate the sigma-1 receptor (Sig-1R), an intracellular chaperone fulfilling an interface role between the endoplasmic reticulum (ER) and mitochondria. It ensures the correct transmission of ER stress into the nucleus resulting in the enhanced production of antistress and antioxidant proteins. Due to this function, the activation of Sig-1R can mitigate the outcome of hypoxia or oxidative stress. In this paper, we aimed to test the hypothesis that DMT plays a neuroprotective role in the brain by activating the Sig-1R. We tested whether DMT can mitigate hypoxic stress in in vitro cultured human cortical neurons (derived from induced pluripotent stem cells, iPSCs), monocyte-derived macrophages (moMACs), and dendritic cells (moDCs). Results showed that DMT robustly increases the survival of these cell types in severe hypoxia (0.5% O2) through the Sig-1R. Furthermore, this phenomenon is associated with the decreased expression and function of the alpha subunit of the hypoxia-inducible factor 1 (HIF-1) suggesting that DMT-mediated Sig-1R activation may alleviate hypoxia-induced cellular stress and increase survival in a HIF-1-independent manner. Our results reveal a novel and important role of DMT in human cellular physiology. We postulate that this compound may be endogenously generated in situations of stress, ameliorating the adverse effects of hypoxic/ischemic insult to the brain.

  19. Baicalin inhibits hypoxia-induced pulmonary artery smooth muscle cell proliferation via the AKT/HIF-1α/p27-associated pathway.

    Science.gov (United States)

    Zhang, Lin; Pu, Zhichen; Wang, Junsong; Zhang, Zhifeng; Hu, Dongmei; Wang, Junjie

    2014-05-09

    Baicalin, a flavonoid compound purified from the dry roots of Scutellaria baicalensis Georgi, has been shown to possess various pharmacological actions. Previous studies have revealed that baicalin inhibits the growth of cancer cells through the induction of apoptosis. Pulmonary arterial hypertension (PAH) is a devastating disease characterized by enhanced pulmonary artery smooth muscle cell (PASMCs) proliferation and suppressed apoptosis. However, the potential mechanism of baicalin in the regulation of PASMC proliferation and the prevention of cardiovascular diseases remains unexplored. To test the effects of baicalin on hypoxia, we used rats treated with or without baicalin (100 mg·kg⁻¹ each rat) at the beginning of the third week after hypoxia. Hemodynamic and pulmonary pathomorphology data showed that right ventricular systolic pressures (RVSP), the weight of the right ventricle/left ventricle plus septum (RV/LV + S) ratio and the medial width of pulmonary arterioles were much higher in chronic hypoxia. However, baicalin treatment repressed the elevation of RVSP, RV/LV + S and attenuated the pulmonary vascular structure remodeling (PVSR) of pulmonary arterioles induced by chronic hypoxia. Additionally, baicalin (10 and 20 μmol·L⁻¹) treatment suppressed the proliferation of PASMCs and attenuated the expression of hypoxia-inducible factor-α (HIF-α) under hypoxia exposure. Meanwhile, baicalin reversed the hypoxia-induced reduction of p27 and increased AKT/protein kinase B phosphorylation p-AKT both in vivo and in vitro. These results suggested that baicalin could effectively attenuate PVSR and hypoxic pulmonary hypertension.

  20. Increased hypoxia-inducible factor-1α in striated muscle of tumor-bearing mice.

    Science.gov (United States)

    Devine, Raymond D; Bicer, Sabahattin; Reiser, Peter J; Wold, Loren E

    2017-06-01

    Cancer cachexia is a progressive wasting disease resulting in significant effects on the quality of life and high mortality. Most studies on cancer cachexia have focused on skeletal muscle; however, the heart is now recognized as a major site of cachexia-related effects. To elucidate possible mechanisms, a proteomic study was performed on the left ventricles of colon-26 (C26) adenocarcinoma tumor-bearing mice. The results revealed several changes in proteins involved in metabolism. An integrated pathway analysis of the results revealed a common mediator in hypoxia-inducible factor-1α (HIF-1α). Work by other laboratories has shown that extensive metabolic restructuring in the C26 mouse model causes changes in gene expression that may be affected directly by HIF-1α, such as glucose metabolic genes. M-mode echocardiography showed progressive decline in heart function by day 19 , exhibited by significantly decreased ejection fraction and fractional shortening, along with posterior wall thickness. Using Western blot analysis, we confirmed that HIF-1α is significantly upregulated in the heart, whereas there were no changes in its regulatory proteins, prolyl hydroxylase domain-containing protein 2 (PHD2) and von Hippel-Lindau protein (VHL). PHD2 requires both oxygen and iron as cofactors for the hydroxylation of HIF-1α, marking it for ubiquination via VHL and subsequent destruction by the proteasome complex. We examined venous blood gas values in the tumor-bearing mice and found significantly lower oxygen concentration compared with control animals in the third week after tumor inoculation. We also examined select skeletal muscles to determine whether they are similarly affected. In the diaphragm, extensor digitorum longus, and soleus, we found significantly increased HIF-1α in tumor-bearing mice, indicating a hypoxic response, not only in the heart, but also in skeletal muscle. These results indicate that HIF-1α may contribute, in part, to the metabolic changes

  1. Cinnamic aldehyde suppresses hypoxia-induced angiogenesis via inhibition of hypoxia-inducible factor-1α expression during tumor progression.

    Science.gov (United States)

    Bae, Woom-Yee; Choi, Jae-Sun; Kim, Ja-Eun; Jeong, Joo-Won

    2015-11-01

    During tumor progression, hypoxia-inducible factor 1 (HIF-1) plays a critical role in tumor angiogenesis and tumor growth by regulating the transcription of several genes in response to a hypoxic environment and changes in growth factors. This study was designed to investigate the effects of cinnamic aldehyde (CA) on tumor growth and angiogenesis and the mechanisms underlying CA's anti-angiogenic activities. We found that CA administration inhibits tumor growth and blocks tumor angiogenesis in BALB/c mice. In addition, CA treatment decreased HIF-1α protein expression and vascular endothelial growth factor (VEGF) expression in mouse tumors and Renca cells exposed to hypoxia in vitro. Interestingly, CA treatment did not affect the stability of von Hippel-Lindau protein (pVHL)-associated HIF-1α and CA attenuated the activation of mammalian target of rapamycin (mTOR) pathway. Collectively, these findings strongly indicate that the anti-angiogenic activity of CA is, at least in part, regulated by the mTOR pathway-mediated suppression of HIF-1α protein expression and these findings suggest that CA may be a potential drug for human cancer therapy. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Effects of cadmium on hypoxia-induced expression of hemoglobin and erythropoietin in larval sheepshead minnow, Cyprinodon variegatus

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    Dangre, A.J.; Manning, S. [Department of Coastal Sciences, University of Southern Mississippi, 703 East Beach Drive, Ocean Springs, MS 39564 (United States); Brouwer, M., E-mail: marius.brouwer@usm.edu [Department of Coastal Sciences, University of Southern Mississippi, 703 East Beach Drive, Ocean Springs, MS 39564 (United States)

    2010-08-15

    Hypoxia and toxic metals are two common stressors found in the estuarine environment. To date little information is available on the combined effects of these stressors on early larval development in fish. We investigated the effect of cadmium and hypoxia exposure alone as well in combination on larval Cyprinodon variegatus. The LC{sub 10} for cadmium was determined to be 0.3 ppm in a 96 h acute exposure. This concentration was used in all studies. Cadmium in larvae increased significantly with exposure time (1, 3, 5 and 7 days post-hatch). The increase was proportional to body weight and not affected by hypoxia. Cadmium responsive genes were identified by suppression subtractive hybridization (SSH) in Cyprinodonvariegatus larvae after exposure to cadmium for 1, 3, 5 and 7 days. We obtained over 700 sequences from the cadmium cDNA library. Blast search of ESTs suggested that cadmium modulates multiple physiological processes. Pertinent to this study, cadmium was found to down-regulate both embryonic {alpha} and {beta} globin, which are expressed in erythrocytes generated during the first, or primitive, wave of erythropoiesis in teleosts. Hemoglobin (Hb) and erythropoietin (Epo) (the hormone that promotes red blood cell production) are known hypoxia-inducible genes. To explore the possibility that cadmium might offset the hypoxia-induced expression of Hb and Epo, we investigated the expression of both genes following hypoxia, cadmium and combined exposures for 1, 3, 5 and 7 days post-hatch. Since Epo had not yet been identified in C. variegatus we first successfully cloned a partial coding sequence of the C. variegatus hormone. Subsequent studies revealed that expression levels of Hb and Epo remained unchanged in the normoxic controls during the time course of the study. Hypoxia increased Epo expression relative to normoxic controls, on days 3, 5 and 7, while cadmium in hypoxia inhibited the increase. Only the changes on days 5 and 7 were statistically significant

  3. Hypoxia induces adipogenic differentitation of myoblastic cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Itoigawa, Yoshiaki [Tohoku University School of Medicine, Sendai (Japan); Juntendo University School of Medicine, Tokyo (Japan); Kishimoto, Koshi N., E-mail: kishimoto@med.tohoku.ac.jp [Tohoku University School of Medicine, Sendai (Japan); Okuno, Hiroshi; Sano, Hirotaka [Tohoku University School of Medicine, Sendai (Japan); Kaneko, Kazuo [Juntendo University School of Medicine, Tokyo (Japan); Itoi, Eiji [Tohoku University School of Medicine, Sendai (Japan)

    2010-09-03

    Research highlights: {yields} C2C12 and G8 myogenic cell lines treated by hypoxia differentiate into adipocytes. {yields} The expression of C/EBP{beta}, {alpha} and PPAR{gamma} were increased under hypoxia. {yields} Myogenic differentiation of C2C12 was inhibited under hypoxia. -- Abstract: Muscle atrophy usually accompanies fat accumulation in the muscle. In such atrophic conditions as back muscles of kyphotic spine and the rotator cuff muscles with torn tendons, blood flow might be diminished. It is known that hypoxia causes trans-differentiation of mesenchymal stem cells derived from bone marrow into adipocytes. However, it has not been elucidated yet if hypoxia turned myoblasts into adipocytes. We investigated adipogenesis in C2C12 and G8 murine myogenic cell line treated by hypoxia. Cells were also treated with the cocktail of insulin, dexamethasone and IBMX (MDI), which has been known to inhibit Wnt signaling and promote adipogenesis. Adipogenic differentiation was seen in both hypoxia and MDI. Adipogenic marker gene expression was assessed in C2C12. CCAAT/enhancer-binding protein (C/EBP) {beta}, {alpha} and peroxisome proliferator activating receptor (PPAR) {gamma} were increased by both hypoxia and MDI. The expression profile of Wnt10b was different between hypoxia and MDI. The mechanism for adipogenesis of myoblasts in hypoxia might be regulated by different mechanism than the modification of Wnt signaling.

  4. Cycling hypoxia: A key feature of the tumor microenvironment.

    Science.gov (United States)

    Michiels, Carine; Tellier, Céline; Feron, Olivier

    2016-08-01

    A compelling body of evidence indicates that most human solid tumors contain hypoxic areas. Hypoxia is the consequence not only of the chaotic proliferation of cancer cells that places them at distance from the nearest capillary but also of the abnormal structure of the new vasculature network resulting in transient blood flow. Hence two types of hypoxia are observed in tumors: chronic and cycling (intermittent) hypoxia. Most of the current work aims at understanding the role of chronic hypoxia in tumor growth, response to treatment and metastasis. Only recently, cycling hypoxia, with spatial and temporal fluctuations in oxygen levels, has emerged as another key feature of the tumor environment that triggers different responses in comparison to chronic hypoxia. Either type of hypoxia is associated with distinct effects not only in cancer cells but also in stromal cells. In particular, cycling hypoxia has been demonstrated to favor, to a higher extent than chronic hypoxia, angiogenesis, resistance to anti-cancer treatments, intratumoral inflammation and tumor metastasis. These review details these effects as well as the signaling pathway it triggers to switch on specific transcriptomic programs. Understanding the signaling pathways through which cycling hypoxia induces these processes that support the development of an aggressive cancer could convey to the emergence of promising new cancer treatments. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Hypoxia-inducible factor-1α/interleukin-1β signaling enhances hepatoma epithelial-mesenchymal transition through macrophages in a hypoxic-inflammatory microenvironment.

    Science.gov (United States)

    Zhang, Jingying; Zhang, Qi; Lou, Yu; Fu, Qihan; Chen, Qi; Wei, Tao; Yang, Jiaqi; Tang, Jinlong; Wang, Jianxin; Chen, Yiwen; Zhang, Xiaoyu; Zhang, Jian; Bai, Xueli; Liang, Tingbo

    2018-05-01

    The development and progression of hepatocellular carcinoma (HCC) are dependent on its local microenvironment. Hypoxia and inflammation are two critical factors that shape the HCC microenvironment; however, the interplay between the two factors and the involvement of cancer cells under such conditions remain poorly understood. We found that tumor-associated macrophages, the primary proinflammatory cells within tumors, secreted more interleukin 1β (IL-1β) under moderate hypoxic conditions due to increased stability of hypoxia inducible factor 1α (HIF-1α). Under persistent and severe hypoxia, we found that the necrotic debris of HCC cells induced potent IL-1β release by tumor-associated macrophages with an M2 phenotype. We further confirmed that the necrotic debris-induced IL-1β secretion was mediated through Toll-like receptor 4/TIR domain-containing adapter-inducing interferon-β/nuclear factor kappa-light-chain-enhancer of activated B cells signaling in a similar, but not identical, fashion to lipopolysaccharide-induced inflammation. Using mass spectrometry, we identified a group of proteins with O-linked glycosylation to be responsible for the necrotic debris-induced IL-1β secretion. Following the increase of IL-1β in the local microenvironment, the synthesis of HIF-1α was up-regulated by IL-1β in HCC cells through cyclooxygenase-2. The epithelial-mesenchymal transition of HCC cells was enhanced by overexpression of HIF-1α. We further showed that IL-1β promoted HCC metastasis in mouse models and was predictive of poor prognosis in HCC patients. Our findings revealed an HIF-1α/IL-1β signaling loop between cancer cells and tumor-associated macrophages in a hypoxic microenvironment, resulting in cancer cell epithelial-mesenchymal transition and metastasis; more importantly, our results suggest a potential role of an anti-inflammatory strategy in HCC treatment. (Hepatology 2018;67:1872-1889). © 2017 by the American Association for the Study of Liver

  6. Feeding behaviour and growth of the Peruvian scallop (Argopecten purpuratus) under daily cyclic hypoxia conditions

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    Aguirre-Velarde, Arturo; Jean, Fred; Thouzeau, Gérard; Flye-Sainte-Marie, Jonathan

    2018-01-01

    As a secondary consequence of the high productivity of the upwelling system, organisms inhabiting Peruvian coastal bays are frequently exposed to hypoxic conditions. The aim of the present paper was to investigate the effects of daily-cyclic-severe hypoxia on energetics of a species presenting little escape ability when facing hypoxia. For this purpose, juvenile Peruvian scallops (Argopecten purpuratus) were exposed to four experimental conditions: fed and starved, combined or not to nightly severe hypoxia (5% oxygen saturation) for ≈ 12 h over a 21-day experiment. In both fed conditions, clearance rate was measured by the mean of an open-flow system. Our results indicate that the Peruvian scallop is able to maintain an active filtration even at low oxygen saturation, at least during expositions up to 12 h. During the first phase of exposure to hypoxia, clearance rate decreased abruptly when oxygen saturation dropped below 10%, but rapidly recovered to values close to those found under normoxia. As a consequence of this ability to feed during hypoxia, no difference in soft tissue dry weight (digestive gland not included) was observed at the end of the experimental period between oxic conditions among fed scallops. However, shell growth was negatively affected by hypoxic condition. Starved individuals exhibited similar weight loss between hypoxic and normoxic conditions indicating no or little effect of oxic condition on maintenance costs. Considering the observed responses for feeding, growth and maintenance, we can hypothesize that this species presents metabolic/bioenergetic efficient adaptations to deal with hypoxic conditions that are recurrent in Peruvian coastal bays. We hypothesize that the small observed effects might be modelled in the context of the Dynamic Energy Budget theory as a restriction of reserve mobilization under hypoxic conditions.

  7. The dual role of autophagy under hypoxia-involvement of interaction between autophagy and apoptosis.

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    Li, Mengmeng; Tan, Jin; Miao, Yuyang; Lei, Ping; Zhang, Qiang

    2015-06-01

    Hypoxia is one of severe cellular stress and it is well known to be associated with a worse outcome since a lack of oxygen accelerates the induction of apoptosis. Autophagy, an important and evolutionarily conserved mechanism for maintaining cellular homeostasis, is closely related to the apoptosis caused by hypoxia. Generally autophagy blocks the induction of apoptosis and inhibits the activation of apoptosis-associated caspase which could reduce cellular injury. However, in special cases, autophagy or autophagy-relevant proteins may help to induce apoptosis, which could aggravate cell damage under hypoxia condition. In addition, the activation of apoptosis-related proteins-caspase can also degrade autophagy-related proteins, such as Atg3, Atg4, Beclin1 protein, inhibiting autophagy. Although the relationship between autophagy and apoptosis has been known for rather complex for more than a decade, the underlying regulatory mechanisms have not been clearly understood. This short review discusses and summarizes the dual role of autophagy and the interaction and molecular regulatory mechanisms between autophagy and apoptosis under hypoxia.

  8. Copper alters hypoxia sensitivity and the behavioural emersion response in the amphibious fish Kryptolebias marmoratus.

    Science.gov (United States)

    Blewett, Tamzin A; Simon, Robyn A; Turko, Andy J; Wright, Patricia A

    2017-08-01

    Elevated levels of metals have been reported in mangrove ecosystems worldwide. Mangrove fishes also routinely experience severe environmental stressors, such as hypoxia. In the amphibious fish Kryptolebias marmoratus (mangrove rivulus), a key behavioural response to avoid aquatic stress is to leave water (emersion). We hypothesized that copper (Cu) exposure would increase the sensitivity of this behavioural hypoxia avoidance response due to histopathological effects of Cu on gill structure and function. K. marmoratus were exposed to either control (no added Cu) or Cu (300μg/L) for 96h. Following this period, fish were exposed to an acute hypoxic challenge (decline in dissolved oxygen to ∼0% over 15min), and the emersion response was recorded. Gills were examined for histological changes. Fish exposed to Cu emersed at a higher dissolved oxygen level (7.5±0.6%), relative to the control treatment group (5.8±0.4%). Histological analysis showed that the gill surface area increased and the interlamellar cell mass (ILCM) was reduced following Cu exposure, contrary to our prediction. Overall, these data indicate that Cu induces hypoxia-like changes to gill morphology and increases the sensitivity of the hypoxia emersion response. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Divergent hypoxia tolerance in adult males and females of the plainfin midshipman (Porichthys notatus).

    Science.gov (United States)

    LeMoine, Christophe M R; Bucking, Carol; Craig, Paul M; Walsh, Patrick J

    2014-01-01

    In the summer, the plainfin midshipman (Poricththys notatus) migrates to reproduce in the nearshore environment, where oxygen levels are influenced by the tidal cycles. Parental males establish nests under rocks in the intertidal zone, where they reside until the eggs they guard are fully developed. In contrast, females and sneaker males leave the nests shortly after spawning. We examined the physiological resistance and metabolic response of parental male and female adult midshipman to hypoxia to test whether they exhibited sex-specific differences reflecting their reproductive strategies. Further, we assessed whether metabolic enzymes and metabolites were differentially enriched in tissues of parental males and females to explain the differences observed in their hypoxia tolerance. While parental males and females exhibited similar depression of their oxygen consumption in response to graded hypoxia, parental males could withstand significantly longer exposures to severe hypoxic stress. At the biochemical level, parental males showed higher hepatic glycogen reserves and higher glycolytic enzyme capacities in gills and skeletal muscles than females. Although some of these enzymatic variations could be explained by differences in body size, we also observed a significant effect of sex on some of these factors. These results suggest that parental male midshipman may benefit from sexual dimorphism at the whole-organismal (larger body size) and biochemical (enzyme activities) levels, conferring on them a higher glycolytic potential to sustain the extensive hypoxia bouts they experience in nature.

  10. Arachidonic Acid Metabolism Pathway Is Not Only Dominant in Metabolic Modulation but Associated With Phenotypic Variation After Acute Hypoxia Exposure

    Directory of Open Access Journals (Sweden)

    Chang Liu

    2018-03-01

    Full Text Available Background: The modulation of arachidonic acid (AA metabolism pathway is identified in metabolic alterations after hypoxia exposure, but its biological function is controversial. We aimed at integrating plasma metabolomic and transcriptomic approaches to systematically explore the roles of the AA metabolism pathway in response to acute hypoxia using an acute mountain sickness (AMS model.Methods: Blood samples were obtained from 53 enrolled subjects before and after exposure to high altitude. Ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry and RNA sequencing were separately performed for metabolomic and transcriptomic profiling, respectively. Influential modules comprising essential metabolites and genes were identified by weighted gene co-expression network analysis (WGCNA after integrating metabolic information with phenotypic and transcriptomic datasets, respectively.Results: Enrolled subjects exhibited diverse response manners to hypoxia. Combined with obviously altered heart rate, oxygen saturation, hemoglobin, and Lake Louise Score (LLS, metabolomic profiling detected that 36 metabolites were highly related to clinical features in hypoxia responses, out of which 27 were upregulated and nine were downregulated, and could be mapped to AA metabolism pathway significantly. Integrated analysis of metabolomic and transcriptomic data revealed that these dominant molecules showed remarkable association with genes in gas transport incapacitation and disorders of hemoglobin metabolism pathways, such as ALAS2, HEMGN. After detailed description of AA metabolism pathway, we found that the molecules of 15-d-PGJ2, PGA2, PGE2, 12-O-3-OH-LTB4, LTD4, LTE4 were significantly up-regulated after hypoxia stimuli, and increased in those with poor response manner to hypoxia particularly. Further analysis in another cohort showed that genes in AA metabolism pathway such as PTGES, PTGS1, GGT1, TBAS1 et al. were excessively

  11. Psychomotor skills learning under chronic hypoxia.

    Science.gov (United States)

    Bouquet, C A; Gardette, B; Gortan, C; Abraini, J H

    1999-09-29

    Psychomotor deficits are a prominent feature in subjects exposed to hypoxia. Eight subjects exposed to chronic hypoxia during a simulated climb to 8848 m (Everest-Comex 97) were investigated using both a simple psychomotor task (Purdue pegboard) and two complex psychomotor tasks including a recognition task of either a color stimulus (high semantic level) or an abstract sign (low semantic level). Exposure to hypoxic stress mainly produced psychomotor skills learning deficits compared to control study, with greater deficits in the complex psychomotor task. The pattern of results suggests disruptions of motor strategic process. Our data further suggest that the relative strength of implicit or automatic memory processes associated with semantic information processing may increase when disturbances occur in brain functions.

  12. Hypoxia-imaging with 18F-Misonidazole and PET: Changes of kinetics during radiotherapy of head-and-neck cancer

    International Nuclear Information System (INIS)

    Eschmann, Susanne Martina; Paulsen, Frank; Bedeshem, Claudia; Machulla, Hans-Juergen; Hehr, Thomas; Bamberg, Michael; Bares, Roland

    2007-01-01

    Background and purpose: PET with 18 F-Misonidazole (FMISO-PET) is a non-invasive method for measuring tumor hypoxia. We analysed changes of FMISO-uptake during radiotherapy and their impact on patient outcome. Materials and methods: Fourteen patients with HNC underwent repeated FMISO-PET prior to radiotherapy and after 30 Gy. Dynamic and static PET-scans (2 + 4 h p.i.) were acquired. FMISO-uptake was quantified by calculating standard uptake values (SUV) and tumor-muscle-ratios (TMR). Kinetic curve types representing tissue hypoxia were defined. Change of curve type was correlated with patient outcome. Results: The mean SUV 4 h p.i. and the TMR decreased significantly during radiotherapy. SUV decreased clearly in 12/14 patients, and increased in 2 patients. TMR decreased in 11 patients, and increased in 3 patients. Prior to radiotherapy, three different shapes of kinetic curve types indicative for the degree of hypoxia could be defined in 12/14 patients: (1) accumulation type (severe hypoxia (n = 8)) (2) intermediate type (intermediate degree of hypoxia (n = 3)), and (3) wash-out type (low degree of hypoxia (n = 1)). Curve type changed towards a lower degree of hypoxia at 30 Gy in all but 3 patients. In three patients curve type remained unchanged. Conclusions: The changes in tumor FMISO-uptake during radiotherapy indicate radio-induced reoxygenation

  13. Hypoxia: Exposure Time Until Significant Performance Effects

    Science.gov (United States)

    2016-03-07

    three alcoholic beverages per day (on average), or were taking any prescription medication (besides oral contraceptives). Likewise, those who were...or tested positively for pregnancy were disqualified from the study, as the risks of hypoxia to a human fetus are currently unknown. Also, those...that could impact inclusion in the study. After the questionnaire, all female participants provided a urine sample for pregnancy testing. Participants

  14. NASA Gulf of Mexico Initiative Hypoxia Research

    Science.gov (United States)

    Armstrong, Curtis D.

    2012-01-01

    The Applied Science & Technology Project Office at Stennis Space Center (SSC) manages NASA's Gulf of Mexico Initiative (GOMI). Addressing short-term crises and long-term issues, GOMI participants seek to understand the environment using remote sensing, in-situ observations, laboratory analyses, field observations and computational models. New capabilities are transferred to end-users to help them make informed decisions. Some GOMI activities of interest to the hypoxia research community are highlighted.

  15. Hypoxia changes the expression of the epidermal growth factor (EGF) system in human hearts and cultured cardiomyocytes

    DEFF Research Database (Denmark)

    Munk, Mathias; Memon, Ashfaque Ahmed; Goetze, Jens Peter

    2012-01-01

    by treatment with trastuzumab (20 nM). This resulted in inhibition of cardiomyocyte proliferation, but interestingly only in hypoxic cells. Co-treatment of HL-1 cells with HB-EGF (10 nM) but not with NRG-1 (5 ng/ml) rescued the cardiomyocytes from HER2 inhibition. HL-1 cardiomyocytes exposed to hypoxia...... revealed nuclear translocation of activated MAPK and the activity of this downstream signaling molecule was decreased by HER2 inhibition (20 nM trastuzumab), and re-established by HB-EGF (10 nM). CONCLUSIONS/SIGNIFICANCE: Hypoxia in the human heart alters the expression of the EGF system. Mimicking the HER...

  16. Complement C3 deficiency attenuates chronic hypoxia-induced pulmonary hypertension in mice.

    Directory of Open Access Journals (Sweden)

    Eileen M Bauer

    Full Text Available Evidence suggests a role of both innate and adaptive immunity in the development of pulmonary arterial hypertension. The complement system is a key sentry of the innate immune system and bridges innate and adaptive immunity. To date there are no studies addressing a role for the complement system in pulmonary arterial hypertension.Immunofluorescent staining revealed significant C3d deposition in lung sections from IPAH patients and C57Bl6/J wild-type mice exposed to three weeks of chronic hypoxia to induce pulmonary hypertension. Right ventricular systolic pressure and right ventricular hypertrophy were increased in hypoxic vs. normoxic wild-type mice, which were attenuated in C3-/- hypoxic mice. Likewise, pulmonary vascular remodeling was attenuated in the C3-/- mice compared to wild-type mice as determined by the number of muscularized peripheral arterioles and morphometric analysis of vessel wall thickness. The loss of C3 attenuated the increase in interleukin-6 and intracellular adhesion molecule-1 expression in response to chronic hypoxia, but not endothelin-1 levels. In wild-type mice, but not C3-/- mice, chronic hypoxia led to platelet activation as assessed by bleeding time, and flow cytometry of platelets to determine cell surface P-selectin expression. In addition, tissue factor expression and fibrin deposition were increased in the lungs of WT mice in response to chronic hypoxia. These pro-thrombotic effects of hypoxia were abrogated in C3-/- mice.Herein, we provide compelling genetic evidence that the complement system plays a pathophysiologic role in the development of PAH in mice, promoting pulmonary vascular remodeling and a pro-thrombotic phenotype. In addition we demonstrate C3d deposition in IPAH patients suggesting that complement activation plays a role in the development of PAH in humans.

  17. Characterization of a hypoxia-response element in the Epo locus of the pufferfish, Takifugu rubripes.

    Science.gov (United States)

    Kulkarni, Rashmi P; Tohari, Sumanty; Ho, Adrian; Brenner, Sydney; Venkatesh, Byrappa

    2010-06-01

    Animals respond to hypoxia by increasing synthesis of the glycoprotein hormone erythropoietin (Epo) which in turn stimulates the production of red blood cells. The gene encoding Epo has been recently cloned in teleost fishes such as the pufferfish Takifugu rubripes (fugu) and zebrafish (Danio rerio). It has been shown that the transcription levels of Epo in teleost fishes increase in response to anemia or hypoxia in a manner similar to its human ortholog. However, the cis-regulatory element(s) mediating the hypoxia response of Epo gene in fishes has not been identified. In the present study, using the human hepatoma cell line (Hep3B), we have identified and characterized a hypoxia response element (HRE) in the fugu Epo locus. The sequence of the fugu HRE (ACGTGCTG) is identical to that of the HRE in the human EPO locus. However, unlike the HRE in the mammalian Epo locus, which is located in the 3' region of the gene, the fugu HRE is located in the 5' flanking region and on the opposite strand of DNA. This HRE is conserved in other teleosts such as Tetraodon and zebrafish in a similar location. A 365-bp fragment containing the fugu HRE was able to drive GFP expression in the liver of transgenic zebrafish. However, we could not ascertain if the expression of transgene is induced by hypoxia in vivo due to the low and variable levels of GFP expression in transgenic zebrafish. Our investigations also revealed that the Epo locus has experienced extensive rearrangements during vertebrate evolution. Copyright © 2010 Elsevier B.V. All rights reserved.

  18. Distinct mechanisms underlying tolerance to intermittent and constant hypoxia in Drosophila melanogaster.

    Directory of Open Access Journals (Sweden)

    Priti Azad

    Full Text Available BACKGROUND: Constant hypoxia (CH and intermittent hypoxia (IH occur during several pathological conditions such as asthma and obstructive sleep apnea. Our research is focused on understanding the molecular mechanisms that lead to injury or adaptation to hypoxic stress using Drosophila as a model system. Our current genome-wide study is designed to investigate gene expression changes and identify protective mechanism(s in D. melanogaster after exposure to severe (1% O(2 intermittent or constant hypoxia. METHODOLOGY/PRINCIPAL FINDINGS: Our microarray analysis has identified multiple gene families that are up- or down-regulated in response to acute CH or IH. We observed distinct responses to IH and CH in gene expression that varied in the number of genes and type of gene families. We then studied the role of candidate genes (up-or down-regulated in hypoxia tolerance (adult survival for longer periods (CH-7 days, IH-10 days under severe CH or IH. Heat shock proteins up-regulation (specifically Hsp23 and Hsp70 led to a significant increase in adult survival (as compared to controls of P-element lines during CH. In contrast, during IH treatment the up-regulation of Mdr49 and l(208717 genes (P-element lines provided survival advantage over controls. This suggests that the increased transcript levels following treatment with either paradigm play an important role in tolerance to severe hypoxia. Furthermore, by over-expressing Hsp70 in specific tissues, we found that up-regulation of Hsp70 in heart and brain play critical role in tolerance to CH in flies. CONCLUSIONS/SIGNIFICANCE: We observed that the gene expression response to IH or CH is specific and paradigm-dependent. We have identified several genes Hsp23, Hsp70, CG1600, l(208717 and Mdr49 that play an important role in hypoxia tolerance whether it is in CH or IH. These data provide further clues about the mechanisms by which IH or CH lead to cell injury and morbidity or adaptation and survival.

  19. Optical imaging of tumor hypoxia dynamics

    Science.gov (United States)

    Palmer, Gregory M.; Fontanella, Andrew N.; Zhang, Guoqing; Hanna, Gabi; Fraser, Cassandra L.; Dewhirst, Mark W.

    2010-11-01

    The influence of the tumor microenvironment and hypoxia plays a significant role in determining cancer progression, treatment response, and treatment resistance. That the tumor microenvironment is highly heterogeneous with significant intratumor and intertumor variability presents a significant challenge in developing effective cancer therapies. Critical to understanding the role of the tumor microenvironment is the ability to dynamically quantify oxygen levels in the vasculature and tissue in order to elucidate the roles of oxygen supply and consumption, spatially and temporally. To this end, we describe the use of hyperspectral imaging to characterize hemoglobin absorption to quantify hemoglobin content and oxygen saturation, as well as dual emissive fluorescent/phosphorescent boron nanoparticles, which serve as ratiometric indicators of tissue oxygen tension. Applying these techniques to a window-chamber tumor model illustrates the role of fluctuations in hemoglobin saturation in driving changes in tissue oxygenation, the two being significantly correlated (r = 0.77). Finally, a green-fluorescence-protein reporter for hypoxia inducible factor-1 (HIF-1) provides an endpoint for hypoxic stress in the tumor, which is used to demonstrate a significant association between tumor hypoxia dynamics and HIF-1 activity in an in vivo demonstration of the technique.

  20. Hypoxia in the changing marine environment

    International Nuclear Information System (INIS)

    Zhang, J; Cowie, G; Naqvi, S W A

    2013-01-01

    The predicted future of the global marine environment, as a combined result of forcing due to climate change (e.g. warming and acidification) and other anthropogenic perturbation (e.g. eutrophication), presents a challenge to the sustainability of ecosystems from tropics to high latitudes. Among the various associated phenomena of ecosystem deterioration, hypoxia can cause serious problems in coastal areas as well as oxygen minimum zones in the open ocean (Diaz and Rosenberg 2008 Science 321 926–9, Stramma et al 2008 Science 320 655–8). The negative impacts of hypoxia include changes in populations of marine organisms, such as large-scale mortality and behavioral responses, as well as variations of species distributions, biodiversity, physiological stress, and other sub-lethal effects (e.g. growth and reproduction). Social and economic activities that are related to services provided by the marine ecosystems, such as tourism and fisheries, can be negatively affected by the aesthetic outcomes as well as perceived or real impacts on seafood quality (STAP 2011 (Washington, DC: Global Environment Facility) p 88). Moreover, low oxygen concentration in marine waters can have considerable feedbacks to other compartments of the Earth system, like the emission of greenhouse gases to the atmosphere, and can affect the global biogeochemical cycles of nutrients and trace elements. It is of critical importance to prediction and adaptation strategies that the key processes of hypoxia in marine environments be precisely determined and understood (cf Zhang et al 2010 Biogeosciences 7 1–24). (synthesis and review)

  1. Hypoxia in the changing marine environment

    Science.gov (United States)

    Zhang, J.; Cowie, G.; Naqvi, S. W. A.

    2013-03-01

    The predicted future of the global marine environment, as a combined result of forcing due to climate change (e.g. warming and acidification) and other anthropogenic perturbation (e.g. eutrophication), presents a challenge to the sustainability of ecosystems from tropics to high latitudes. Among the various associated phenomena of ecosystem deterioration, hypoxia can cause serious problems in coastal areas as well as oxygen minimum zones in the open ocean (Diaz and Rosenberg 2008 Science 321 926-9, Stramma et al 2008 Science 320 655-8). The negative impacts of hypoxia include changes in populations of marine organisms, such as large-scale mortality and behavioral responses, as well as variations of species distributions, biodiversity, physiological stress, and other sub-lethal effects (e.g. growth and reproduction). Social and economic activities that are related to services provided by the marine ecosystems, such as tourism and fisheries, can be negatively affected by the aesthetic outcomes as well as perceived or real impacts on seafood quality (STAP 2011 (Washington, DC: Global Environment Facility) p 88). Moreover, low oxygen concentration in marine waters can have considerable feedbacks to other compartments of the Earth system, like the emission of greenhouse gases to the atmosphere, and can affect the global biogeochemical cycles of nutrients and trace elements. It is of critical importance to prediction and adaptation strategies that the key processes of hypoxia in marine environments be precisely determined and understood (cf Zhang et al 2010 Biogeosciences 7 1-24).

  2. Intrauterine hypoxia: clinical consequences and therapeutic perspectives

    Directory of Open Access Journals (Sweden)

    Thompson LP

    2015-09-01

    Full Text Available Loren P Thompson,1 Sarah Crimmins,1 Bhanu P Telugu,2 Shifa Turan1 1Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, USA; 2Department of Animal Sciences, University of Maryland, College Park, MD, USA Abstract: Intrauterine hypoxia is a significant clinical challenge in obstetrics that affects both the pregnant mother and fetus. Intrauterine hypoxia can occur in pregnant women living at high altitude and/or with cardiovascular disease. In addition, placental hypoxia can be generated by altered placental development and spiral artery remodeling leading to placental insufficiency and dysfunction. Both conditions can impact normal maternal cardiovascular homeostasis leading to preeclampsia and/or impair transfer of O2/nutrient supply resulting in fetal growth restriction. This review discusses the mechanisms underlying altered placental vessel remodeling, maternal and fetal consequences, patient management, and potential future therapies for improving these conditions. Keywords: fetal growth restriction, oxidative stress, extravillous trophoblast invasion, Doppler ultrasound, pulsatility index, preeclampsia 

  3. Endogenous markers of tumor hypoxia. Predictors of clinical radiation resistance?

    International Nuclear Information System (INIS)

    Vordermark, D.; Brown, J.M.

    2003-01-01

    Background: Eppendorf electrode measurements of tumor oxygenation have defined an adverse effect of tumor hypoxia on prognosis after radiotherapy and other treatment modalities, in particular in head and neck and cervix carcinomas as well as soft tissue sarcomas. Recently, the immunohistochemical detection of proteins involved in the ''hypoxic response'' of tumor cells has been discussed as a method to estimate hypoxia in clinical tumor specimens. Material and Methods: This review focuses on clinical and experimental data, regarding prognostic impact and comparability with other methods of hypoxia detection, for three proteins suggested as endogenous markers of tumor hypoxia: hypoxia-inducible factor-1α (HIF-1α), carbonic anhydrase 9 (CA 9), and glucose transporter 1 (GLUT1). Results: None of the three potential hypoxia markers is exclusively hypoxia-specific, and in each case protein can be detected under normoxic conditions in vitro. HIF-1α responds rapidly to hypoxia but also to reoxygenation, making this marker quite unstable in the context of clinical sample collection. The perinecrotic labeling pattern typical of chronic hypoxia and a reasonable agreement with injectable hypoxia markers such as pimonidazole have most consistently been described for CA 9. All three markers showed correlation with Eppendorf electrode measurements of tumor oxygenation in carcinoma of the cervix. In nine of 13 reports, among them all three that refer to curative radiotherapy for head and neck cancer, HIF-1α overexpression was associated with poor outcome. CA 9 was an adverse prognostic factor in cervix, head and neck and lung cancer, but not in two other head and neck cancer reports. GLUT1 predicted for poor survival in colorectal, cervix and lung cancer. Conclusion: Endogenous markers have the potential to indicate therapeutically relevant levels of hypoxia within tumors. Clinical trials assessing a marker's ability to predict a benefit from specific hypoxia

  4. 4-Guanidino-n-butyl syringate (Leonurine, SCM 198) protects H9c2 rat ventricular cells from hypoxia-induced apoptosis.

    Science.gov (United States)

    Liu, Xin-hua; Chen, Pei-fang; Pan, Li-long; Silva, Ranil De; Zhu, Yi-zhun

    2009-11-01

    In the present study, we examined the ability of a chemically synthesized compound based on the structure of leonurine, a phytochemical component of Herba leonuri, to protect H9c2 rat ventricular cells from apoptosis induced by hypoxia and serum deprivation, as a model of ischemia. The results revealed a concentration-dependent increase in cell viability associated with leonurine treatment, accompanied by a consistent decline in lactate dehydrogenase leakage into the culture medium. The fraction of annexin V-fluorescein isothiocyanate-positive cells was increased by hypoxia but reduced by leonurine. These changes were associated with increased expression of the antiapoptotic gene, Bcl-2, and reduced expression of the proapoptotic gene, Bax. Leonurine also reduced the cytosolic Ca overload induced by hypoxia. These results suggest that leonurine elicits potent cardioprotective effects in H9c2 cells, and these effects may be mediated by inhibition of intracellular Ca overload and apoptosis during hypoxia.

  5. The retinoblastoma protein regulates hypoxia-inducible genetic programs, tumor cell invasiveness and neuroendocrine differentiation in prostate cancer cells

    Science.gov (United States)

    Labrecque, Mark P.; Takhar, Mandeep K.; Nason, Rebecca; Santacruz, Stephanie; Tam, Kevin J.; Massah, Shabnam; Haegert, Anne; Bell, Robert H.; Altamirano-Dimas, Manuel; Collins, Colin C.; Lee, Frank J.S.; Prefontaine, Gratien G.; Cox, Michael E.; Beischlag, Timothy V.

    2016-01-01

    Loss of tumor suppressor proteins, such as the retinoblastoma protein (Rb), results in tumor progression and metastasis. Metastasis is facilitated by low oxygen availability within the tumor that is detected by hypoxia inducible factors (HIFs). The HIF1 complex, HIF1α and dimerization partner the aryl hydrocarbon receptor nuclear translocator (ARNT), is the master regulator of the hypoxic response. Previously, we demonstrated that Rb represses the transcriptional response to hypoxia by virtue of its association with HIF1. In this report, we further characterized the role Rb plays in mediating hypoxia-regulated genetic programs by stably ablating Rb expression with retrovirally-introduced short hairpin RNA in LNCaP and 22Rv1 human prostate cancer cells. DNA microarray analysis revealed that loss of Rb in conjunction with hypoxia leads to aberrant expression of hypoxia-regulated genetic programs that increase cell invasion and promote neuroendocrine differentiation. For the first time, we have established a direct link between hypoxic tumor environments, Rb inactivation and progression to late stage metastatic neuroendocrine prostate cancer. Understanding the molecular pathways responsible for progression of benign prostate tumors to metastasized and lethal forms will aid in the development of more effective prostate cancer therapies. PMID:27015368

  6. Central nervous system hypoxia in children due to near drowning

    International Nuclear Information System (INIS)

    Fitch, S.J.; Gerald, B.; Magill, H.L.; Tonkin, I.L.D.

    1985-01-01

    Fourteen children who experienced acute, profound central nervous system hypoxia secondary to near drowning, aspiration, or respiratory arrest underwent CT examination. During the first week after the episode, the most frequent finding was a loss of gray-white matter differentiation. Other findings included effacement of sulci and cisterns, focal areas of edema in the cerebral cortex or basal ganglia, and hemorrhagic infarctions of the basal ganglia. Subsequent CT scans obtained from two weeks to five months after the hypoxic episode showed progression of cerebral loss from cortical infarction with gyral hemorrhage and enhancement to global parenchymal atrophy. The prognosis is poor in these patients: seven children experienced severe neurologic deficits and seven died

  7. An Unusual Case of Refractory Hypoxia on the ICU

    Science.gov (United States)

    Phillips, Caroline; Harris, Clare; Pulimood, Thomas; Ring, Liam

    2018-01-01

    We present the case of a 68-year-old gentleman who presented with breathlessness and was found to have NSTEMI, pulmonary oedema, and hypoxia. He remained hypoxic despite appropriate treatment and was found to have preserved LV function and raised cardiac output. CT pulmonary angiogram was negative but a cirrhotic liver was incidentally noted and later confirmed via ultrasound. Bedside examination was positive for orthodeoxia, suggesting a diagnosis of hepatopulmonary syndrome (HPS). The finding of significant intrapulmonary shunting on “bubble” echocardiography confirmed the diagnosis. This patient did not have previously diagnosed liver disease and had largely normal LFTs when the diagnosis was first suspected. We discuss HPS in the context of ICU and suggest how it may be screened for using simple tests. There is no correlation between the presence of HPS and severity of liver disease, yet we believe this is the first reported adult case of HPS on the ICU without previously diagnosed cirrhosis. PMID:29850271

  8. Phosphorylation of eIF2α is required for mRNA translation inhibition and survival during moderate hypoxia

    International Nuclear Information System (INIS)

    Koritzinsky, Marianne; Rouschop, Kasper M.A.; Beucken, Twan van den; Magagnin, Michael G.; Savelkouls, Kim; Lambin, Philippe; Wouters, Bradly G.

    2007-01-01

    Abstracts: Background and purpose: Human tumors are characterized by temporal fluctuations in oxygen tension. The biological pathways that respond to the dynamic tumor microenvironment represent potential molecular targets for cancer therapy. Anoxic conditions result in eIF2α dependent inhibition of overall mRNA translation, differential gene expression, hypoxia tolerance and tumor growth. The signaling pathway which governs eIF2α phosphorylation has therefore emerged as a potential molecular target. In this study, we investigated the role of eIF2α in regulating mRNA translation and hypoxia tolerance during moderate hypoxia. Since other molecular pathways that regulate protein synthesis are frequently mutated in cancer, we also assessed mRNA translation in a panel of cell lines from different origins. Materials and methods: Immortalized human fibroblast, transformed mouse embryo fibroblasts (MEFs) and cells from six cancer cell lines were exposed to 0.2% or 0.0% oxygen. We assayed global mRNA translation efficiency by polysome analysis, as well as proliferation and clonogenic survival. The role of eIF2α was assessed in MEFs harboring a homozygous inactivating mutation (S51A) as well as in U373-MG cells overexpressing GADD34 (C-term) under a tetracycline-dependent promoter. The involvement of eIF4E regulation was investigated in HeLa cells stably expressing a short hairpin RNA (shRNA) targeting 4E-BP1. Results: All cells investigated inhibited mRNA translation severely in response to anoxia and modestly in response to hypoxia. Two independent genetic cell models demonstrated that inhibition of mRNA translation in response to moderate hypoxia was dependent on eIF2α phosphorylation. Disruption of eIF2α phosphorylation caused sensitivity to hypoxia and anoxia. Conclusions: Disruption of eIF2α phosphorylation is a potential target for hypoxia-directed molecular cancer therapy

  9. Combining Optical Reporter Proteins with Different Half-lives to Detect Temporal Evolution of Hypoxia and Reoxygenation in Tumors

    Directory of Open Access Journals (Sweden)

    Pierre Danhier

    2015-12-01

    Full Text Available Here we have developed a hypoxia response element driven imaging strategy that combined the hypoxia-driven expression of two optical reporters with different half-lives to detect temporal changes in hypoxia and hypoxia inducible factor (HIF activity. For this purpose, human prostate cancer PC3 cells were transfected with the luciferase gene fused with an oxygen-dependent degradation domain (ODD-luc and a variant of the enhanced green fluorescent protein (EGFP. Both ODD-luciferase and EGFP were under the promotion of a poly-hypoxia-response element sequence (5xHRE. The cells constitutively expressed tdTomato red fluorescent protein. For validating the imaging strategy, cells were incubated under hypoxia (1% O2 for 48 hours and then reoxygenated. The luciferase activity of PC3-HRE-EGFP/HRE-ODD-luc/tdtomato cells detected by bioluminescent imaging rapidly decreased after reoxygenation, whereas EGFP levels in these cells remained stable for several hours. After in vitro validation, PC3-HRE-EGFP/HRE-ODD-luc/tdtomato tumors were implanted subcutaneously and orthotopically in nude male mice and imaged in vivo and ex vivo using optical imaging in proof-of-principle studies to demonstrate differences in optical patterns between EGFP expression and bioluminescence. This novel "timer" imaging strategy of combining the short-lived ODD-luciferase and the long-lived EGFP can provide a time frame of HRE activation in PC3 prostate cancer cells and will be useful to understand the temporal changes in hypoxia and HIF activity during cancer progression and following treatments including HIF targeting strategies.

  10. Intermittent hypoxia impairs glucose homeostasis in C57BL6/J mice: partial improvement with cessation of the exposure.

    Science.gov (United States)

    Polak, Jan; Shimoda, Larissa A; Drager, Luciano F; Undem, Clark; McHugh, Holly; Polotsky, Vsevolod Y; Punjabi, Naresh M

    2013-10-01

    Obstructive sleep apnea is associated with insulin resistance, glucose intolerance, and type 2 diabetes mellitus. Although several studies have suggested that intermittent hypoxia in obstructive sleep apnea may induce abnormalities in glucose homeostasis, it remains to be determined whether these abnormalities improve after discontinuation of the exposure. The objective of this study was to delineate the effects of intermittent hypoxia on glucose homeostasis, beta cell function, and liver glucose metabolism and to investigate whether the impairments improve after the hypoxic exposure is discontinued. C57BL6/J mice were exposed to 14 days of intermittent hypoxia, 14 days of intermittent air, or 7 days of intermittent hypoxia followed by 7 days of intermittent air (recovery paradigm). Glucose and insulin tolerance tests were performed to estimate whole-body insulin sensitivity and calculate measures of beta cell function. Oxidative stress in pancreatic tissue and glucose output from isolated hepatocytes were also assessed. Intermittent hypoxia increased fasting glucose levels and worsened glucose tolerance by 67% and 27%, respectively. Furthermore, intermittent hypoxia exposure was associated with impairments in insulin sensitivity and beta cell function, an increase in liver glycogen, higher hepatocyte glucose output, and an increase in oxidative stress in the pancreas. While fasting glucose levels and hepatic glucose output normalized after discontinuation of the hypoxic exposure, glucose intolerance, insulin resistance, and impairments in beta cell function persisted. Intermittent hypoxia induces insulin resistance, impairs beta cell function, enhances hepatocyte glucose output, and increases oxidative stress in the pancreas. Cessation of the hypoxic exposure does not fully reverse the observed changes in glucose metabolism.

  11. Cognitive responses to hypobaric hypoxia: implications for aviation training

    Directory of Open Access Journals (Sweden)

    Neuhaus C

    2014-11-01

    Full Text Available Christopher Neuhaus,1,2 Jochen Hinkelbein2,31Department of Anesthesiology, Heidelberg University Hospital, Ruprecht Karls University of Heidelberg, Heidelberg, 2Emergency Medicine and Air Rescue Working Group, German Society of Aviation and Space Medicine (DGLRM, Munich, 3Department of Anesthesiology and Intensive Care Medicine, University Hospital of Cologne, Cologne, GermanyAbstract: The aim of this narrative review is to provide an overview on cognitive responses to hypobaric hypoxia and to show relevant implications for aviation training. A principal element of hypoxia-awareness training is the intentional evocation of hypoxia symptoms during specific training sessions within a safe and controlled environment. Repetitive training should enable pilots to learn and recognize their personal hypoxia symptoms. A time span of 3–6 years is generally considered suitable to refresh knowledge of the more subtle and early symptoms especially. Currently, there are two different technical approaches available to induce hypoxia during training: hypobaric chamber training and reduced-oxygen breathing devices. Hypoxia training for aircrew is extremely important and effective, and the hypoxia symptoms should be emphasized clearly to aircrews. The use of tight-fitting masks, leak checks, and equipment checks should be taught to all aircrew and reinforced regularly. It is noteworthy that there are major differences in the required quality and quantity of hypoxia training for both military and civilian pilots.Keywords: cognitive response, aviation training, pilot, hypoxia, oxygen, loss of consciousness

  12. Expression patterns of the hypoxia-related genes osteopontin, CA9, erythropoietin, VEGF and HIF-1α in human glioma in vitro and in vivo

    International Nuclear Information System (INIS)

    Said, Harun M.; Hagemann, Carsten; Staab, Adrian; Stojic, Jelena; Kuehnel, Siglinde; Vince, Giles H.; Flentje, Michael; Roosen, Klaus; Vordermark, Dirk

    2007-01-01

    Background and purpose: To identify molecular markers of tumor hypoxia and potential therapeutic targets in glioblastoma (GBM), we investigated the hypoxia-related expression of osteopontin (OPN), carbonic anhydrase 9 (CA9), erythropoietin (EPO), vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α) in vitro in human GBM cell lines and in vivo in human tumor samples of GBM, compared to low-grade astrocytoma (LGA). Materials and methods: Expression of the hypoxia-induced genes OPN, CA9, EPO, VEGF and HIF-1α was analyzed in three GBM cell lines, GaMG, U373 and U251, under in vitro hypoxia (1, 6 or 24 h at 5%, 1% or 0.1% O 2 ) and in tumor samples from two patient groups with LGA and GBM (n = 15 each), at the mRNA level (semiquantitative RT-PCR). Selected conditions and representative tumor samples were also evaluated at the protein level by Western blot. Results: OPN and CA9 mRNA was most consistently upregulated in relation to severity and duration of in vitro hypoxia. In tumor samples, mean expression levels (LGA vs. GBM, normalized to mean expression in normal brain) were 1.71 vs. 4.57 (p < 0.001) for OPN, 1.11 vs. 3.35 (p < 0.001) for CA9, 2.79 vs. 5.28 (not significant, n.s.) for Epo, 1.13 vs. 2.0 (p = 0.007) for VEGF and 0.97 vs. 0.97 (n.s.) for HIF-1α. In tumor samples, GBM showed a particularly strong protein expression of OPN. Conclusions: Among a panel of known hypoxia-inducible genes, OPN and CA9 emerge as most consistently induced by in vitro hypoxia in human GBM cell lines and most specifically expressed in patient GBM tumor tissue, rendering these two genes attractive targets for hypoxia-directed treatment approaches

  13. Effect of hypoxia on benthic nutrient fluxes in the northwestern Black Sea

    Science.gov (United States)

    Friedrich, J.

    2012-04-01

    The western Black Sea shelf has been affected by eutrophication from the 1960s to the mid 1990s. A combination of increased nutrient loads from the major inflowing rivers Danube, Dniester and Dnepr and favourable climate conditions led to high productivity regimes. As a consequence, increased oxygen consumption due to decomposition of organic matter caused recurrent seasonal bottom water hypoxia for more than 20 years. In addition, recycling of nutrients from organic matter settling to the seafloor along with tight benthic-pelagic coupling represents an important internal source for productivity, hence internally supporting eutrophication. From the 1970s to 1990s, the benthic and pelagic systems deteriorated and ecosystem structure and functioning changed. Following the collapse of the centrally planned economies in the eastern European countries during the 1990s, the riverine nutrient input decreased, and the ecosystem, now slowly responding, shows signs of recovery; e.g. by a decrease in hypoxic events. In this study, benthic nutrient flux data from in-situ and ex-situ experiments during the 1990s on the Danube-influenced north-western Black Sea shelf and data from the 2000s, including the EU-FP7 HYPOX experiments, are analysed to reveal the effect of hypoxia on benthic nutrient fluxes. Mann-Whitney statistical tests have been applied to demonstrate the significance of differences in fluxes due to varying oxygen conditions in the water. During the 1990s experiments, bottom water hypoxia was encountered in all locations, while during the 2000s hypoxia has been met only during summer in the Danube Prodelta area and near the Dniester mouth. Indeed, bottom water oxygen in the 1990s has been statistically significantly lower than in the 2000s while benthic oxygen consumption was higher during eutrophication-induced hypoxia. The benthic nutrient fluxes in the 1990s and the 2000s however do not differ significantly. During hypoxia, despite ceasing eutrophication

  14. Air breathing and aquatic gas exchange during hypoxia in armoured catfish.

    Science.gov (United States)

    Scott, Graham R; Matey, Victoria; Mendoza, Julie-Anne; Gilmour, Kathleen M; Perry, Steve F; Almeida-Val, Vera M F; Val, Adalberto L

    2017-01-01

    Air breathing in fish is commonly believed to have arisen as an adaptation to aquatic hypoxia. The effectiveness of air breathing for tissue O 2 supply depends on the ability to avoid O 2 loss as oxygenated blood from the air-breathing organ passes through the gills. Here, we evaluated whether the armoured catfish (Hypostomus aff. pyreneusi)-a facultative air breather-can avoid branchial O 2 loss while air breathing in aquatic hypoxia, and we measured various other respiratory and metabolic traits important for O 2 supply and utilization. Fish were instrumented with opercular catheters to measure the O 2 tension (PO 2 ) of expired water, and air breathing and aquatic respiration were measured during progressive stepwise hypoxia in the water. Armoured catfish exhibited relatively low rates of O 2 consumption and gill ventilation, and gill ventilation increased in hypoxia due primarily to increases in ventilatory stroke volume. Armoured catfish began air breathing at a water PO 2 of 2.5 kPa, and both air-breathing frequency and hypoxia tolerance (as reflected by PO 2 at loss of equilibrium, LOE) was greater in individuals with a larger body mass. Branchial O 2 loss, as reflected by higher PO 2 in expired than in inspired water, was observed in a minority (4/11) of individuals as water PO 2 approached that at LOE. Armoured catfish also exhibited a gill morphology characterized by short filaments bearing short fused lamellae, large interlamellar cell masses, low surface area, and a thick epithelium that increased water-to-blood diffusion distance. Armoured catfish had a relatively low blood-O 2 binding affinity when sampled in normoxia (P 50 of 3.1 kPa at pH 7.4), but were able to rapidly increase binding affinity during progressive hypoxia exposure (to a P 50 of 1.8 kPa). Armoured catfish also had low activities of several metabolic enzymes in white muscle, liver, and brain. Therefore, low rates of metabolism and gill ventilation, and a reduction in branchial gas

  15. Developmental Hypoxia Has Negligible Effects on Long-Term Hypoxia Tolerance and Aerobic Metabolism of Atlantic Salmon (Salmo salar).

    Science.gov (United States)

    Wood, Andrew T; Clark, Timothy D; Andrewartha, Sarah J; Elliott, Nicholas G; Frappell, Peter B

    Exposure to developmental hypoxia can have long-term impacts on the physiological performance of fish because of irreversible plasticity. Wild and captive-reared Atlantic salmon (Salmo salar) can be exposed to hypoxic conditions during development and continue to experience fluctuating oxygen levels as juveniles and adults. Here, we examine whether developmental hypoxia impacts subsequent hypoxia tolerance and aerobic performance of Atlantic salmon. Individuals at 8°C were exposed to 50% (hypoxia) or 100% (normoxia) dissolved oxygen (DO) saturation (as percent of air saturation) from fertilization for ∼100 d (800 degree days) and then raised in normoxic conditions for a further 15 mo. At 18 mo after fertilization, aerobic scope was calculated in normoxia (100% DO) and acute (18 h) hypoxia (50% DO) from the difference between the minimum and maximum oxygen consumption rates ([Formula: see text] and [Formula: see text], respectively) at 10°C. Hypoxia tolerance was determined as the DO at which loss of equilibrium (LOE) occurred in a constantly decreasing DO environment. There was no difference in [Formula: see text], [Formula: see text], or aerobic scope between fish raised in hypoxia or normoxia. There was some evidence that hypoxia tolerance was lower (higher DO at LOE) in hypoxia-raised fish compared with those raised in normoxia, but the magnitude of the effect was small (12.52% DO vs. 11.73% DO at LOE). Acute hypoxia significantly reduced aerobic scope by reducing [Formula: see text], while [Formula: see text] remained unchanged. Interestingly, acute hypoxia uncovered individual-level relationships between DO at LOE and [Formula: see text], [Formula: see text], and aerobic scope. We discuss our findings in the context of developmental trajectories and the role of aerobic performance in hypoxia tolerance.

  16. Hypoxia, blackwater and fish kills: experimental lethal oxygen thresholds in juvenile predatory lowland river fishes.

    Directory of Open Access Journals (Sweden)

    Kade Small

    Full Text Available Hypoxia represents a growing threat to biodiversity in freshwater ecosystems. Here, aquatic surface respiration (ASR and oxygen thresholds required for survival in freshwater and simulated blackwater are evaluated for four lowland river fishes native to the Murray-Darling Basin (MDB, Australia. Juvenile stages of predatory species including golden perch Macquaria ambigua, silver perch Bidyanus bidyanus, Murray cod Maccullochella peelii, and eel-tailed catfish Tandanus tandanus were exposed to experimental conditions of nitrogen-induced hypoxia in freshwater and hypoxic blackwater simulations using dried river red gum Eucalyptus camaldulensis leaf litter. Australia's largest freshwater fish, M. peelii, was the most sensitive to hypoxia but given that we evaluated tolerances of juveniles (0.99 ± 0.04 g; mean mass ±SE, the low tolerance of this species could not be attributed to its large maximum attainable body mass (>100,000 g. Concentrations of dissolved oxygen causing 50% mortality (LC50 in freshwater ranged from 0.25 ± 0.06 mg l(-1 in T. tandanus to 1.58 ± 0.01 mg l(-1 in M. peelii over 48 h at 25-26 °C. Logistic models predicted that first mortalities may start at oxygen concentrations ranging from 2.4 mg l(-1 to 3.1 mg l(-1 in T. tandanus and M. peelii respectively within blackwater simulations. Aquatic surface respiration preceded mortality and this behaviour is documented here for the first time in juveniles of all four species. Despite the natural occurrence of hypoxia and blackwater events in lowland rivers of the MDB, juvenile stages of these large-bodied predators are vulnerable to mortality induced by low oxygen concentration and water chemistry changes associated with the decomposition of organic material. Given the extent of natural flow regime alteration and climate change predictions of rising temperatures and more severe drought and flooding, acute episodes of hypoxia may represent an underappreciated risk to riverine fish

  17. Unique flexibility in energy metabolism allows mycobacteria to combat starvation and hypoxia.

    Directory of Open Access Journals (Sweden)

    Michael Berney

    Full Text Available Mycobacteria are a group of obligate aerobes that require oxygen for growth, but paradoxically have the ability to survive and metabolize under hypoxia. The mechanisms responsible for this metabolic plasticity are unknown. Here, we report on the adaptation of Mycobacterium smegmatis to slow growth rate and hypoxia using carbon-limited continuous culture. When M. smegmatis is switched from a 4.6 h to a 69 h doubling time at a constant oxygen saturation of 50%, the cells respond through the down regulation of respiratory chain components and the F1Fo-ATP synthase, consistent with the cells lower demand for energy at a reduced growth rate. This was paralleled by an up regulation of molecular machinery that allowed more efficient energy generation (i.e. Complex I and the use of alternative electron donors (e.g. hydrogenases and primary dehydrogenases to maintain the flow of reducing equivalents to the electron transport chain during conditions of severe energy limitation. A hydrogenase mutant showed a 40% reduction in growth yield highlighting the importance of this enzyme in adaptation to low energy supply. Slow growing cells at 50% oxygen saturation subjected to hypoxia (0.6% oxygen saturation responded by switching on oxygen scavenging cytochrome bd, proton-translocating cytochrome bc1-aa3 supercomplex, another putative hydrogenase, and by substituting NAD+-dependent enzymes with ferredoxin-dependent enzymes thus highlighting a new pattern of mycobacterial adaptation to hypoxia. The expression of ferredoxins and a hydrogenase provides a potential conduit for disposing of and transferring electrons in the absence of exogenous electron acceptors. The use of ferredoxin-dependent enzymes would allow the cell to maintain a high carbon flux through its central carbon metabolism independent of the NAD+/NADH ratio. These data demonstrate the remarkable metabolic plasticity of the mycobacterial cell and provide a new framework for understanding their

  18. Slit2 ameliorates renal inflammation and fibrosis after hypoxia-and lipopolysaccharide-induced epithelial cells injury in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Xiangjun [Department of Urology, Taihe Hospital, Hubei University of Medicine, Hubei (China); Yao, Qisheng, E-mail: yymcyqs@126.com [Department of Urology, Taihe Hospital, Hubei University of Medicine, Hubei (China); Sun, Xinbo; Gong, Xiaoxin; Yang, Yong; Chen, Congbo [Department of Urology, Taihe Hospital, Hubei University of Medicine, Hubei (China); Shan, Guang [Department of Urology, Renmin Hospital of Wuhan University, Hubei (China)

    2017-03-01

    Hypoxic acute kidney injury (AKI) is often incompletely repaired and leads to chronic kidney disease (CKD), which is characterized by tubulointerstitial inflammation and fibrosis. The Slit2 family of secreted glycoproteins is expressed in the kidney, it has been shown to exert an anti-inflammatory activity and prevent ischemic renal injury in vivo. However, whether Slit2 reduces renal fibrosis and inflammation after hypoxic and inflammatory epithelial cells injury in vitro remains unknown. In this study, we aimed to evaluate whether Slit2 ameliorated fibrosis and inflammation in two renal epithelial cells line challenged with hypoxia and lipopolysaccharide (LPS). Renal epithelial cells were treated with hypoxia and LPS to induce cell injury. Hoechst staining and Western blot analysis was conducted to examine epithelial cells injury. Immunofluorescence staining and Western blot analysis was performed to evaluate tubulointerstitial fibrosis. Real-time polymerase chain reaction (PCR) tested the inflammatory factor interleukin (IL)−1β and tumor necrosis factor (TNF)-α, and Western blot analysis determined the hypoxia-inducible factor (HIF)−1α, Toll-like receptor 4 (TLR4) and nuclear factor (NF)-κB. Results revealed that hypoxia induced epithelial cells apoptosis, inflammatory factor IL-1β and TNF-α release and tubulointerstitial fibrosis. LPS could exacerbate hypoxia -induced epithelial cells apoptosis, IL-1β and TNF-α release and fibrosis. Slit2 reduced the expression of fibronectin, the rate of epithelial cell apoptosis, and the expression of inflammatory factor. Slit2 could also inhibit the expression of TLR4 and NF-κB, but not the expression of HIF-1α. Therefore, Slit2 attenuated inflammation and fibrosis after LPS- and hypoxia-induced epithelial cells injury via the TLR4/NF-κB signaling pathway, but not depending on the HIF-1α signaling pathway. - Highlights: • Slit2 ameliorates inflammation after hypoxia-and LPS-induced epithelial cells injury

  19. Mechanisms of Sympathetic Activation and Blood Pressure Elevation by Intermittent Hypoxia

    OpenAIRE

    Prabhakar, Nanduri R.; Kumar, Ganesh K.

    2010-01-01

    Sleep disordered breathing with recurrent apneas is one of the most frequently encountered breathing disorder in adult humans and preterm infants. Recurrent apnea patients exhibit several co-morbidities including hypertension and persistent sympathetic activation. Intermittent hypoxia (IH) resulting from apneas appears to be the primary stimulus for evoking autonomic changes. The purpose of this article is to briefly review the effects of IH on chemo-and baro-reflexes and circulating vasoacti...

  20. Phrenicotomy alters phrenic long-term facilitation following intermittent hypoxia in anesthetized rats

    OpenAIRE

    Sandhu, M. S.; Lee, K. Z.; Fregosi, R. F.; Fuller, D. D.

    2010-01-01

    Intermittent hypoxia (IH) can induce a persistent increase in neural drive to the respiratory muscles known as long-term facilitation (LTF). LTF of phrenic inspiratory activity is often studied in anesthetized animals after phrenicotomy (PhrX), with subsequent recordings being made from the proximal stump of the phrenic nerve. However, severing afferent and efferent axons in the phrenic nerve has the potential to alter the excitability of phrenic motoneurons, which has been hypothesized to be...

  1. Expression of EGFR Under Tumor Hypoxia: Identification of a Subpopulation of Tumor Cells Responsible for Aggressiveness and Treatment Resistance

    Energy Technology Data Exchange (ETDEWEB)

    Hoogsteen, Ilse J., E-mail: i.hoogsteen@rther.umcn.nl [Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, Nijmegen (Netherlands); Marres, Henri A.M.; Hoogen, Franciscus J.A. van den [Department of Otorhinolaryngology/Head-Neck Surgery, Radboud University Nijmegen Medical Centre, Nijmegen (Netherlands); Rijken, Paul F.J.W.; Lok, Jasper; Bussink, Johan; Kaanders, Johannes H.A.M. [Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, Nijmegen (Netherlands)

    2012-11-01

    Purpose: Overexpression of epidermal growth factor receptor (EGFR) and tumor hypoxia have been shown to correlate with worse outcome in several types of cancer including head-and-neck squamous cell carcinoma. Little is known about the combination and possible interactions between the two phenomena. Methods and Materials: In this study, 45 cases of histologically confirmed squamous cell carcinomas of the head and neck were analyzed. All patients received intravenous infusions of the exogenous hypoxia marker pimonidazole prior to biopsy. Presence of EGFR, pimonidazole binding, and colocalization between EGFR and tumor hypoxia were examined using immunohistochemistry. Results: Of all biopsies examined, respectively, 91% and 60% demonstrated EGFR- and pimonidazole-positive areas. A weak but significant association was found between the hypoxic fractions of pimonidazole (HFpimo) and EGFR fractions (F-EGFR) and between F-EGFR and relative vascular area. Various degrees of colocalization between hypoxia and EGFR were found, increasing with distance from the vasculature. A high fraction of EGFR was correlated with better disease-free and metastasis-free survival, whereas a high degree of colocalization correlated with poor outcome. Conclusions: Colocalization of hypoxia and EGFR was demonstrated in head-and-neck squamous cell carcinomas, predominantly at longer distances from vessels. A large amount of colocalization was associated with poor outcome, which points to a survival advantage of hypoxic cells that are also able to express EGFR. This subpopulation of tumor cells might be indicative of tumor aggressiveness and be partly responsible for treatment resistance.

  2. Antihypertrophic Effects of Small Molecules that Maintain Mitochondrial ATP Levels Under Hypoxia

    Directory of Open Access Journals (Sweden)

    Hiroaki Nagai

    2017-10-01

    Full Text Available Since impaired mitochondrial ATP production in cardiomyocytes is thought to lead to heart failure, a drug that protects mitochondria and improves ATP production under disease conditions would be an attractive treatment option. In this study, we identified small-molecule drugs, including the anti-parasitic agent, ivermectin, that maintain mitochondrial ATP levels under hypoxia in cardiomyocytes. Mechanistically, transcriptomic analysis and gene silencing experiments revealed that ivermectin increased mitochondrial ATP production by inducing Cox6a2, a subunit of the mitochondrial respiratory chain. Furthermore, ivermectin inhibited the hypertrophic response of human induced pluripotent stem cell-derived cardiomyocytes. Pharmacological inhibition of importin β, one of the targets of ivermectin, exhibited protection against mitochondrial ATP decline and cardiomyocyte hypertrophy. These findings indicate that maintaining mitochondrial ATP under hypoxia may prevent hypertrophy and improve cardiac function, providing therapeutic options for mitochondrial dysfunction.

  3. Neurons have an active glycogen metabolism that contributes to tolerance to hypoxia

    Science.gov (United States)

    Saez, Isabel; Duran, Jordi; Sinadinos, Christopher; Beltran, Antoni; Yanes, Oscar; Tevy, María F; Martínez-Pons, Carlos; Milán, Marco; Guinovart, Joan J

    2014-01-01

    Glycogen is present in the brain, where it has been found mainly in glial cells but not in neurons. Therefore, all physiologic roles of brain glycogen have been attributed exclusively to astrocytic glycogen. Working with primary cultured neurons, as well as with genetically modified mice and flies, here we report that—against general belief—neurons contain a low but measurable amount of glycogen. Moreover, we also show that these cells express the brain isoform of glycogen phosphorylase, allowing glycogen to be fully metabolized. Most importantly, we show an active neuronal glycogen metabolism that protects cultured neurons from hypoxia-induced death and flies from hypoxia-induced stupor. Our findings change the current view of the role of glycogen in the brain and reveal that endogenous neuronal glycogen metabolism participates in the neuronal tolerance to hypoxic stress. PMID:24569689

  4. Neurons have an active glycogen metabolism that contributes to tolerance to hypoxia.

    Science.gov (United States)

    Saez, Isabel; Duran, Jordi; Sinadinos, Christopher; Beltran, Antoni; Yanes, Oscar; Tevy, María F; Martínez-Pons, Carlos; Milán, Marco; Guinovart, Joan J

    2014-06-01

    Glycogen is present in the brain, where it has been found mainly in glial cells but not in neurons. Therefore, all physiologic roles of brain glycogen have been attributed exclusively to astrocytic glycogen. Working with primary cultured neurons, as well as with genetically modified mice and flies, here we report that-against general belief-neurons contain a low but measurable amount of glycogen. Moreover, we also show that these cells express the brain isoform of glycogen phosphorylase, allowing glycogen to be fully metabolized. Most importantly, we show an active neuronal glycogen metabolism that protects cultured neurons from hypoxia-induced death and flies from hypoxia-induced stupor. Our findings change the current view of the role of glycogen in the brain and reveal that endogenous neuronal glycogen metabolism participates in the neuronal tolerance to hypoxic stress.

  5. Transcriptome analysis of severe hypoxic stress during development in zebrafish

    Directory of Open Access Journals (Sweden)

    I.G. Woods

    2015-12-01

    Full Text Available Hypoxia causes critical cellular injury both in early human development and in adulthood, leading to cerebral palsy, stroke, and myocardial infarction. Interestingly, a remarkable phenomenon known as hypoxic preconditioning arises when a brief hypoxia exposure protects target organs against subsequent, severe hypoxia. Although hypoxic preconditioning has been demonstrated in several model organisms and tissues including the heart and brain, its molecular mechanisms remain poorly understood. Accordingly, we used embryonic and larval zebrafish to develop a novel vertebrate model for hypoxic preconditioning, and used this model to identify conserved hypoxia-regulated transcripts for further functional study as published in Manchenkov et al. (2015 in G3: Genes|Genomes|Genetics. In this Brief article, we provide extensive annotation for the most strongly hypoxia-regulated genes in zebrafish, including their human orthologs, and describe in detail the methods used to identify, filter, and annotate hypoxia-regulated transcripts for downstream functional and bioinformatic assays using the source data provided in Gene Expression Omnibus Accession GSE68473.

  6. Early Life Exposure to Chronic Intermittent Hypoxia Primes Increased Susceptibility to Hypoxia-Induced Weakness in Rat Sternohyoid Muscle During Adulthood

    Directory of Open Access Journals (Sweden)

    Fiona B Mcdonald

    2016-03-01

    Full Text Available Intermittent hypoxia is a feature of apnea of prematurity, chronic lung disease and sleep apnea. Despite the clinical relevance, the long-term effects of hypoxic exposure in early life on respiratory control are not well defined. We recently reported that exposure to chronic intermittent hypoxia (CIH during postnatal development (pCIH causes upper airway muscle weakness in both sexes, which persists for several weeks. We sought to examine if there are persistent sex-dependent effects of pCIH on respiratory muscle function into adulthood and/or increased susceptibility to re-exposure to CIH in adulthood in animals previously exposed to CIH during postnatal development. We hypothesized that pCIH would cause long-lasting muscle impairment and increased susceptibility to subsequent hypoxia. Within 24 hours of delivery, pups and their respective dams were exposed to CIH: 90s of hypoxia reaching 5% O2 at nadir; once every 5 min, 8 hrs per day for 3 weeks. Sham groups were exposed to normoxia in parallel. Three groups were studied: sham; pCIH; and pCIH combined with adult CIH (p+aCIH, where a subset of the pCIH-exposed pups were re-exposed to the same CIH paradigm beginning at 13 weeks. Following gas exposures, sternohyoid and diaphragm muscle isometric contractile and endurance properties were examined ex vivo. There was no apparent lasting effect of pCIH on respiratory muscle function in adults. However, in both males and females, re-exposure to CIH in adulthood in pCIH-exposed animals caused sternohyoid (but not diaphragm weakness. Exposure to this paradigm of CIH in adulthood alone had no effect on muscle function. Persistent susceptibility in pCIH-exposed airway dilator muscle to subsequent hypoxic insult may have implications for the control of airway patency in adult humans exposed to intermittent hypoxic stress during early life.

  7. Early life exposure to chronic intermittent Hypoxia Primes Increased Susceptibility to Hypoxia-Induced Weakness in Rat Sternohyoid Muscle during adulthood.

    LENUS (Irish Health Repository)

    McDonald, Fiona B

    2016-03-01

    Intermittent hypoxia is a feature of apnea of prematurity (AOP), chronic lung disease, and sleep apnea. Despite the clinical relevance, the long-term effects of hypoxic exposure in early life on respiratory control are not well defined. We recently reported that exposure to chronic intermittent hypoxia (CIH) during postnatal development (pCIH) causes upper airway muscle weakness in both sexes, which persists for several weeks. We sought to examine if there are persistent sex-dependent effects of pCIH on respiratory muscle function into adulthood and\\/or increased susceptibility to re-exposure to CIH in adulthood in animals previously exposed to CIH during postnatal development. We hypothesized that pCIH would cause long-lasting muscle impairment and increased susceptibility to subsequent hypoxia. Within 24 h of delivery, pups and their respective dams were exposed to CIH: 90 s of hypoxia reaching 5% O2 at nadir; once every 5 min, 8 h per day for 3 weeks. Sham groups were exposed to normoxia in parallel. Three groups were studied: sham; pCIH; and pCIH combined with adult CIH (p+aCIH), where a subset of the pCIH-exposed pups were re-exposed to the same CIH paradigm beginning at 13 weeks. Following gas exposures, sternohyoid and diaphragm muscle isometric contractile and endurance properties were examined ex vivo. There was no apparent lasting effect of pCIH on respiratory muscle function in adults. However, in both males and females, re-exposure to CIH in adulthood in pCIH-exposed animals caused sternohyoid (but not diaphragm) weakness. Exposure to this paradigm of CIH in adulthood alone had no effect on muscle function. Persistent susceptibility in pCIH-exposed airway dilator muscle to subsequent hypoxic insult may have implications for the control of airway patency in adult humans exposed to intermittent hypoxic stress during early life.

  8. Hypoxia positron emission tomography imaging: combining information on perfusion and tracer retention to improve hypoxia specificity

    DEFF Research Database (Denmark)

    Busk, Morten; Munk, Ole L; Jakobsen, Steen S

    2017-01-01

    BACKGROUND: Static positron emission tomography (PET) allows mapping of tumor hypoxia, but low resolution and slow tracer retention/clearance results in poor image contrast and the risk of missing areas where hypoxic cells and necrosis are intermixed. Fully dynamic PET may improve accuracy but scan...

  9. Human erythropoietin response to hypocapnic hypoxia, normocapnic hypoxia, and hypocapnic normoxia

    DEFF Research Database (Denmark)

    Klausen, T; Christensen, H; Hansen, J M

    1996-01-01

    This study investigated the human erythropoietin (EPO) response to short-term hypocapnic hypoxia, its relationship to a normoxic or hypoxic increase of the haemoglobin oxygen affinity, and its suppression by the addition of CO2 to the hypoxic gas. On separate days, eight healthy male subjects were...

  10. Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function

    Science.gov (United States)

    McNamee, Eóin N.; Johnson, Darlynn Korns; Homann, Dirk

    2014-01-01

    Oxygen is a molecule that is central to cellular respiration and viability, yet there are multiple physiologic and pathological contexts in which cells experience conditions of insufficient oxygen availability, a state known as hypoxia. Given the metabolic challenges of a low oxygen environment, hypoxia elicits a range of adaptive responses at the cellular, tissue, and systemic level to promote continued survival and function. Within this context, T lymphocytes are a highly migratory cell type of the adaptive immune system that frequently encounters a wide range of oxygen tensions in both health and disease. It is now clear that oxygen availability regulates T cell differentiation and function, a response orchestrated in large part by the hypoxia-inducible factor transcription factors. Here, we discuss the physiologic scope of hypoxia and hypoxic signaling, the contribution of these pathways in regulating T cell biology, and current gaps in our understanding. Finally, we discuss how emerging therapies that modulate the hypoxic response may offer new modalities to alter T cell function and the outcome of acute and chronic pathologies. PMID:22961658

  11. Intermittent hypoxia training in prediabetes patients: Beneficial effects on glucose homeostasis, hypoxia tolerance and gene expression.

    Science.gov (United States)

    Serebrovska, Tetiana V; Portnychenko, Alla G; Drevytska, Tetiana I; Portnichenko, Vladimir I; Xi, Lei; Egorov, Egor; Gavalko, Anna V; Naskalova, Svitlana; Chizhova, Valentina; Shatylo, Valeriy B

    2017-09-01

    The present study aimed at examining beneficial effects of intermittent hypoxia training (IHT) under prediabetic conditions. We investigate the effects of three-week IHT on blood glucose level, tolerance to acute hypoxia, and leukocyte mRNA expression of hypoxia inducible factor 1α (HIF-1α) and its target genes, i.e. insulin receptor, facilitated glucose transporter-solute carrier family-2, and potassium voltage-gated channel subfamily J. Seven healthy and 11 prediabetic men and women (44-70 years of age) were examined before, next day and one month after three-week IHT (3 sessions per week, each session consisting 4 cycles of 5-min 12% O 2 and 5-min room air breathing). We found that IHT afforded beneficial effects on glucose homeostasis in patients with prediabetes reducing fasting glucose and during standard oral glucose tolerance test. The most pronounced positive effects were observed at one month after IHT termination. IHT also significantly increased the tolerance to acute hypoxia (i.e. SaO 2 level at 20th min of breathing with 12% O 2 ) and improved functional parameters of respiratory and cardiovascular systems. IHT stimulated HIF-1α mRNA expression in blood leukocytes in healthy and prediabetic subjects, but in prediabetes patients the maximum increase was lagged. The greatest changes in mRNA expression of HIF-1α target genes occurred a month after IHT and coincided with the largest decrease in blood glucose levels. The higher expression of HIF-1α was positively associated with higher tolerance to hypoxia and better glucose homeostasis. In conclusion, our results suggest that IHT may be useful for preventing the development of type 2 diabetes. Impact statement The present study investigated the beneficial effects of intermittent hypoxia training (IHT) in humans under prediabetic conditions. We found that three-week moderate IHT induced higher HIF-1α mRNA expressions as well as its target genes, which were positively correlated with higher tolerance

  12. Hepatocyte Hypoxia Inducible Factor-1 Mediates the Development of Liver Fibrosis in a Mouse Model of Nonalcoholic Fatty Liver Disease.

    Directory of Open Access Journals (Sweden)

    Omar A Mesarwi

    Full Text Available Obstructive sleep apnea (OSA is associated with the progression of non-alcoholic fatty liver disease (NAFLD to steatohepatitis and fibrosis. This progression correlates with the severity of OSA-associated hypoxia. In mice with diet induced obesity, hepatic steatosis leads to liver tissue hypoxia, which worsens with exposure to intermittent hypoxia. Emerging data has implicated hepatocyte cell signaling as an important factor in hepatic fibrogenesis. We hypothesized that hepatocyte specific knockout of the oxygen sensing α subunit of hypoxia inducible factor-1 (HIF-1, a master regulator of the global response to hypoxia, may be protective against the development of liver fibrosis.Wild-type mice and mice with hepatocyte-specific HIF-1α knockout (Hif1a-/-hep were fed a high trans-fat diet for six months, as a model of NAFLD. Hepatic fibrosis was evaluated by Sirius red stain and hydroxyproline assay. Liver enzymes, fasting insulin, and hepatic triglyceride content were also assessed. Hepatocytes were isolated from Hif1a-/-hep mice and wild-type controls and were exposed to sustained hypoxia (1% O2 or normoxia (16% O2 for 24 hours. The culture media was used to reconstitute type I collagen and the resulting matrices were examined for collagen cross-linking.Wild-type mice on a high trans-fat diet had 80% more hepatic collagen than Hif1a-/-hep mice (2.21 μg collagen/mg liver tissue, versus 1.23 μg collagen/mg liver tissue, p = 0.03, which was confirmed by Sirius red staining. Body weight, liver weight, mean hepatic triglyceride content, and fasting insulin were similar between groups. Culture media from wild-type mouse hepatocytes exposed to hypoxia allowed for avid collagen cross-linking, but very little cross-linking was seen when hepatocytes were exposed to normoxia, or when hepatocytes from Hif1a-/-hep mice were used in hypoxia or normoxia.Hepatocyte HIF-1 mediates an increase in liver fibrosis in a mouse model of NAFLD, perhaps due to liver

  13. Evaluation of Notch and Hypoxia Signaling Pathways in Chemically ...

    African Journals Online (AJOL)

    Hepatocellular carcinoma (HCC) is a common worldwide malignancy. Notch signaling pathway contributes to the genesis of diverse cancers, however, its role in HCC is unclear. Hypoxia is a common feature of HCC. Signal integration between Notch and hypoxia may be involved in HCC. The aim of this study was to ...

  14. Comparative aspects of hypoxia tolerance of the ectothermic vertebrate heart

    DEFF Research Database (Denmark)

    Gesser, Hans; Overgaard, Johannes

    2009-01-01

    This chapter reviews cardiac contractile performance and its regulation during hypoxia/anoxia with regard to cellular metabolism and energy state, in particular hypoxia-tolerant ectothermic vertebrates. Overall the contractile performance of the hypoxic isolated heart muscle varies in a way...

  15. Role of hypoxia-inducible factor in diabetic myocardial hypertrophy ...

    African Journals Online (AJOL)

    Purpose: This study was carried out to investigate the role of hypoxia-inducible factor (HIF) in diabetic cardiomyopathy in vitro. Methods: Hypoxia was induced chemically in H9C2 cells (cardiac hypertrophy model), and the cells were treated with phenylephrine (PE), deferoxamine (DFO), PE + DFO, and HIF-1α siRNA under ...

  16. Hypoxic hypoxia as a means of modifying radiosensibility

    International Nuclear Information System (INIS)

    Neumeister, K.; Niemiec, C.; Bolck, M.; Jahns, J.; Kamprad, F.; Arnold, P.; Johannsen, U.; Koch, F.; Mehlhorn, G.

    1977-01-01

    Following an overview of the various possibilities of creating hypoxia in mammals, the problem of reducing radioresistance of hypoxic tumor cells is treated. Furthermore, the results of irradiation experiments with mice, rats and pigs breathing hypoxic mixtures of O 2 and N 2 are given and discussed with a view to applying hypoxic hypoxia in the radiotherapy of human tumors. (author)

  17. Hypoxia-induced dysfunction of rat diaphragm: role of peroxynitrite.

    NARCIS (Netherlands)

    Zhu, X.; Heunks, L.M.A.; Versteeg, E.M.M.; Heijden, E. van der; Ennen, L.; Kuppevelt, A.H.M.S.M. van; Vina, J.; Dekhuijzen, P.N.R.

    2005-01-01

    Oxidants may play a role in hypoxia-induced respiratory muscle dysfunction. In the present study we hypothesized that hypoxia-induced impairment in diaphragm contractility is associated with elevated peroxynitrite generation. In addition, we hypothesized that strenuous contractility of the diaphragm

  18. Brain adaptation to hypoxia and hyperoxia in mice

    Directory of Open Access Journals (Sweden)

    Laura Terraneo

    2017-04-01

    Conclusion: Prolonged mild hyperoxia leads to persistent cerebral damage, comparable to that inferred by prolonged mild hypoxia. The underlying mechanism appears related to a model whereby the imbalance between ROS generation and anti-ROS defense is similar, but occurs at higher levels in hypoxia than in hyperoxia.

  19. The infectious hypoxia: occurrence and causes during Shigella infection.

    Science.gov (United States)

    Arena, Ellen T; Tinevez, Jean-Yves; Nigro, Giulia; Sansonetti, Philippe J; Marteyn, Benoit S

    2017-03-01

    Hypoxia is defined as a tissue oxygenation status below physiological needs. During Shigella infection, an infectious hypoxia is induced within foci of infection. In this review, we discuss how Shigella physiology and virulence are modulated and how the main recruited immune cells, the neutrophils, adapt to this environment. Copyright © 2016 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

  20. Mitochondrial Reactive Oxygen Species Trigger Hypoxia-Induced Transcription

    Science.gov (United States)

    Chandel, N. S.; Maltepe, E.; Goldwasser, E.; Mathieu, C. E.; Simon, M. C.; Schumacker, P. T.

    1998-09-01

    Transcriptional activation of erythropoietin, glycolytic enzymes, and vascular endothelial growth factor occurs during hypoxia or in response to cobalt chloride (CoCl2) in Hep3B cells. However, neither the mechanism of cellular O2 sensing nor that of cobalt is fully understood. We tested whether mitochondria act as O2 sensors during hypoxia and whether hypoxia and cobalt activate transcription by increasing generation of reactive oxygen species (ROS). Results show (i) wild-type Hep3B cells increase ROS generation during hypoxia (1.5% O2) or CoCl2 incubation, (ii) Hep3B cells depleted of mitochondrial DNA (ρ 0 cells) fail to respire, fail to activate mRNA for erythropoietin, glycolytic enzymes, or vascular endothelial growth factor during hypoxia, and fail to increase ROS generation during hypoxia; (iii) ρ 0 cells increase ROS generation in response to CoCl2 and retain the ability to induce expression of these genes; and (iv) the antioxidants pyrrolidine dithiocarbamate and ebselen abolish transcriptional activation of these genes during hypoxia or CoCl2 in wild-type cells, and abolish the response to CoCl2 in ρ 0 cells. Thus, hypoxia activates transcription via a mitochondria-dependent signaling process involving increased ROS, whereas CoCl2 activates transcription by stimulating ROS generation via a mitochondria-independent mechanism.

  1. Effect of hypoxia on the activity and binding of glycolytic and associated enzymes in sea scorpion tissues

    Directory of Open Access Journals (Sweden)

    Lushchak V.I.

    1998-01-01

    Full Text Available The effect of hypoxia on the levels of glycogen, glucose and lactate as well as the activities and binding of glycolytic and associated enzymes to subcellular structures was studied in brain, liver and white muscle of the teleost fish, Scorpaena porcus. Hypoxia exposure decreased glucose levels in liver from 2.53 to 1.70 µmol/g wet weight and in muscle led to its increase from 3.64 to 25.1 µmol/g wet weight. Maximal activities of several enzymes in brain were increased by hypoxia: hexokinase by 23%, phosphoglucoisomerase by 47% and phosphofructokinase (PFK by 56%. However, activities of other enzymes in brain as well as enzymes in liver and white muscle were largely unchanged or decreased during experimental hypoxia. Glycolytic enzymes in all three tissues were partitioned between soluble and particulate-bound forms. In several cases, the percentage of bound enzymes was reduced during hypoxia; bound aldolase in brain was reduced from 36.4 to 30.3% whereas glucose-6-phosphate dehydrogenase fell from 55.7 to 28.7% bound. In muscle PFK was reduced from 57.4 to 41.7% bound. Oppositely, the proportion of bound aldolase and triosephosphate isomerase increased in hypoxic muscle. Phosphoglucomutase did not appear to occur in a bound form in liver and bound phosphoglucomutase disappeared in muscle during hypoxia exposure. Anoxia exposure also led to the disappearance of bound fructose-1,6-bisphosphatase in liver, whereas a bound fraction of this enzyme appeared in white muscle of anoxic animals. The possible function of reversible binding of glycolytic enzymes to subcellular structures as a regulatory mechanism of carbohydrate metabolism is discussed.

  2. Effect of acute exposure to moderate altitude on muscle power: hypobaric hypoxia vs. normobaric hypoxia.

    Directory of Open Access Journals (Sweden)

    Belén Feriche

    Full Text Available When ascending to a higher altitude, changes in air density and oxygen levels affect the way in which explosive actions are executed. This study was designed to compare the effects of acute exposure to real or simulated moderate hypoxia on the dynamics of the force-velocity relationship observed in bench press exercise. Twenty-eight combat sports athletes were assigned to two groups and assessed on two separate occasions: G1 (n = 17 in conditions of normoxia (N1 and hypobaric hypoxia (HH and G2 (n = 11 in conditions of normoxia (N2 and normobaric hypoxia (NH. Individual and complete force-velocity relationships in bench press were determined on each assessment day. For each exercise repetition, we obtained the mean and peak velocity and power shown by the athletes. Maximum power (Pmax was recorded as the highest P(mean obtained across the complete force-velocity curve. Our findings indicate a significantly higher absolute load linked to P(max (∼ 3% and maximal strength (1 RM (∼ 6% in G1 attributable to the climb to altitude (P<0.05. We also observed a stimulating effect of natural hypoxia on P(mean and P(peak in the middle-high part of the curve (≥ 60 kg; P<0.01 and a 7.8% mean increase in barbell displacement velocity (P<0.001. No changes in any of the variables examined were observed in G2. According to these data, we can state that acute exposure to natural moderate altitude as opposed to simulated normobaric hypoxia leads to gains in 1 RM, movement velocity and power during the execution of a force-velocity curve in bench press.

  3. Hypoxia Aggravates Inactivity-Related Muscle Wasting

    Directory of Open Access Journals (Sweden)

    Tadej Debevec

    2018-05-01

    Full Text Available Poor musculoskeletal state is commonly observed in numerous clinical populations such as chronic obstructive pulmonary disease (COPD and heart failure patients. It, however, remains unresolved whether systemic hypoxemia, typically associated with such clinical conditions, directly contributes to muscle deterioration. We aimed to experimentally elucidate the effects of systemic environmental hypoxia upon inactivity-related muscle wasting. For this purpose, fourteen healthy, male participants underwent three 21-day long interventions in a randomized, cross-over designed manner: (i bed rest in normoxia (NBR; PiO2 = 133.1 ± 0.3 mmHg, (ii bed rest in normobaric hypoxia (HBR; PiO2 = 90.0 ± 0.4 mmHg and ambulatory confinement in normobaric hypoxia (HAmb; PiO2 = 90.0 ± 0.4 mmHg. Peripheral quantitative computed tomography and vastus lateralis muscle biopsies were performed before and after the interventions to obtain thigh and calf muscle cross-sectional areas and muscle fiber phenotype changes, respectively. A significant reduction of thigh muscle size following NBR (-6.9%, SE 0.8%; P < 0.001 was further aggravated following HBR (-9.7%, SE 1.2%; P = 0.027. Bed rest-induced muscle wasting in the calf was, by contrast, not exacerbated by hypoxic conditions (P = 0.47. Reductions in both thigh (-2.7%, SE 1.1%, P = 0.017 and calf (-3.3%, SE 0.7%, P < 0.001 muscle size were noted following HAmb. A significant and comparable increase in type 2× fiber percentage of the vastus lateralis muscle was noted following both bed rest interventions (NBR = +3.1%, SE 2.6%, HBR = +3.9%, SE 2.7%, P < 0.05. Collectively, these data indicate that hypoxia can exacerbate inactivity-related muscle wasting in healthy active participants and moreover suggest that the combination of both, hypoxemia and lack of activity, as seen in COPD patients, might be particularly harmful for muscle tissue.

  4. 2013 Gulf of Mexico Hypoxia Forecast

    Science.gov (United States)

    Scavia, Donald; Evans, Mary Anne; Obenour, Dan

    2013-01-01

    The Gulf of Mexico annual summer hypoxia forecasts are based on average May total nitrogen loads from the Mississippi River basin for that year. The load estimate, recently released by USGS, is 7,316 metric tons per day. Based on that estimate, we predict the area of this summer’s hypoxic zone to be 18,900 square kilometers (95% credible interval, 13,400 to 24,200), the 7th largest reported and about the size of New Jersey. Our forecast hypoxic volume is 74.5 km3 (95% credible interval, 51.5 to 97.0), also the 7th largest on record.

  5. 2014 Gulf of Mexico Hypoxia Forecast

    Science.gov (United States)

    Scavia, Donald; Evans, Mary Anne; Obenour, Dan

    2014-01-01

    The Gulf of Mexico annual summer hypoxia forecasts are based on average May total nitrogen loads from the Mississippi River basin for that year. The load estimate, recently released by USGS, is 4,761 metric tons per day. Based on that estimate, we predict the area of this summer’s hypoxic zone to be 14,000 square kilometers (95% credible interval, 8,000 to 20,000) – an “average year”. Our forecast hypoxic volume is 50 km3 (95% credible interval, 20 to 77).

  6. Plasma metabolite score correlates with Hypoxia time in a newly born piglet model for asphyxia

    Directory of Open Access Journals (Sweden)

    Julia Kuligowski

    2017-08-01

    Full Text Available Hypoxic-ischemic encephalopathy (HIE secondary to perinatal asphyxia is a leading cause of mortality and acquired long-term neurologic co-morbidities in the neonate. The most successful intervention for the treatment of moderate to severe HIE is moderate whole body hypothermia initiated within 6 h from birth. The objective and prompt identification of infants who are at risk of developing moderate to severe HIE in the critical first hours still remains a challenge. This work proposes a metabolite score calculated based on the relative intensities of three metabolites (choline, 6,8-dihydroxypurine and hypoxanthine that showed maximum correlation with hypoxia time in a consolidated piglet model for neonatal hypoxia-ischemia. The metabolite score's performance as a biomarker for perinatal hypoxia and its usefulness for clinical grading and decision making have been assessed and compared to the performance of lactate which is currently considered the gold standard. For plasma samples withdrawn before and directly after a hypoxic insult, the metabolite score performed similar to lactate. However, it provided an enhanced predictive capacity at 2 h after resuscitation. The present study evidences the usefulness of the metabolite score for improving the early assessment of the severity of the hypoxic insult based on serial determinations in a minimally invasive biofluid. The applicability of the metabolite score for clinical diagnosis and patient stratification for hypothermia treatment has to be confirmed in multicenter trials involving newborns suffering from HIE. Keywords: Hypoxia, Perinatal asphyxia, Newborn, Metabolic biomarker, Neonatal piglet model, Liquid Chromatography – Time-of-Flight Mass Spectrometry (LC-TOF-MS

  7. Acclimatory responses of the Daphnia pulex proteome to environmental changes. I. Chronic exposure to hypoxia affects the oxygen transport system and carbohydrate metabolism

    Directory of Open Access Journals (Sweden)

    Madlung Johannes

    2009-04-01

    Full Text Available Abstract Background Freshwater planktonic crustaceans of the genus Daphnia show a remarkable plasticity to cope with environmental changes in oxygen concentration and temperature. One of the key proteins of adaptive gene control in Daphnia pulex under hypoxia is hemoglobin (Hb, which increases in hemolymph concentration by an order of magnitude and shows an enhanced oxygen affinity due to changes in subunit composition. To explore the full spectrum of adaptive protein expression in response to low-oxygen conditions, two-dimensional gel electrophoresis and mass spectrometry were used to analyze the proteome composition of animals acclimated to normoxia (oxygen partial pressure [Po2]: 20 kPa and hypoxia (Po2: 3 kPa, respectively. Results The comparative proteome analysis showed an up-regulation of more than 50 protein spots under hypoxia. Identification of a major share of these spots revealed acclimatory changes for Hb, glycolytic enzymes (enolase, and enzymes involved in the degradation of storage and structural carbohydrates (e.g. cellubiohydrolase. Proteolytic enzymes remained constitutively expressed on a high level. Conclusion Acclimatory adjustments of the D. pulex proteome to hypoxia included a strong induction of Hb and carbohydrate-degrading enzymes. The scenario of adaptive protein expression under environmental hypoxia can be interpreted as a process to improve oxygen transport and carbohydrate provision for the maintenance of ATP production, even during short episodes of tissue hypoxia requiring support from anaerobic metabolism.

  8. Expression of angiopoietin-1 in hypoxic pericytes: Regulation by hypoxia-inducible factor-2α and participation in endothelial cell migration and tube formation.

    Science.gov (United States)

    Park, Yoon Shin; Kim, Gyungah; Jin, Yoon Mi; Lee, Jee Young; Shin, Jong Wook; Jo, Inho

    2016-01-08

    We previously reported that hypoxia increases angiopoietin-1 (Ang1), but not Ang2, mRNA expression in bovine retinal pericytes (BRP). However, the mechanism underlying Ang1 expression is unknown. Here, we report that Ang1 protein expression increased in hypoxic BRP in a dose- and time-dependent manner. This increase was accompanied by an increase in hypoxia-inducible factor-2α (HIF2α) expression. Transfection with an antisense oligonucleotide for HIF2α partially inhibited the hypoxia-induced increase in Ang1 expression. HIF2α overexpression further potentiated hypoxia-stimulated Ang1 expression, suggesting that HIF2α plays an important role in Ang1 regulation in BRP. When fused the Ang1 promoter (-3040 to +199) with the luciferase reporter gene, we found that hypoxia significantly increased promoter activity by 4.02 ± 1.68 fold. However, progressive 5'-deletions from -3040 to -1799, which deleted two putative hypoxia response elements (HRE), abolished the hypoxia-induced increase in promoter activity. An electrophoretic mobility shift assay revealed that HIF2α was predominantly bound to a HRE site, located specifically at nucleotides -2715 to -2712. Finally, treatment with conditioned medium obtained from hypoxic pericytes stimulated endothelial cell migration and tube formation, which was completely blocked by co-treatment with anti-Ang1 antibody. This study is the first to demonstrate that hypoxia upregulates Ang1 expression via HIF2α-mediated transcriptional activation in pericytes, which plays a key role in angiogenesis. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. Hypoxia preconditioning of mesenchymal stromal cells enhances PC3 cell lymphatic metastasis accompanied by VEGFR-3/CCR7 activation.

    Science.gov (United States)

    Huang, Xin; Su, Kunkai; Zhou, Limin; Shen, Guofang; Dong, Qi; Lou, Yijia; Zheng, Shu

    2013-12-01

    Mesenchymal stromal cells (MSCs) in bone marrow may enhance tumor metastases through the secretion of chemokines. MSCs have been reported to home toward the hypoxic tumor microenvironment in vivo. In this study, we investigated prostate cancer PC3 cell behavior under the influence of hypoxia preconditioned MSCs and explored the related mechanism of prostate cancer lymphatic metastases in mice. Transwell assays revealed that VEGF-C receptor, VEGFR-3, as well as chemokine CCL21 receptor, CC chemokine receptor 7 (CCR7), were responsible for the migration of PC3 cells toward hypoxia preconditioned MSCs. Knock-in Ccr7 in PC3 cells also improved cell migration in vitro. Furthermore, when PC3 cells were labeled using the hrGfp-lentiviral vector, and were combined with hypoxia preconditioned MSCs for xenografting, it resulted in an enhancement of lymph node metastases accompanied by up-regulation of VEGFR-3 and CCR7 in primary tumors. Both PI3K/Akt/IκBα and JAK2/STAT3 signaling pathways were activated in xenografts in the presence of hypoxia-preconditioned MSCs. Unexpectedly, the p-VEGFR-2/VEGFR-2 ratio was attenuated accompanied by decreased JAK1 expression, indicating a switching-off of potential vascular signal within xenografts in the presence of hypoxia-preconditioned MSCs. Unlike results from other studies, VEGF-C maintained a stable expression in both conditions, which indicated that hypoxia preconditioning of MSCs did not influence VEGF-C secretion. Our results provide the new insights into the functional molecular events and signalings influencing prostate tumor metastases, suggesting a hopeful diagnosis and treatment in new approaches. © 2013 Wiley Periodicals, Inc.

  10. A biology-driven approach identifies the hypoxia gene signature as a predictor of the outcome of neuroblastoma patients

    Directory of Open Access Journals (Sweden)

    Fardin Paolo

    2010-07-01

    Full Text Available Abstract Background Hypoxia is a condition of low oxygen tension occurring in the tumor microenvironment and it is related to poor prognosis in human cancer. To examine the relationship between hypoxia and neuroblastoma, we generated and tested an in vitro derived hypoxia gene signature for its ability to predict patients' outcome. Results We obtained the gene expression profile of 11 hypoxic neuroblastoma cell lines and we derived a robust 62 probesets signature (NB-hypo taking advantage of the strong discriminating power of the l1-l2 feature selection technique combined with the analysis of differential gene expression. We profiled gene expression of the tumors of 88 neuroblastoma patients and divided them according to the NB-hypo expression values by K-means clustering. The NB-hypo successfully stratifies the neuroblastoma patients into good and poor prognosis groups. Multivariate Cox analysis revealed that the NB-hypo is a significant independent predictor after controlling for commonly used risk factors including the amplification of MYCN oncogene. NB-hypo increases the resolution of the MYCN stratification by dividing patients with MYCN not amplified tumors in good and poor outcome suggesting that hypoxia is associated with the aggressiveness of neuroblastoma tumor independently from MYCN amplification. Conclusions Our results demonstrate that the NB-hypo is a novel and independent prognostic factor for neuroblastoma and support the view that hypoxia is negatively correlated with tumors' outcome. We show the power of the biology-driven approach in defining hypoxia as a critical molecular program in neuroblastoma and the potential for improvement in the current criteria for risk stratification.

  11. Inhibition of the H3K9 methyltransferase G9A attenuates oncogenicity and activates the hypoxia signaling pathway.

    Directory of Open Access Journals (Sweden)

    Jolene Caifeng Ho

    Full Text Available Epigenetic mechanisms play important roles in the regulation of tumorigenesis, and hypoxia-induced epigenetic changes may be critical for the adaptation of cancer cells to the hypoxic microenvironment of solid tumors. Previously, we showed that loss-of-function of the hypoxia-regulated H3K9 methyltransferase G9A attenuates tumor growth. However, the mechanisms by which blockade of G9A leads to a tumor suppressive effect remain poorly understood. We show that G9A is highly expressed in breast cancer and is associated with poor patient prognosis, where it may function as a potent oncogenic driver. In agreement with this, G9A inhibition by the small molecule inhibitor, BIX-01294, leads to increased cell death and impaired cell migration, cell cycle and anchorage-independent growth. Interestingly, whole transcriptome analysis revealed that genes involved in diverse cancer cell functions become hypoxia-responsive upon G9A inhibition. This was accompanied by the upregulation of the hypoxia inducible factors HIF1α and HIF2α during BIX-01294 treatment even in normoxia that may facilitate the tumor suppressive effects of BIX-01294. HIF inhibition was able to reverse some of the transcriptional changes induced by BIX-01294 in hypoxia, indicating that the HIFs may be important drivers of these derepressed target genes. Therefore, we show that G9A is a key mediator of oncogenic processes in breast cancer cells and G9A inhibition by BIX-01294 can successfully attenuate oncogenicity even in hypoxia.

  12. Hypoxia-response plasmid vector producing bcl-2 shRNA enhances the apoptotic cell death of mouse rectum carcinoma.

    Science.gov (United States)

    Fujioka, Takashi; Matsunaga, Naoya; Okazaki, Hiroyuki; Koyanagi, Satoru; Ohdo, Shigehiro

    2010-01-01

    Hypoxia-induced gene expression frequently occurs in malignant solid tumors because they often have hypoxic areas in which circulation is compromised due to structurally disorganized blood vessels. Hypoxia-response elements (HREs) are responsible for activating gene transcription in response to hypoxia. In this study, we constructed a hypoxia-response plasmid vector producing short hairpin RNA (shRNA) against B-cell leukemia/lymphoma-2 (bcl-2), an anti-apoptotic factor. The hypoxia-response promoter was made by inserting tandem repeats of HREs upstream of cytomegalovirus (CMV) promoter (HRE-CMV). HRE-CMV shbcl-2 vector consisted of bcl-2 shRNA under the control of HRE-CMV promoter. In hypoxic mouse rectum carcinoma cells (colon-26), the production of bcl-2 shRNA driven by HRE-CMV promoter was approximately 2-fold greater than that driven by CMV promoter. A single intratumoral (i.t.) injection of 40 microg HRE-CMV shbcl-2 to colon-26 tumor-bearing mice caused apoptotic cell death, and repetitive treatment with HRE-CMV shbcl-2 (40 microg/mouse, i.t.) also significantly suppressed the growth of colon-26 tumor cells implanted in mice. Apoptotic and anti-tumor effects were not observed in tumor-bearing mice treated with CMV shbcl-2. These results reveal the ability of HRE-CMV shbcl-2 vector to suppress the expression of bcl-2 in hypoxic tumor cells and suggest the usefulness of our constructed hypoxia-response plasmid vector to treat malignant tumors. [Supplementary Figures: available only at http://dx.doi.org/10.1254/jphs.10054FP].

  13. Ontogenetic Responses of Calanus chilensis to Hypoxia from Northern Chile (23ºS), Humboldt Current Ecosystem

    Science.gov (United States)

    Ruz, P. M.; Hidalgo, P.; Escribano, R.; Franco-Cisterna, B.; Yebra, L.; Keister, J. E.

    2016-02-01

    Eastern Boundary Upwelling Systems are being subjected to expansion, intensification and shoaling of Oxygen Minimum Zones (OMZ's), as a result of ongoing climate change. To understand how dominant epipelagic copepods may respond to stressful conditions induced by low oxygen, we experimentally studied the effect of hypoxia over the stage-specific physiology of Calanus chilensis from the Mejillones Bay (23°S — 70°W), northern Chile, during the winters of 2013 and 2014. Females, eggs and nauplii (NI to NIV) of C. chilensis were incubated under hypoxia ( 0.7 mg O2 L-1) and normoxia ( 8.3 mg O2 L-1) conditions at a constant temperature of 14ºC as to estimate egg production rate (EPR), hatching success (HS) and naupliar growth and development time. Additionally, we estimated survivorship by using Neutral Red technique, and also examined female metabolism by measuring specific activity of the enzymes Aminoacyl-tRNA synthetases (spAARS) (growth index) and the electron transport system (spETS) (potential respiration). Survival of females and EPR were not significantly affected by dissolved oxygen (DO) conditions, coinciding with no significant changes in their metabolism. By contrast, HS was reduced from normoxia (70%) to hypoxia (30%), whereas naupliar growth (NI to NIII) was lower under hypoxia (0.155 ± 0.007 d-1) than normoxia (0.237 ± 0.006 d-1), resulting also in a longer development time, 6.490 ± 0.353 d and 4.238 ± 0.149 d, respectively. Most eggs and nauplii collected at the end of the experiments were alive, although a higher proportion of organisms were recovered in normoxia than hypoxia. Our results revealed stage-specific responses to hypoxia in C. chilensis and the importance of ontogenetic responses to variable levels of oxygenation in the upwelling zone.

  14. Influence of obstructive sleep apnea on fatty liver disease: role of chronic intermittent hypoxia.

    Science.gov (United States)

    Türkay, Cansel; Ozol, Duygu; Kasapoğlu, Benan; Kirbas, Ismail; Yıldırım, Zeki; Yiğitoğlu, Ramazan

    2012-02-01

    Currently the common pathogenetic mechanisms in nonalcoholic fatty liver disease (NAFLD) and obstructive sleep apnea (OSA) are gaining increased attention. The aim of this study is to find out the influence of chronic intermittent hypoxemia and OSA related parameters to the severity of NAFLD. We examined the liver functions tests and ultrasonographic data of liver as well as markers of OSA severity (apnea-hypopnea index [AHI], oxygen desaturation index, minimum oxygen saturation, percentage of time spent with S(pO(2)) hypoxia during sleep. The prevalence of NAFLD was higher in patients with severe OSA, suggesting a role for nocturnal hypoxemia in the pathogenesis of fatty liver disease.

  15. Hypoxia, hypoxia-inducible transcription factor, and macrophages in human atherosclerotic plaques are correlated with intraplaque angiogenesis

    NARCIS (Netherlands)

    Sluimer, Judith C.; Gasc, Jean-Marie; van Wanroij, Job L.; Kisters, Natasja; Groeneweg, Mathijs; Sollewijn Gelpke, Maarten D.; Cleutjens, Jack P.; van den Akker, Luc H.; Corvol, Pierre; Wouters, Bradly G.; Daemen, Mat J.; Bijnens, Ann-Pascale J.

    2008-01-01

    We sought to examine the presence of hypoxia in human carotid atherosclerosis and its association with hypoxia-inducible transcription factor (HIF) and intraplaque angiogenesis. Atherosclerotic plaques develop intraplaque angiogenesis, which is a typical feature of hypoxic tissue and expression of

  16. Modulation of Radioprotective Effects of Respiratory Hypoxia by Changing the Duration of Hypoxia before Irradiation and by Combining Hypoxia and Administration of Hemopoiesis-Stimulating Agents

    Czech Academy of Sciences Publication Activity Database

    Vacek, Antonín; Tačev, T.; Hofer, Michal

    2001-01-01

    Roč. 177, č. 9 (2001), s. 474-481 ISSN 0179-7158 Institutional research plan: CEZ:AV0Z5004920 Keywords : radioprotection * mice * hypoxia Subject RIV: BO - Biophysics Impact factor: 3.005, year: 2001

  17. Efficacy and biological effects of techniques used to induce hypoxia in tumors

    International Nuclear Information System (INIS)

    Rockwell, S.; Moulder, J.E.; Martin, D.F.

    1985-01-01

    The authors tested several aspects of the assumptions using BA1112 rat rhabdomyosacromas and EMT6 mouse mammary tumors. Both techniques were effective in producing hypoxia: survival curves for tumors made hypoxic by the 2 techniques were the same, and were indistinguishable from survival curves for hypoxic tumor cells in vitro. Induction of hypoxia for the 30-60 min necessary for irradiation did not alter the yield or clonogenicity of cells suspended from the tumors. Longer clamping was cytotoxic. Clamping did not alter tumor growth unless a major blood vessel was injured. However, clamping BA1112 tumors for 30 min and removing the clamp just before irradiation altered the tumor cell survival curve and TCD/sub 50/. Anesthesia or restrain, often used during clamping, can have major effects

  18. NMR study of damage on isolated perfused rat heart exposed to ischemia and hypoxia

    International Nuclear Information System (INIS)

    Luo Xuechun; Yan Yongbin; Zhang Riqing; Fan Lili

    2001-01-01

    Myocardial ischemia is the most common and primary cause of myocardium damage. Numerous conventional techniques and methods have been developed for ischemia and reperfusion studies. However, because of damage to the heart sample, most of these techniques can not be used to continuously monitor the full dynamic course of the myocardial metabolic pathway. The nuclear magnetic resonance (NMR) surface coil technique, which overcomes the limitations of conventional instrumentation, can be used to quantitatively study every stage of the perfused heart (especially after perfusion stoppage) continuously, dynamically, and without damage under normal or designed physiological conditions at the molecular level. In this paper, 31 P-NMR was used to study the effects of ischemia and hypoxia on isolated perfused hearts. The results show that complete hypoxia caused more severe functional damage to the myocardial cells than complete ischemia

  19. A neonatal mouse model of intermittent hypoxia associated with features of apnea in premature infants.

    Science.gov (United States)

    Cai, Jun; Tuong, Chi Minh; Gozal, David

    2011-09-15

    A neonatal mouse model of intermittent hypoxia (IH) simulating the recurring hypoxia/reoxygenation episodes of apnea of prematurity (AOP) was developed. C57BL/6 P2 pups were culled for exposure to either intermittent hypoxia or intermittent air as control. The IH paradigms consisted of alternation cycles of 20.9% O2 and either 8.0% or 5.7% O2 every 120 or 140s for 6h a day during daylight hours from day 2 to day 10 postnatally, i.e., roughly equivalent to human brain development in the perinatal period. IH exposures elicited modest to severe decrease in oxygen saturation along with bradycardia in neonatal mice, which were severity-dependent. Hypomyelination in both central and peripheral nervous systems was observed despite the absence of visible growth retardation. The neonatal mouse model of IH in this study partially fulfills the current diagnostic criteria with features of AOP, and provides opportunities to reproduce in rodents some of the pathophysiological changes associated with this disorder, such as alterations in myelination. Copyright © 2011 Elsevier B.V. All rights reserved.

  20. The usability of a 15-gene hypoxia classifier as a universal hypoxia profile in various cancer cell types

    DEFF Research Database (Denmark)

    Sørensen, Brita Singers; Knudsen, Anders Bisgård; Wittrup, Catja Foged

    2015-01-01

    genes, with BNIP3 not being upregulated at hypoxic conditions in 3 out of 6 colon cancer cell lines, and ALDOA in OE21 and FAM162A and SLC2A1 in SW116 only showing limited hypoxia induction. Furthermore, in the esophagus cell lines, the normoxic and hypoxic expression levels of LOX and BNIP3 were below...... the tissue type dependency of hypoxia induced genes included in a 15-gene hypoxic profile in carcinoma cell lines from prostate, colon, and esophagus cancer, and demonstrated that in vitro, with minor fluctuations, the genes in the hypoxic profile are hypoxia inducible, and the hypoxia profile may......BACKGROUND AND PURPOSE: A 15-gene hypoxia profile has previously demonstrated to have both prognostic and predictive impact for hypoxic modification in squamous cell carcinoma of the head and neck. This gene expression profile may also have a prognostic value in other histological cancer types...

  1. Hypoxia-induced autophagy is inhibited by PADI4 knockdown, which promotes apoptosis of fibroblast-like synoviocytes in rheumatoid arthritis

    Science.gov (United States)

    Fan, Tingting; Zhang, Changsong; Zong, Ming; Fan, Lieying

    2018-01-01

    Impaired apoptosis of rheumatoid arthritis (RA)-fibroblast-like synoviocytes (FLS) is pivotal in the process of RA. Peptidyl arginine deiminase type IV (PADI4) is associated with autoantibody regulation via histone citrullination in RA. The present study aimed to investigate the role of PADI4 in the apoptosis of RA-FLS. FLS were isolated from patients with RA and a rat model. The effects of PADI4 on RA-FLS were investigated in vitro and in vivo. Hypoxia-induced autophagy was induced by 1% O2 and was detected by immunohistochemical and immunofluorescence analysis; in addition, apoptosis was detected by flow cytometry. RA-FLS obtained from RA rat model exhibited significant proliferation under severe hypoxia conditions. Hypoxia also significantly induced autophagy and elevated the expression of PADI4. Subsequently, short hairpin RNA-mediated PADI4 knockdown was demonstrated to significantly inhibit hypoxia-induced autophagy and promote apoptosis in RA-FLS. The results of these in vitro and in vivo studies suggested that PADI4 may be closely associated with hypoxia-induced autophagy, and the inhibition of hypoxia-induced autophagy by PADI4 knockdown may contribute to an increase in the apoptosis of RA-FLS. PMID:29393388

  2. Identification of Hypoxia-Regulated Proteins Using MALDI-Mass Spectrometry Imaging Combined with Quantitative Proteomics

    DEFF Research Database (Denmark)

    Djidja, Marie-Claude; Chang, Joan; Hadjiprocopis, Andreas

    2014-01-01

    Hypoxia is present in most solid tumors and is clinically correlated with increased metastasis and poor patient survival. While studies have demonstrated the role of hypoxia and hypoxia-regulated proteins in cancer progression, no attempts have been made to identify hypoxia-regulated proteins using...

  3. New small molecule inhibitors of UPR activation demonstrate that PERK, but not IRE1α signaling is essential for promoting adaptation and survival to hypoxia

    International Nuclear Information System (INIS)

    Cojocari, Dan; Vellanki, Ravi N.; Sit, Brandon; Uehling, David; Koritzinsky, Marianne; Wouters, Bradly G.

    2013-01-01

    Background and purpose: The unfolded protein response (UPR) is activated in response to hypoxia-induced stress in the endoplasmic reticulum (ER) and consists of three distinct signaling arms. Here we explore the potential of targeting two of these arms with new potent small-molecule inhibitors designed against IRE1α and PERK. Methods: We utilized shRNAs and small-molecule inhibitors of IRE1α (4μ8c) and PERK (GSK-compound 39). XBP1 splicing and DNAJB9 mRNA was measured by qPCR and was used to monitor IRE1α activity. PERK activity was monitored by immunoblotting eIF2α phosphorylation and qPCR of DDIT3 mRNA. Hypoxia tolerance was measured using proliferation and clonogenic cell survival assays of cells exposed to mild or severe hypoxia in the presence of the inhibitors. Results: Using knockdown experiments we show that PERK is essential for survival of KP4 cells while knockdown of IRE1α dramatically decreases the proliferation and survival of HCT116 during hypoxia. Further, we show that in response to both hypoxia and other ER stress-inducing agents both 4μ8c and the PERK inhibitor are selective and potent inhibitors of IRE1α and PERK activation, respectively. However, despite potent inhibition of IRE1α activation, 4μ8c had no effect on cell proliferation or clonogenic survival of cells exposed to hypoxia. This was in contrast to the inactivation of PERK signaling with the PERK inhibitor, which reduced tolerance to hypoxia and other ER stress inducing agents. Conclusions: Our results demonstrate that IRE1α but not its splicing activity is important for hypoxic cell survival. The PERK signaling arm is uniquely important for promoting adaptation and survival during hypoxia-induced ER stress and should be the focus of future therapeutic efforts

  4. Hypoxia-inducible factor 1–mediated characteristic features of cancer cells for tumor radioresistance

    International Nuclear Information System (INIS)

    Harada, Hiroshi

    2016-01-01

    Tumor hypoxia has been attracting increasing attention in the fields of radiation biology and oncology since Thomlinson and Gray detected hypoxic cells in malignant solid tumors and showed that they exert a negative impact on the outcome of radiation therapy. This unfavorable influence has, at least partly, been attributed to cancer cells acquiring a radioresistant phenotype through the activation of the transcription factor, hypoxia-inducible factor 1 (HIF-1). On the other hand, accumulating evidence has recently revealed that, even though HIF-1 is recognized as an important regulator of cellular adaptive responses to hypoxia, it may not become active and induce tumor radioresistance under hypoxic conditions only. The mechanisms by which HIF-1 is activated in cancer cells not only under hypoxic conditions, but also under normoxic conditions, through cancer-specific genetic alterations and the resultant imbalance in intermediate metabolites have been summarized herein. The relevance of the HIF-1–mediated characteristic features of cancer cells, such as the production of antioxidants through reprogramming of the glucose metabolic pathway and cell cycle regulation, for tumor radioresistance has also been reviewed

  5. ANTAGONISM OF PROGESTERONE RECEPTOR SUPPRESSES CAROTID BODY RESPONSES TO HYPOXIA AND NICOTINE IN RAT PUPS

    Science.gov (United States)

    JOSEPH, V.; NIANE, L. M.; BAIRAM, A.

    2013-01-01

    We tested the hypothesis that antagonism of progesterone receptor (PR) in newborn rats alters carotid body and respiratory responses to hypoxia and nicotinic receptor agonists. Rats were treated with the PR antagonist mifepristone (daily oral gavage 40 μg/g/d) or vehicle between post-natal days 3 and 15. In 11–14-day-old rats, we used in vitro carotid body/carotid sinus nerve preparation and whole body plethysmography to assess the carotid body and ventilatory responses to hypoxia (65 mmHg in vitro, 10% O2 in vivo) and to nicotinic receptor agonists (as an excitatory modulator of carotid body activity—nicotine 100 μM for in vitro studies, and epibatidine 5 μg/kg, i.p., which mainly acts on peripheral nicotinic receptors, for in vivo studies). The carotid body responses to hypoxia and nicotine were drastically reduced by mifepristone. Compared with vehicle, mifepristone-treated rats had a reduced body weight. The ventilatory response to epibatidine was attenuated; however, the hypoxic ventilatory response was similar between vehicle and mifepristone-treated pups. Immunohistochemical staining revealed that mifepristone treatment did not change carotid body morphology. We conclude that PR activity is a critical factor ensuring proper carotid body function in newborn rats. PMID:22326965

  6. A Novel Chip for Cyclic Stretch and Intermittent Hypoxia Cell Exposures Mimicking Obstructive Sleep Apnea

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    Noelia Campillo

    2016-07-01

    Full Text Available Intermittent hypoxia (IH, a hallmark of obstructive sleep apnea (OSA, plays a critical role in the pathogenesis of OSA-associated morbidities, especially in the cardiovascular and respiratory systems. Oxidative stress and inflammation induced by IH are suggested as main contributors of end-organ dysfunction in OSA patients and animal models. Since the molecular mechanisms underlying these in vivo pathological responses remain poorly understood, implementation of experimental in vitro cell-based systems capable of inducing high-frequency IH would be highly desirable. Here, we describe the design, fabrication and validation of a versatile chip for subjecting cultured cells to fast changes in gas partial pressure and to cyclic stretch. The chip is fabricated with polydimethylsiloxane (PDMS and consists of a cylindrical well covered by a thin membrane. Cells cultured on top of the membrane can be subjected to fast changes in oxygen concentration (equilibrium time 6 s. Moreover, cells can be subjected to cyclic stretch at cardiac or respiratory frequencies independently or simultaneously. Rat bone marrow-derived mesenchymal stem cells (MSCs exposed to IH mimicking OSA and cyclic stretch at cardiac frequencies revealed that hypoxia-inducible factor 1α (HIF-1α expression was increased in response to both stimuli. Thus, the chip provides a versatile tool for the study of cellular responses to cyclical hypoxia and stretch.

  7. Effects of hypoxia on 13NH4+ fluxes in rice roots: kinetics and compartmental analysis

    International Nuclear Information System (INIS)

    Kronzucker, H.J.; Kirk, G.J.D.; Siddiqi, M.Y.; Glass, A.D.M.

    1998-01-01

    Techniques of compartmental (efflux) and kinetic influx analyses with the radiotracer 13NH4+ were used to examine the adaptation to hypoxia (15, 35, and 50% O2 saturation) of root N uptake and metabolism in 3-week-old hydroponically grown rice (Oryza sativa L., cv IR72) seedlings. A time-dependence study of NH4+ influx into rice roots after onset of hypoxia (15% O2) revealed an initial increase in the first 1 to 2.5 h after treatment imposition, followed by a decline to less than 50% of influx in control plants by 4 d. Efflux analyses conducted 0, 1, 3, and 5 d after the treatment confirmed this adaptation pattern of NH4+ uptake. Half-lives for NH4+ exchange with subcellular compartments, cytoplasmic NH4+ concentrations, and efflux (as percentage of influx) were unaffected by hypoxia. However, significant differences were observed in the relative amounts of N allocated to NH4+ assimilation and the vacuole versus translocation to the shoot. Kinetic experiments conducted at 100, 50, 35, and 15% O2 saturation showed no significant change in the K(m) value for NH4+ uptake with varying O2 supply. However, V(max) was 42% higher than controls at 50% O2 saturation, unchanged at 35%, and 10% lower than controls at 15% O2. The significance of these flux adaptations is discussed

  8. An innovative intermittent hypoxia model for cell cultures allowing fast Po2 oscillations with minimal gas consumption.

    Science.gov (United States)

    Minoves, Mélanie; Morand, Jessica; Perriot, Frédéric; Chatard, Morgane; Gonthier, Brigitte; Lemarié, Emeline; Menut, Jean-Baptiste; Polak, Jan; Pépin, Jean-Louis; Godin-Ribuot, Diane; Briançon-Marjollet, Anne

    2017-10-01

    Performing hypoxia-reoxygenation cycles in cell culture with a cycle duration accurately reflecting what occurs in obstructive sleep apnea (OSA) patients is a difficult but crucial technical challenge. Our goal was to develop a novel device to expose multiple cell culture dishes to intermittent hypoxia (IH) cycles relevant to OSA with limited gas consumption. With gas flows as low as 200 ml/min, our combination of plate holders with gas-permeable cultureware generates rapid normoxia-hypoxia cycles. Cycles alternating 1 min at 20% O 2 followed by 1 min at 2% O 2 resulted in Po 2 values ranging from 124 to 44 mmHg. Extending hypoxic and normoxic phases to 10 min allowed Po 2 variations from 120 to 25 mmHg. The volume of culture medium or the presence of cells only modestly affected the Po 2 variations. In contrast, the nadir of the hypoxia phase increased when measured at different heights above the membrane. We validated the physiological relevance of this model by showing that hypoxia inducible factor-1α expression was significantly increased by IH exposure in human aortic endothelial cells, murine breast carcinoma (4T1) cells as well as in a blood-brain barrier model (2.5-, 1.5-, and 6-fold increases, respectively). In conclusion, we have established a new device to perform rapid intermittent hypoxia cycles in cell cultures, with minimal gas consumption and the possibility to expose several culture dishes simultaneously. This device will allow functional studies of the consequences of IH and deciphering of the molecular biology of IH at the cellular level using oxygen cycles that are clinically relevant to OSA. Copyright © 2017 the American Physiological Society.

  9. Inflammatory cytokine tumor necrosis factor α suppresses neuroprotective endogenous erythropoietin from astrocytes mediated by hypoxia-inducible factor-2α.

    Science.gov (United States)

    Nagaya, Yoshiaki; Aoyama, Mineyoshi; Tamura, Tetsuya; Kakita, Hiroki; Kato, Shin; Hida, Hideki; Saitoh, Shinji; Asai, Kiyofumi

    2014-12-01

    Interest in erythropoietin (EPO) as a neuroprotective mediator has grown since it was found that systemically administered EPO is protective in several animal models of disease. However, given that the blood-brain barrier limits EPO entry into the brain, alternative approaches that induce endogenous EPO production in the brain may be more effective clinically and associated with fewer untoward side-effects. Astrocytes are the main source of EPO in the central nervous system. In the present study we investigated the effect of the inflammatory cytokine tumor necrosis factor α (TNFα) on hypoxia-induced upregulation of EPO in rat brain. Hypoxia significantly increased EPO mRNA expression in the brain and kidney, and this increase was suppressed by TNFα in vivo. In cultured astrocytes exposed to hypoxic conditions for 6 and 12 h, TNFα suppressed the hypoxia-induced increase in EPO mRNA expression in a concentration-dependent manner. TNFα inhibition of hypoxia-induced EPO expression was mediated primarily by hypoxia-inducible factor (HIF)-2α rather than HIF-1α. The effects of TNFα in reducing hypoxia-induced upregulation of EPO mRNA expression probably involve destabilization of HIF-2α, which is regulated by the nuclear factor (NF)-κB signaling pathway. TNFα treatment attenuated the protective effects of astrocytes on neurons under hypoxic conditions via EPO signaling. The effective blockade of TNFα signaling may contribute to the maintenance of the neuroprotective effects of EPO even under hypoxic conditions with an inflammatory response. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  10. Hypoxia causes IL-8 secretion, Charcot Leyden crystal formation, and suppression of corticosteroid-induced apoptosis in human eosinophils.

    Science.gov (United States)

    Porter, L M; Cowburn, A S; Farahi, N; Deighton, J; Farrow, S N; Fiddler, C A; Juss, J K; Condliffe, A M; Chilvers, E R

    2017-06-01

    Inflamed environments are typically hypercellular, rich in pro-inflammatory cytokines, and profoundly hypoxic. While the effects of hypoxia on neutrophil longevity and function have been widely studied, little is known about the consequences of this stimulus on eosinophils. We sought to investigate the effects of hypoxia on several key aspects of eosinophil biology, namely secretion, survival, and their sensitivity to glucocorticosteroids (GCS), agents that normally induce eosinophil apoptosis. Eosinophils derived from patients with asthma/atopy or healthy controls were incubated under normoxia and hypoxia, with or without glucocorticoids. Activation was measured by flow cytometry, ELISA of cultured supernatants, and F-actin staining; apoptosis and efferocytosis by morphology and flow cytometry; and GCS efficacy by apoptosis assays and qPCR. Hypoxic incubation (3 kPa) caused (i) stabilization of HIF-2α and up-regulation of hypoxia-regulated genes including BNIP3 (BCL2/adenovirus E1B 19-kDa protein-interacting protein 3) and GLUT1 (glucose transporter 1); (ii) secretion of pre-formed IL-8, and Charcot Leyden crystal (CLC) formation, which was most evident in eosinophils derived from atopic and asthmatic donors; (iii) enhanced F-actin formation; (iv) marked prolongation of eosinophil lifespan (via a NF-κB and Class I PI3-kinase-dependent mechanism); and (v) complete abrogation of the normal pro-apoptotic effect of dexamethasone and fluticasone furoate. This latter effect was evident despite preservation of GCS-mediated gene transactivation under hypoxia. These data indicate that hypoxia promotes an eosinophil pro-inflammatory phenotype by enhancing eosinophil secretory function, delaying constitutive apoptosis, and importantly, antagonizing the normal pro-apoptotic effect of GCS. As eosinophils typically accumulate at sites that are relatively hypoxic, particularly during periods of inflammation, these findings may have important implications to understanding the

  11. Heterogeneous role of the glutathione antioxidant system in modulating the response of ESFT to fenretinide in normoxia and hypoxia.

    Directory of Open Access Journals (Sweden)

    Tapiwanashe Magwere

    Full Text Available Glutathione (GSH is implicated in drug resistance mechanisms of several cancers and is a key regulator of cell death pathways within cells. We studied Ewing's sarcoma family of tumours (ESFT cell lines and three mechanistically distinct anticancer agents (fenretinide, doxorubicin, and vincristine to investigate whether the GSH antioxidant system is involved in the reduced sensitivity to these chemotherapeutic agents in hypoxia. Cell viability and death were assessed by the trypan blue exclusion assay and annexin V-PI staining, respectively. Hypoxia significantly decreased the sensitivity of all ESFT cell lines to fenretinide-induced death, whereas the effect of doxorubicin or vincristine was marginal and cell-line-specific. The response of the GSH antioxidant system in ESFT cell lines to hypoxia was variable and also cell-line-specific, although the level of GSH appeared to be most dependent on de novo biosynthesis rather than recycling. RNAi-mediated knockdown of key GSH regulatory enzymes γ-glutamylcysteine synthetase or glutathione disulfide reductase partially reversed the hypoxia-induced resistance to fenretinide, and increasing GSH levels using N-acetylcysteine augmented the hypoxia-induced resistance in a cell line-specific manner. These observations are consistent with the conclusion that the role of the GSH antioxidant system in modulating the sensitivity of ESFT cells to fenretinide is heterogeneous depending on environment and cell type. This is likely to limit the value of targeting GSH as a therapeutic strategy to overcome hypoxia-induced drug resistance in ESFT. Whether targeting the GSH antioxidant system in conjunction with other therapeutics may benefit some patients with ESFT remains to be seen.

  12. The relationship between temporal variation of hypoxia, polarographic measurements and predictions of tumour response to radiation

    Science.gov (United States)

    Toma-Dasu, Iuliana; Dasu, Alexandru; Karlsson, Mikael

    2004-10-01

    The polarographic oxygen sensor is one of the most used devices for in vivo measurements of oxygen and many other measurement techniques for measuring tumour hypoxia are correlated with electrode measurements. Little is known however about the relationship between electrode measurements and the real tissue oxygenation. This paper investigates the influence of the temporal change of the hypoxic pattern on the electrode measurements and the tumour response. Electrode measurements and tumour response were simulated using a computer program that allows both the calculation of the tissue oxygenation with respect to the two types of hypoxia that might arise in tumours and the virtual insertion of the electrode into the tissue. It was therefore possible to control the amount of each type of hypoxia in order to investigate their influence on the measurement results. Tissues with several vascular architectures ranging from well oxygenated to poorly oxygenated were taken into consideration as might be seen in practice. The influence of the electrode measurements on the treatment outcome was estimated by calculating the tumour control probability for the tumours characterized either by the real or by the measured tumour oxygenation. We have simulated electrode oxygen measurements in different types of tissues, covering a wide range of tumour oxygenations. The results of the simulations showed that the measured distribution depends on the details of the vascular network and not on the type of hypoxia. We have also simulated the effects of the temporal change of the acute hypoxic pattern due to the opening and the closure of different blood vessels during a full fractionated treatment. The results of this simulation suggested that the temporal variation of the hypoxic pattern does not lead to significantly different results for the electrode measurements or the predicted tumour control probabilities. In conclusion, it was found that the averaging effect of the electrode leads

  13. 2-Iminobiotin Superimposed on Hypothermia Protects Human Neuronal Cells from Hypoxia-Induced Cell Damage: An in Vitro Study

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    Karina Zitta

    2018-01-01

    Full Text Available Perinatal asphyxia represents one of the major causes of neonatal morbidity and mortality. Hypothermia is currently the only established treatment for hypoxic-ischemic encephalopathy (HIE, but additional pharmacological strategies are being explored to further reduce the damage after perinatal asphyxia. The aim of this study was to evaluate whether 2-iminobiotin (2-IB superimposed on hypothermia has the potential to attenuate hypoxia-induced injury of neuronal cells. In vitro hypoxia was induced for 7 h in neuronal IMR-32 cell cultures. Afterwards, all cultures were subjected to 25 h of hypothermia (33.5°C, and incubated with vehicle or 2-IB (10, 30, 50, 100, and 300 ng/ml. Cell morphology was evaluated by brightfield microscopy. Cell damage was analyzed by LDH assays. Production of reactive oxygen species (ROS was measured using fluorometric assays. Western blotting for PARP, Caspase-3, and the phosphorylated forms of akt and erk1/2 was conducted. To evaluate early apoptotic events and signaling, cell protein was isolated 4 h post-hypoxia and human apoptosis proteome profiler arrays were performed. Twenty-five hour after the hypoxic insult, clear morphological signs of cell damage were visible and significant LDH release as well as ROS production were observed even under hypothermic conditions. Post-hypoxic application of 2-IB (10 and 30 ng/ml reduced the hypoxia-induced LDH release but not ROS production. Phosphorylation of erk1/2 was significantly increased after hypoxia, while phosphorylation of akt, protein expression of Caspase-3 and cleavage of PARP were only slightly increased. Addition of 2-IB did not affect any of the investigated proteins. Apoptosis proteome profiler arrays performed with cellular protein obtained 4 h after hypoxia revealed that post-hypoxic application of 2-IB resulted in a ≥ 25% down regulation of 10/35 apoptosis-related proteins: Bad, Bax, Bcl-2, cleaved Caspase-3, TRAILR1, TRAILR2, PON2, p21, p27, and phospho

  14. Aromatic Hydrocarbon Receptor Suppresses Prostate Cancer Bone Metastasis Cells-Induced Vasculogenesis of Endothelial Progenitor Cells under Hypoxia

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    Shuai Huang

    2016-07-01

    Full Text Available Background/Aims: Hypoxia leads to the development of neovascularization in solid tumor by regulating VEGF expression. Aromatic hydrocarbon receptor (AHR, a receptor for dioxin-like compounds, functions as a transcription factor through dimerization with hypoxia-inducible factors 1β (HIF-1β and inhibits the secretion of vascular endothelial growth factor (VEGF. The purpose of this study was to explore whether AHR can suppress hypoxia-induced VEGF production in prostate bone metastasis cells and repress neovascularization in endothelial progenitor cells (EPCs, and, if so, through what mechanisms. Methods: PC-3 or LNCaP cells induced angiogenesis was detected by Matrigel-based tube formation assay, mRNA expression levels was measured by qRT-PCR, VEGF secretion level was determined by ELISA assay, respectively. Results: AHR activation inhibits hypoxia-induced adhesiveness and vasculogenesis of EPCs induced by PC-3 or LNCaP cells under hypoxia. Moreover, AHR activation suppressed hypoxia-induced VEGF production in PC-3 and LNCaP cells (48 ± 14% in PC-3, p = 0.000; 41 ± 14% in LNCaP, p = 0.000 by attenuating HIF-1α and HIF-1β level that in turn diminished the angiogenic ability of EPCs in vitro. Furthermore, we found the mRNA level of hypoxia-inducible factors 1α (HIF-1α (1.54 ± 0.13 fold in PC-3, p = 0.002, 1.62 ± 0.12 fold in LNCaP, p = 0.001 and HIF-1β (1.67 ± 0.23 fold in PC-3, p = 0.007; 1.75 ± 0.26 fold in LNCaP, p=0.008 were upregulated in prostate cancer bone metastasis PC-3 and LNCaP cell lines in response to hypoxia, and revealed that the regulation of VEGF by HIF-1α and HIF-1β was possibly mediated by the activation of phosphatidylinositol 3-kinase pathway. Conclusion: By providing a mechanistic insight into the modulation of neovascularization by AHR ligand, we suggest that AHR ligand has a strong potential of being a new therapeutic agent with applications in the field of bone metastatic prostate cancer.

  15. PPARδ deficiency disrupts hypoxia-mediated tumorigenic potential of colon cancer cells.

    Science.gov (United States)

    Jeong, Eunshil; Koo, Jung Eun; Yeon, Sang Hyeon; Kwak, Mi-Kyoung; Hwang, Daniel H; Lee, Joo Young

    2014-11-01

    Peroxisome proliferator-activated receptor (PPAR) δ is highly expressed in colon epithelial cells and closely linked to colon carcinogenesis. However, the role of PPARδ in colon cancer cells in a hypoxic tumor microenvironment is not fully understood. We found that expression of the tumor-promoting cytokines, IL-8 and VEGF, induced by hypoxia (colon cancer cells. Consequently, PPARδ-knockout colon cancer cells exposed to hypoxia and deferoxamine failed to stimulate endothelial cell vascularization and macrophage migration/proliferation, whereas wild-type cells were able to induce angiogenesis and macrophage activation in response to hypoxic stress. Hypoxic stress induced transcriptional activation of PPARδ, but not its protein expression, in HCT116 cells. Exogenous expression of p300 potentiated deferoxamine-induced PPARδ transactivation, while siRNA knockdown of p300 abolished hypoxia- and deferoxamine-induced PPARδ transactivation. PPARδ associated with p300 upon hypoxic stress as demonstrated by coimmunoprecipitation studies. PI3K inhibitors or siRNA knockdown of Akt suppressed the PPARδ transactivation induced by hypoxia and deferoxamine in HCT116 cells, leading to decreased expression of IL-8 and VEGF. Collectively, these results reveal that PPARδ is required for hypoxic stress-mediated cytokine expression in colon cancer cells, resulting in promotion of angiogenesis, macrophage recruitment, and macrophage proliferation in the tumor microenvironment. p300 and the PI3K/Akt pathway play a role in the regulation of PPARδ transactivation induced by hypoxic stress. Our results demonstrate the positive crosstalk between PPARδ in tumor cells and the hypoxic tumor microenvironment and provide potential therapeutic targets for colon cancer. © 2014 Wiley Periodicals, Inc.

  16. Construction and Development of a Cardiac Tissue-Specific and Hypoxia-Inducible Expression Vector

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    Shahrooz Ghaderi

    2018-03-01

    Full Text Available Purpose: Cardiovascular gene therapy is a sophisticated approach, thanks to the safety of vectors, stable transgene expression, delivery method, and different layers of the heart. To date, numerous expression vectors have been introduced in biotechnology and biopharmacy industries in relation to genetic manipulation. Despite the rapid growth of these modalities, they must be intelligently designed, addressing the cardiac-specific transgene expression and less side effects. Herein, we conducted a pilot project aiming to design a cardiac-specific hypoxia-inducible expression cassette. Methods: We explored a new approach to design an expression cassette containing cardiac specific enhancer, hypoxia response elements (HRE, cardiac specific promoter, internal ribosome entry site (IRES, and beta globin poly A sequence to elicit specific and inducible expression of the gene of interest. Enhanced green fluorescent protein (eGFP was sub-cloned by BglII and NotI into the cassette. The specificity and inducible expression of the cassette was determined in both mouse myoblast C2C12 and mammary glandular tumor 4T1 as ‘twin’ cells. eGFP expression was evaluated by immunofluorescence microscope and flow cytometry at 520 nm emission peak. Results: Our data revealed that the designed expression cassette provided tissue specific and hypoxia inducible (O2<1% transgene expression. Conclusion: It is suggested that cardiac-specific enhancer combined with cardiac-specific promoter are efficient for myoblast specific gene expression. As well, this is for the first time that HRE are derived from three well known hypoxia-regulated promoters. Therefore, there is no longer need to overlap PCR process for one repeated sequence just in one promoter.

  17. Hypoxia-Mediated Epigenetic Regulation of Stemness in Brain Tumor Cells.

    Science.gov (United States)

    Prasad, Pankaj; Mittal, Shivani Arora; Chongtham, Jonita; Mohanty, Sujata; Srivastava, Tapasya

    2017-06-01

    Activation of pluripotency regulatory circuit is an important event in solid tumor progression and the hypoxic microenvironment is known to enhance the stemness feature of some cells. The distinct population of cancer stem cells (CSCs)/tumor initiating cells exist in a niche and augment invasion, metastasis, and drug resistance. Previously, studies have reported global hypomethylation and site-specific aberrant methylation in gliomas along with other epigenetic modifications as important contributors to genomic instability during glioma progression. Here, we have demonstrated the role of hypoxia-mediated epigenetic modifications in regulating expression of core pluripotency factors, OCT4 and NANOG, in glioma cells. We observe hypoxia-mediated induction of demethylases, ten-eleven-translocation (TET) 1 and 3, but not TET2 in our cell-line model. Immunoprecipitation studies reveal active demethylation and direct binding of TET1 and 3 at the Oct4 and Nanog regulatory regions. Tet1 and 3 silencing assays further confirmed induction of the pluripotency pathway involving Oct4, Nanog, and Stat3, by these paralogues, although with varying degrees. Knockdown of Tet1 and Tet3 inhibited the formation of neurospheres in hypoxic conditions. We observed independent roles of TET1 and TET3 in differentially regulating pluripotency and differentiation associated genes in hypoxia. Overall, this study demonstrates an active demethylation in hypoxia by TET1 and 3 as a mechanism of Oct4 and Nanog overexpression thus contributing to the formation of CSCs in gliomas. Stem Cells 2017;35:1468-1478. © 2017 AlphaMed Press.

  18. Cytoprotective effects of fisetin against hypoxia-induced cell death in PC12 cells.

    Science.gov (United States)

    Chen, Pei-Yi; Ho, Yi-Ru; Wu, Ming-Jiuan; Huang, Shun-Ping; Chen, Po-Kong; Tai, Mi-Hsueh; Ho, Chi-Tang; Yen, Jui-Hung

    2015-01-01

    Fisetin (3,7,3',4'-tetrahydroxyflavone), a flavonol compound of flavonoids, exhibits a broad spectrum of biological activities including anti-oxidant, anti-inflammatory, anti-cancer and neuroprotective effects. The aim of this study is to investigate the cytoprotective effect of fisetin and the underlying molecular mechanism against hypoxia-induced cell death in PC12 cells. The results of this study showed that fisetin significantly restored the cell viability of PC12 cells under both cobalt chloride (CoCl₂)- and low oxygen-induced hypoxic conditions. Treatment with fisetin successfully reduced the CoCl₂-mediated reactive oxygen species (ROS) production, which was accompanied by an increase in the cell viability of PC12 cells. Furthermore, we found that treatment of PC12 cells with fisetin markedly upregulated hypoxia-inducible factor 1α (HIF-1α), its nuclear accumulation and the hypoxia-response element (HRE)-driven transcriptional activation. The fisetin-mediated cytoprotection during CoCl₂ exposure was significantly attenuated through the administration of HIF-1α siRNA. Moreover, we demonstrated that MAPK/ERK kinase 1/2 (MEK1/2), p38 MAPK and phosphatidylinositol 3-kinase (PI3 K) inhibitors significantly blocked the increase in cell survival that was induced by fisetin treatment under hypoxic conditions. Consistently, increased phosphorylation of ERK, p38 and Akt proteins was observed in PC12 cells treated with fisetin. However, the fisetin-induced HRE-driven transcription was not affected by inhibition of these kinase signaling pathways. Current results reveal for the first time that fisetin promotes cell survival and protects against hypoxia-induced cell death through ROS scavenging and the activation of HIF1α-, MAPK/ERK-, p38 MAPK- and PI3 K/Akt-dependent signaling pathways in PC12 cells.

  19. The roles of autophagy and hypoxia in human inflammatory periapical lesions.

    Science.gov (United States)

    Huang, H Y; Wang, W C; Lin, P Y; Huang, C P; Chen, C Y; Chen, Y K

    2018-02-01

    To determine the expressions of hypoxia-related [hypoxia-inducible transcription factors (HIF)-1α, BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) and phospho-adenosine monophosphate activated protein kinase (pAMPK)] and autophagy-related [microtubule-associated protein 1 light chain 3 (LC3), beclin-1 (BECN-1), autophagy-related gene (Atg)5-12, and p62] proteins in human inflammatory periapical lesions. Fifteen samples of radicular cysts (RCs) and 21 periapical granulomas (PGs), combined with 17 healthy dental pulp tissues, were examined. Enzyme-linked immunosorbent assay (ELISA) was used to detect interleukin (IL)-1β cytokine; immunohistochemical (IHC) and Western blot (WB) analyses were employed to examine autophagy-related and hypoxia-related proteins. Transmission electron microscopy (TEM) was used to explore the ultrastructural morphology of autophagy in periapical lesions. Nonparametric Kruskal-Wallis tests and Mann-Whitney U-tests were used for statistical analyses. ELISA revealed a significantly higher (P periapical lesions than in normal pulp tissue. Immunoscores of IHC expressions of pAMPK, HIF-1α, BNIP3, BECN-1 and Atg5-12 proteins in periapical lesions were significantly higher (P periapical lesions were noted as compared to normal pulp tissue. Upon TEM, ultrastructural double-membrane autophagosomes and autolysosomes were observed in PGs and RCs. Autophagy associated with hypoxia may play a potential causative role in the development and maintenance of inflamed periapical lesions. © 2017 International Endodontic Journal. Published by John Wiley & Sons Ltd.

  20. Tumor hypoxia and reoxygenation: the yin and yang for radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Hong, Beom Ju; Kim, Jong Woo; Jeong, Hoi Bin; Bok, Seo Yeon; Kim, Young Eun; Ahn, G One [Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang (Korea, Republic of)

    2016-12-15

    Tumor hypoxia, a common feature occurring in nearly all human solid tumors is a major contributing factor for failures of anticancer therapies. Because ionizing radiation depends heavily on the presence of molecular oxygen to produce cytotoxic effect, the negative impact of tumor hypoxia had long been recognized. In this review, we will highlight some of the past attempts to overcome tumor hypoxia including hypoxic radiosensitizers and hypoxia-selective cytotoxin. Although they were (still are) a very clever idea, they lacked clinical efficacy largely because of ‘reoxygenation’ phenomenon occurring in the conventional low dose hyperfractionation radiotherapy prevented proper activation of these compounds. Recent meta-analysis and imaging studies do however indicate that there may be a significant clinical benefit in lowering the locoregional failures by using these compounds. Latest technological advancement in radiotherapy has allowed to deliver high doses of radiation conformally to the tumor volume. Although this technology has brought superb clinical responses for many types of cancer, recent modeling studies have predicted that tumor hypoxia is even more serious because ‘reoxygenation’ is low thereby leaving a large portion of hypoxic tumor cells behind. Wouldn’t it be then reasonable to combine hypoxic radiosensitizers and/or hypoxia-selective cytotoxin with the latest radiotherapy? We will provide some preclinical and clinical evidence to support this idea hoping to revamp an enthusiasm for hypoxic radiosensitizers or hypoxia-selective cytotoxins as an adjunct therapy for radiotherapy.

  1. Radiation, hypoxia and genetic stimulation: implications for future therapies

    International Nuclear Information System (INIS)

    Adams, Gerald E.; Hasan, Na'il M.; Joiner, Michael C.

    1997-01-01

    The cellular stress response, whereby very low doses of cytotoxic agents induce resistance to much higher doses, is an evolutionary defence mechanism and is stimulated following challenges by numerous chemical, biological and physical agents including particularly radiation, drugs, heat and hypoxia. There is much homology in the effects of these agents which are manifest through the up-regulation of various genetic pathways. Low-dose radiation stress influences processes involved in cell-cycle control, signal transduction pathways, radiation sensitivity, changes in cell adhesion and cell growth. There is also homology between radiation and other cellular stress agents, particularly hypoxia. Whereas traditionally, hypoxia was regarded mainly as an agent conferring resistance to radiation, there is now much evidence illustrating the cytokine-like properties of hypoxia as well as radiation. Stress phenomena are likely to be important in risks arising from low doses of radiation. Conversely, exploitation of the stress response in settings appropriate to therapy can be particularly beneficial not only in regard to radiation alone but in combinations of radiation and drugs. Similarly, tissue hypoxia can be exploited in novel ways of enhancing therapeutic efficacy. Bioreductive drugs, which are cytotoxically activated in hypoxic regions of tissue, can be rendered even more effective by hypoxia-induced increased expression of enzyme reductases. Nitric oxide pathways are influenced by hypoxia thereby offering possibilities for novel vascular based therapies. Other approaches are discussed

  2. Intermittent hypoxia increases insulin resistance in genetically obese mice.

    Science.gov (United States)

    Polotsky, Vsevolod Y; Li, Jianguo; Punjabi, Naresh M; Rubin, Arnon E; Smith, Philip L; Schwartz, Alan R; O'Donnell, Christopher P

    2003-10-01

    Obstructive sleep apnoea, a syndrome that leads to recurrent intermittent hypoxia, is associated with insulin resistance in obese individuals, but the mechanisms underlying this association remain unknown. We utilized a mouse model to examine the effects of intermittent hypoxia on insulin resistance in lean C57BL/6J mice and leptin-deficient obese (C57BL/6J-Lepob) mice. In lean mice, exposure to intermittent hypoxia for 5 days (short term) resulted in a decrease in fasting blood glucose levels (from 173 +/- 11 mg dl-1 on day 0 to 138 +/- 10 mg dl-1 on day 5, P obese mice, short-term intermittent hypoxia led to a decrease in blood glucose levels accompanied by a 607 +/- 136 % (P intermittent hypoxia was completely abolished by prior leptin infusion. Obese mice exposed to intermittent hypoxia for 12 weeks (long term) developed a time-dependent increase in fasting serum insulin levels (from 3.6 +/- 1.1 ng ml-1 at baseline to 9.8 +/- 1.8 ng ml-1 at week 12, P intermittent hypoxia is dependent on the disruption of leptin pathways.

  3. The radiation response of cells recovering after chronic hypoxia

    International Nuclear Information System (INIS)

    Kwok, T.T.; Sutherland, R.M.

    1989-01-01

    Experiments were performed to study the influence of hypoxic pretreatment on the radiation response of A431 human squamous carcinoma cells. Reaeration for 10 min after chronic hypoxia (greater than 2 h) was found to enhance the radiosensitivity of A431 cells, and the maximal effect was seen for those cells reaerated after 12 h of hypoxia. The radiosensitivity enhancement for reaerated cells after 12 h of hypoxia was maximized by 5 min after the return to aerobic conditions and reached the control level by 12 h of reaeration. This enhanced radiosensitive state was characterized by a reduced shoulder region and increased slope of the radiation dose-response curve for cells in both the exponential and plateau phases of growth. There was a slight increase in the number of G1 and decrease in the number of S and G2 + M cells for both exponential- and plateau-phase cultures following 12 h hypoxic treatment. Although growth inhibition induced by 12 h of hypoxia was seen for cells in the exponential phase, there was no cell number change in the plateau-phase culture after hypoxia. Plating efficiency (PE) of cells in both growth phases was reduced by 30% after hypoxia. Furthermore, in the exponential-phase culture, the extent of reduction in PE after hypoxia was similar among cells in different phases of the cell cycle. Although S-phase cells in exponentially growing cultures were relatively more resistant to radiation than G1 and G2 + M cells, the cell age-response pattern was the same whether the cells had been aerobic or hypoxic before reaeration and irradiation. Furthermore, the enhancement ratio associated with reaeration after 12 h of hypoxia for these three subpopulations of cells was 1.3. Our results indicate that the increase in radiosensitivity due to reaeration after chronic hypoxia is unlikely to be related to the changes of cell cycle stage and growth phase during hypoxic treatment

  4. The effect of altitude hypoxia on glucose homeostasis in men

    DEFF Research Database (Denmark)

    Larsen, J J; Hansen, J M; Olsen, Niels Vidiendal

    1997-01-01

    1. Exposure to altitude hypoxia elicits changes in glucose homeostasis with increases in glucose and insulin concentrations within the first few days at altitude. Both increased and unchanged hepatic glucose production (HGP) have previously been reported in response to acute altitude hypoxia...... (noradrenaline and adrenaline) and day 7 (adrenaline), but not at sea level. 4. In conclusion, insulin action decreases markedly in response to two days of altitude hypoxia, but improves with more prolonged exposure. HGP is always unchanged. The changes in insulin action may in part be explained by the changes...

  5. Endogenous markers of tumor hypoxia. Predictors of clinical radiation resistance?

    Energy Technology Data Exchange (ETDEWEB)

    Vordermark, D. [Dept. of Radiation Oncology, Univ. of Wuerzburg (Germany); Dept. of Radiation Oncology, Stanford Univ. School of Medicine, Stanford, CA (United States); Brown, J.M. [Dept. of Radiation Oncology, Stanford Univ. School of Medicine, Stanford, CA (United States)

    2003-12-01

    Background: Eppendorf electrode measurements of tumor oxygenation have defined an adverse effect of tumor hypoxia on prognosis after radiotherapy and other treatment modalities, in particular in head and neck and cervix carcinomas as well as soft tissue sarcomas. Recently, the immunohistochemical detection of proteins involved in the ''hypoxic response'' of tumor cells has been discussed as a method to estimate hypoxia in clinical tumor specimens. Material and Methods: This review focuses on clinical and experimental data, regarding prognostic impact and comparability with other methods of hypoxia detection, for three proteins suggested as endogenous markers of tumor hypoxia: hypoxia-inducible factor-1{alpha} (HIF-1{alpha}), carbonic anhydrase 9 (CA 9), and glucose transporter 1 (GLUT1). Results: None of the three potential hypoxia markers is exclusively hypoxia-specific, and in each case protein can be detected under normoxic conditions in vitro. HIF-1{alpha} responds rapidly to hypoxia but also to reoxygenation, making this marker quite unstable in the context of clinical sample collection. The perinecrotic labeling pattern typical of chronic hypoxia and a reasonable agreement with injectable hypoxia markers such as pimonidazole have most consistently been described for CA 9. All three markers showed correlation with Eppendorf electrode measurements of tumor oxygenation in carcinoma of the cervix. In nine of 13 reports, among them all three that refer to curative radiotherapy for head and neck cancer, HIF-1{alpha} overexpression was associated with poor outcome. CA 9 was an adverse prognostic factor in cervix, head and neck and lung cancer, but not in two other head and neck cancer reports. GLUT1 predicted for poor survival in colorectal, cervix and lung cancer. Conclusion: Endogenous markers have the potential to indicate therapeutically relevant levels of hypoxia within tumors. Clinical trials assessing a marker's ability to predict a

  6. Culture media from hypoxia conditioned endothelial cells protect human intestinal cells from hypoxia/reoxygenation injury.

    Science.gov (United States)

    Hummitzsch, Lars; Zitta, Karina; Bein, Berthold; Steinfath, Markus; Albrecht, Martin

    2014-03-10

    Remote ischemic preconditioning (RIPC) is a phenomenon, whereby short episodes of non-lethal ischemia to an organ or tissue exert protection against ischemia/reperfusion injury in a distant organ. However, there is still an apparent lack of knowledge concerning the RIPC-mediated mechanisms within the target organ and the released factors. Here we established a human cell culture model to investigate cellular and molecular effects of RIPC and to identify factors responsible for RIPC-mediated intestinal protection. Human umbilical vein cells (HUVEC) were exposed to repeated episodes of hypoxia (3 × 15 min) and conditioned culture media (CM) were collected after 24h. Human intestinal cells (CaCo-2) were cultured with or without CM and subjected to 90 min of hypoxia/reoxygenation injury. Reverse transcription-polymerase chain reaction, Western blotting, gelatin zymography, hydrogen peroxide measurements and lactate dehydrogenase (LDH) assays were performed. In HUVEC cultures hypoxic conditioning did not influence the profile of secreted proteins but led to an increased gelatinase activity (Pcultures 90 min of hypoxia/reoxygenation resulted in morphological signs of cell damage, increased LDH levels (Pculture model may help to unravel RIPC-mediated cellular events and to identify molecules released by RIPC. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Hypoxia-Inducible Factor 3 Is an Oxygen-Dependent Transcription Activator and Regulates a Distinct Transcriptional Response to Hypoxia

    Directory of Open Access Journals (Sweden)

    Peng Zhang

    2014-03-01

    Full Text Available Hypoxia-inducible factors (HIFs play key roles in the cellular response to hypoxia. It is widely accepted that whereas HIF-1 and HIF-2 function as transcriptional activators, HIF-3 inhibits HIF-1/2α action. Contrary to this idea, we show that zebrafish Hif-3α has strong transactivation activity. Hif-3α is degraded under normoxia. Mutation of P393, P493, and L503 inhibits this oxygen-dependent degradation. Transcriptomics and chromatin immunoprecipitation analyses identify genes that are regulated by Hif-3α, Hif-1α, or both. Under hypoxia or when overexpressed, Hif-3α binds to its target gene promoters and upregulates their expression. Dominant-negative inhibition and knockdown of Hif-3α abolish hypoxia-induced Hif-3α-promoter binding and gene expression. Hif-3α not only mediates hypoxia-induced growth and developmental retardation but also possesses hypoxia-independent activities. Importantly, transactivation activity is conserved and human HIF-3α upregulates similar genes in human cells. These findings suggest that Hif-3 is an oxygen-dependent transcription factor and activates a distinct transcriptional response to hypoxia.

  8. Melatonin Protects the Heart, Lungs and Kidneys from Oxidative Stress under Intermittent Hypobaric Hypoxia in Rats

    Directory of Open Access Journals (Sweden)

    Jorge G Farías

    2012-01-01

    Full Text Available Melatonin (N-acetyl-5-methoxytryptamine is the main secretory product of the pineal gland in all mammals including humans, but it is also produced in other organs. It has been previously demonstrated to be a powerful organ-protective substance under oxidative stress conditions. The aim of this study was to evaluate the protective effect of melatonin in several organs such as heart, lung, kidney, and of the reproductive system, such as testis and epididymis in animals exposed to intermittent hypobaric hypoxia and therefore exposed to oxidative stress and analyzed by lipid peroxidation. Ten-week-old male Wistar rats were divided into 6 groups for 96 hours during 32 days under: 1 Normobaric conditions, 2 plus physiologic solution, 3 plus melatonin, 4 intermittent hypobaric hypoxia, 5 plus physiologic solution and 6 plus melatonin. The animals were injected with melatonin (10 mg/kg body weight at an interval of 96 hours during 32 days. Results indicated that melatonin decreased lipid peroxidation in heart, kidneys and lung under intermittent hypobaric hypoxia conditions. However, it did not exhibit any protective effect in liver, testis, epididymis and sperm count.

  9. Hif1a inactivation rescues photoreceptor degeneration induced by a chronic hypoxia-like stress.

    Science.gov (United States)

    Barben, Maya; Ail, Divya; Storti, Federica; Klee, Katrin; Schori, Christian; Samardzija, Marijana; Michalakis, Stylianos; Biel, Martin; Meneau, Isabelle; Blaser, Frank; Barthelmes, Daniel; Grimm, Christian

    2018-04-17

    Reduced choroidal blood flow and tissue changes in the ageing human eye impair oxygen delivery to photoreceptors and the retinal pigment epithelium. As a consequence, mild but chronic hypoxia may develop and disturb cell metabolism, function and ultimately survival, potentially contributing to retinal pathologies such as age-related macular degeneration (AMD). Here, we show that several hypoxia-inducible genes were expressed at higher levels in the aged human retina suggesting increased activity of hypoxia-inducible transcription factors (HIFs) during the physiological ageing process. To model chronically elevated HIF activity and investigate ensuing consequences for photoreceptors, we generated mice lacking von Hippel Lindau (VHL) protein in rods. This activated HIF transcription factors and led to a slowly progressing retinal degeneration in the ageing mouse retina. Importantly, this process depended mainly on HIF1 with only a minor contribution of HIF2. A gene therapy approach using AAV-mediated RNA interference through an anti-Hif1a shRNA significantly mitigated the degeneration suggesting a potential intervention strategy that may be applicable to human patients.

  10. Glycobiology Modifications in Intratumoral Hypoxia: The Breathless Side of Glycans Interaction

    Directory of Open Access Journals (Sweden)

    Antônio F. Silva-filho

    2017-04-01

    Full Text Available Post-translational and co-translational enzymatic addition of glycans (glycosylation to proteins, lipids, and other carbohydrates, is a powerful regulator of the molecular machinery involved in cell cycle, adhesion, invasion, and signal transduction, and is usually seen in both in vivo and in vitro cancer models. Glycosyltransferases can alter the glycosylation pattern of normal cells, subsequently leading to the establishment and progression of several diseases, including cancer. Furthermore, a growing amount of research has shown that different oxygen tensions, mainly hypoxia, leads to a markedly altered glycosylation, resulting in altered glycan-receptor interactions. Alteration of intracellular glucose metabolism, from aerobic cellular respiration to anaerobic glycolysis, inhibition of integrin 3α1β translocation to the plasma membrane, decreased 1,2-fucosylation of cell-surface glycans, and galectin overexpression are some consequences of the hypoxic tumor microenvironment. Additionally, increased expression of gangliosides carrying N-glycolyl sialic acid can also be significantly affected by hypoxia. For all these reasons, it is possible to realize that hypoxia strongly alters glycobiologic events within tumors, leading to changes in their behavior. This review aims to analyze the complexity and importance of glycoconjugates and their molecular interaction network in the hypoxic context of many solid tumors.

  11. [18F]-FMISO PET study of hypoxia in gliomas before surgery: correlation with molecular markers of hypoxia and angiogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Bekaert, Lien [CHU de Caen, Department of Neurology, Caen (France); Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, Caen (France); CHU de Caen, Department of Neurosurgery, Caen (France); CHU de Caen, Service de Neurochirurgie, Caen (France); Valable, Samuel; Collet, Solene; Bordji, Karim; Petit, Edwige; Bernaudin, Myriam [Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, Caen (France); Lechapt-Zalcman, Emmanuele [Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, Caen (France); CHU de Caen, Department of Pathology, Caen (France); Ponte, Keven [CHU de Caen, Department of Neurosurgery, Caen (France); Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, Caen (France); Constans, Jean-Marc [Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, Caen (France); CHU de Caen, Department of Neuroradiology, Caen (France); Levallet, Guenaelle [CHU de Caen, Department of Pathology, Caen (France); Branger, Pierre [CHU de Caen, Department of Neurology, Caen (France); Emery, Evelyne [CHU de Caen, Department of Neurosurgery, Caen (France); Manrique, Alain [CHU de Caen, Department of Nuclear Medicine, Caen (France); Barre, Louisa [Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/LDM-TEP group, Caen (France); Guillamo, Jean-Sebastien [CHU de Caen, Department of Neurology, Caen (France); Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, Caen (France); CHU de Nimes, Department of Neurology, Nimes (France)

    2017-08-15

    Hypoxia in gliomas is associated with tumor resistance to radio- and chemotherapy. However, positron emission tomography (PET) imaging of hypoxia remains challenging, and the validation of biological markers is, therefore, of great importance. We investigated the relationship between uptake of the PET hypoxia tracer [18F]-FMISO and other markers of hypoxia and angiogenesis and with patient survival. In this prospective single center clinical study, 33 glioma patients (grade IV: n = 24, III: n = 3, and II: n = 6) underwent [18F]-FMISO PET and MRI including relative cerebral blood volume (rCBV) maps before surgery. Maximum standardized uptake values (SUVmax) and hypoxic volume were calculated, defining two groups of patients based on the presence or absence of [18F]-FMISO uptake. After surgery, molecular quantification of CAIX, VEGF, Ang2 (rt-qPCR), and HIF-1α (immunohistochemistry) were performed on tumor specimens. [18F]-FMISO PET uptake was closely linked to tumor grade, with high uptake in glioblastomas (GB, grade IV). Expression of biomarkers of hypoxia (CAIX, HIF-1α), and angiogenesis markers (VEGF, Ang2, rCBV) were significantly higher in the [18F]-FMISO uptake group. We found correlations between the degree of hypoxia (hypoxic volume and SUVmax) and expression of HIF-1α, CAIX, VEGF, Ang2, and rCBV (p < 0.01). Patients without [18F]-FMISO uptake had a longer survival time than uptake positive patients (log-rank, p < 0.005). Tumor hypoxia as evaluated by [18F]-FMISO PET is associated with the expression of hypoxia markers on a molecular level and is related to angiogenesis. [18F]-FMISO uptake is a mark of an aggressive tumor, almost always a glioblastoma. Our results underline that [18F]-FMISO PET could be useful to guide glioma treatment, and in particular radiotherapy, since hypoxia is a well-known factor of resistance. (orig.)

  12. SirT1 confers hypoxia-induced radioresistance via the modulation of c-Myc stabilization on hepatoma cells

    International Nuclear Information System (INIS)

    Xie Yuexia; Zhang Jianghong; Shao Chunlin; Xu Yanwu

    2012-01-01

    Intratumoral hypoxia is an important contributory factor to tumor cell resistance to radiotherapy. SirT1, a nicotinamide adenine dinucleotide (NAD + )-dependent histone/protein deacetylase, has been linked to the decrease of radiation-induced DNA damage and seems to be critical for cancer therapy. The purpose of this study was to investigate the role of SirT1 in hypoxia-induced radiation response on hepatoma cells. It was found that the administration with resveratrol, a putative SirT1 activator, enhanced the resistance of HepG2 cells against radiation-induced DNA damage of MN formation under hypoxia condition; while nicotinamide, a well-known SirT1 inhibitor, sensitized this radiation damage. Nevertheless, pretreatment of cells with 10058-F4, a specific inhibitor of c-Myc, almost eliminated the nicotinamide-induced radiosensitive effect. Further studies revealed that resveratrol inhibited c-Myc protein accumulation via up-regulation of SirT1 expression and deacetylase activity, and this loss of c-Myc protein was abolished by inhibiting its degradation in the presence of MG132, a potent inhibitor of proteasome. In contrast, nicotinamide attenuated c-Myc protein degradation induced by radiation under hypoxia through inhibition of SirT1 deacetylase activity. Our findings suggest that SirT1 could serve as a novel potent target of radiation-induced DNA damage and thus as a potential strategy to advance the efficiency of radiation therapy in hepatoma entities. (author)

  13. Hypoxia-inducible factor-2α-dependent hypoxic induction of Wnt10b expression in adipogenic cells.

    Science.gov (United States)

    Park, Young-Kwon; Park, Bongju; Lee, Seongyeol; Choi, Kang; Moon, Yunwon; Park, Hyunsung

    2013-09-06

    Adipocyte hyperplasia and hypertrophy in obesity can lead to many changes in adipose tissue, such as hypoxia, metabolic dysregulation, and enhanced secretion of cytokines. In this study, hypoxia increased the expression of Wnt10b in both human and mouse adipogenic cells, but not in hypoxia-inducible factor (HIF)-2α-deficient adipogenic cells. Chromatin immunoprecipitation analysis revealed that HIF-2α, but not HIF-1α, bound to the Wnt10b enhancer region as well as upstream of the Wnt1 gene, which is encoded by an antisense strand of the Wnt10b gene. Hypoxia-conditioned medium (H-CM) induced phosphorylation of lipoprotein-receptor-related protein 6 as well as β-catenin-dependent gene expression in normoxic cells, which suggests that H-CM contains canonical Wnt signals. Furthermore, adipogenesis of both human mesenchymal stem cells and mouse preadipocytes was inhibited by H-CM even under normoxic conditions. These results suggest that O2 concentration gradients influence the formation of Wnt ligand gradients, which are involved in the regulation of pluripotency, cell proliferation, and cell differentiation.

  14. Hypoxia-Inducible Factor 1 Is an Inductor of Transcription Factor Activating Protein 2 Epsilon Expression during Chondrogenic Differentiation

    Directory of Open Access Journals (Sweden)

    Stephan Niebler

    2015-01-01

    Full Text Available The transcription factor AP-2ε (activating enhancer-binding protein epsilon is expressed in cartilage of humans and mice. However, knowledge about regulatory mechanisms influencing AP-2ε expression is limited. Using quantitative real time PCR, we detected a significant increase in AP-2ε mRNA expression comparing initial and late stages of chondrogenic differentiation processes in vitro and in vivo. Interestingly, in these samples the expression pattern of the prominent hypoxia marker gene angiopoietin-like 4 (Angptl4 strongly correlated with that of AP-2ε suggesting that hypoxia might represent an external regulator of AP-2ε expression in mammals. In order to show this, experiments directly targeting the activity of hypoxia-inducible factor-1 (HIF1, the complex mediating responses to oxygen deprivation, were performed. While the HIF1-activating compounds 2,2′-dipyridyl and desferrioxamine resulted in significantly enhanced mRNA concentration of AP-2ε, siRNA against HIF1α led to a significantly reduced expression rate of AP-2ε. Additionally, we detected a significant upregulation of the AP-2ε mRNA level after oxygen deprivation. In sum, these different experimental approaches revealed a novel role for the HIF1 complex in the regulation of the AP-2ε gene in cartilaginous cells and underlined the important role of hypoxia as an important external regulatory stimulus during chondrogenic differentiation modulating the expression of downstream transcription factors.

  15. Neuroprotective Role of Intermittent Hypobaric Hypoxia in Unpredictable Chronic Mild Stress Induced Depression in Rats

    Science.gov (United States)

    Deep, Satayanarayan; Prasad, Dipti; Singh, Shashi Bala; Khan, Nilofar

    2016-01-01

    Hypoxic exposure results in several pathophysiological conditions associated with nervous system, these include acute and chronic mountain sickness, loss of memory, and high altitude cerebral edema. Previous reports have also suggested the role of hypoxia in pathogenesis of depression and related psychological conditions. On the other hand, sub lethal intermittent hypoxic exposure induces protection against future lethal hypoxia and may have beneficial effect. Therefore, the present study was designed to explore the neuroprotective role of intermittent hypobaric hypoxia (IHH) in Unpredictable Chronic Mild Stress (UCMS) induced depression like behaviour in rats. The IHH refers to the periodic exposures to hypoxic conditions interrupted by the normoxic or lesser hypoxic conditions. The current study examines the effect of IHH against UCMS induced depression, using elevated plus maze (EPM), open field test (OFT), force swim test (FST), as behavioural paradigm and related histological and molecular approaches. The data indicated the UCMS induced depression like behaviour as evident from decreased exploration activity in OFT with increased anxiety levels in EPM, and increased immobility time in the FST; whereas on providing the IHH (5000m altitude, 4hrs/day for two weeks) these behavioural changes were ameliorated. The morphological and molecular studies also validated the neuroprotective effect of IHH against UCMS induced neuronal loss and decreased neurogenesis. Here, we also explored the role of Brain-Derived Neurotrophic Factor (BDNF) in anticipatory action of IHH against detrimental effect of UCMS as upon blocking of BDNF-TrkB signalling the beneficial effect of IHH was nullified. Taken together, the findings of our study demonstrate that the intermittent hypoxia has a therapeutic potential similar to an antidepressant in animal model of depression and could be developed as a preventive therapeutic option against this pathophysiological state. PMID:26901349

  16. Neuroprotective Role of Intermittent Hypobaric Hypoxia in Unpredictable Chronic Mild Stress Induced Depression in Rats.

    Directory of Open Access Journals (Sweden)

    Neetu Kushwah

    Full Text Available Hypoxic exposure results in several pathophysiological conditions associated with nervous system, these include acute and chronic mountain sickness, loss of memory, and high altitude cerebral edema. Previous reports have also suggested the role of hypoxia in pathogenesis of depression and related psychological conditions. On the other hand, sub lethal intermittent hypoxic exposure induces protection against future lethal hypoxia and may have beneficial effect. Therefore, the present study was designed to explore the neuroprotective role of intermittent hypobaric hypoxia (IHH in Unpredictable Chronic Mild Stress (UCMS induced depression like behaviour in rats. The IHH refers to the periodic exposures to hypoxic conditions interrupted by the normoxic or lesser hypoxic conditions. The current study examines the effect of IHH against UCMS induced depression, using elevated plus maze (EPM, open field test (OFT, force swim test (FST, as behavioural paradigm and related histological and molecular approaches. The data indicated the UCMS induced depression like behaviour as evident from decreased exploration activity in OFT with increased anxiety levels in EPM, and increased immobility time in the FST; whereas on providing the IHH (5000m altitude, 4hrs/day for two weeks these behavioural changes were ameliorated. The morphological and molecular studies also validated the neuroprotective effect of IHH against UCMS induced neuronal loss and decreased neurogenesis. Here, we also explored the role of Brain-Derived Neurotrophic Factor (BDNF in anticipatory action of IHH against detrimental effect of UCMS as upon blocking of BDNF-TrkB signalling the beneficial effect of IHH was nullified. Taken together, the findings of our study demonstrate that the intermittent hypoxia has a therapeutic potential similar to an antidepressant in animal model of depression and could be developed as a preventive therapeutic option against this pathophysiological state.

  17. Neuroepithelial cells and the hypoxia emersion response in the amphibious fish Kryptolebias marmoratus.

    Science.gov (United States)

    Regan, Kelly S; Jonz, Michael G; Wright, Patricia A

    2011-08-01

    Teleost fish have oxygen-sensitive neuroepithelial cells (NECs) in the gills that appear to mediate physiological responses to hypoxia, but little is known about oxygen sensing in amphibious fish. The mangrove rivulus, Kryptolebias marmoratus, is an amphibious fish that respires via the gills and/or the skin. First, we hypothesized that both the skin and gills are sites of oxygen sensing in K. marmoratus. Serotonin-positive NECs were abundant in both gills and skin, as determined by immunohistochemical labelling and fluorescence microscopy. NECs retained synaptic vesicles and were found near nerve fibres labelled with the neuronal marker zn-12. Skin NECs were 42% larger than those of the gill, as estimated by measurement of projection area, and 45% greater in number. Moreover, for both skin and gill NECs, NEC area increased significantly (30-60%) following 7 days of exposure to hypoxia (1.5 mg l(-1) dissolved oxygen). Another population of cells containing vesicular acetylcholine transporter (VAChT) proteins were also observed in the skin and gills. The second hypothesis we tested was that K. marmoratus emerse in order to breathe air cutaneously when challenged with severe aquatic hypoxia, and this response will be modulated by neurochemicals associated chemoreceptor activity. Acute exposure to hypoxia induced fish to emerse at 0.2 mg l(-1). When K. marmoratus were pre-exposed to serotonin or acetylcholine, they emersed at a significantly higher concentration of oxygen than untreated fish. Pre-exposure to receptor antagonists (ketanserin and hexamethonium) predictably resulted in fish emersing at a lower concentration of oxygen. Taken together, these results suggest that oxygen sensing occurs at the branchial and/or cutaneous surfaces in K. marmoratus and that serotonin and acetylcholine mediate, in part, the emersion response.

  18. Hypobaric Hypoxia: Effects on Intraocular Pressure and Corneal Thickness

    Directory of Open Access Journals (Sweden)

    Marcella Nebbioso

    2014-01-01

    Full Text Available Objective. The purpose of this study focused on understanding the mechanisms underlying ocular hydrodynamics and the changes which occur in the eyes of subjects exposed to hypobaric hypoxia (HH to permit the achievement of more detailed knowledge in glaucomatous disease. Methods. Twenty male subjects, aged 32±5 years, attending the Italian Air Force, were enrolled for this study. The research derived from hypobaric chamber, using helmet and mask supplied to jet pilotes connected to oxygen cylinder and equipped with a preset automatic mixer. Results. The baseline values of intraocular pressure (IOP, recorded at T1, showed a mean of 16±2.23 mmHg, while climbing up to 18,000 feet the mean value was 13.7±4.17 mmHg, recorded at T2. The last assessment was performed returning to sea level (T4 where the mean IOP value was 12.8±2.57 mmHg, with a significant change (P<0.05 compared to T1. Pachymetry values related to corneal thickness in conditions of hypobarism revealed a statistically significant increase (P<0.05. Conclusions. The data collected in this research seem to confirm the increasing outflow of aqueous humor (AH in the trabecular meshwork (TM under conditions of HH.

  19. Heterogeneous Effects of Direct Hypoxia Pathway Activation in Kidney Cancer.

    Directory of Open Access Journals (Sweden)

    Rafik Salama

    Full Text Available General activation of hypoxia-inducible factor (HIF pathways is classically associated with adverse prognosis in cancer and has been proposed to contribute to oncogenic drive. In clear cell renal carcinoma (CCRC HIF pathways are upregulated by inactivation of the von-Hippel-Lindau tumor suppressor. However HIF-1α and HIF-2α have contrasting effects on experimental tumor progression. To better understand this paradox we examined pan-genomic patterns of HIF DNA binding and associated gene expression in response to manipulation of HIF-1α and HIF-2α and related the findings to CCRC prognosis. Our findings reveal distinct pan-genomic organization of canonical and non-canonical HIF isoform-specific DNA binding at thousands of sites. Overall associations were observed between HIF-1α-specific binding, and genes associated with favorable prognosis and between HIF-2α-specific binding and adverse prognosis. However within each isoform-specific set, individual gene associations were heterogeneous in sign and magnitude, suggesting that activation of each HIF-α isoform contributes a highly complex mix of pro- and anti-tumorigenic effects.

  20. A preclinical model for noninvasive imaging of hypoxia-induced gene expression; comparison with an exogenous marker of tumor hypoxia

    Energy Technology Data Exchange (ETDEWEB)

    Wen Bixiu; Burgman, Paul; Zanzonico, Pat; O' Donoghue, Joseph; Li, Gloria C.; Ling, C. Clifton [Memorial Sloan-Kettering Cancer Center, Department of Medical Physics, New York (United States); Cai Shangde; Finn, Ron [Memorial Sloan-Kettering Cancer Center, Department of Radiology, New York (United States); Serganova, Inna [Memorial Sloan-Kettering Cancer Center, Department of Neurology, New York (United States); Blasberg, Ronald; Gelovani, Juri [Memorial Sloan-Kettering Cancer Center, Department of Radiology, New York (United States); Memorial Sloan-Kettering Cancer Center, Department of Neurology, New York (United States)

    2004-11-01

    Hypoxia is associated with tumor aggressiveness and is an important cause of resistance to radiation therapy and chemotherapy. Assays of tumor hypoxia could provide selection tools for hypoxia-modifying treatments. The purpose of this study was to develop and characterize a rodent tumor model with a reporter gene construct that would be transactivated by the hypoxia-inducible molecular switch, i.e., the upregulation of HIF-1. The reporter gene construct is the herpes simplex virus 1-thymidine kinase (HSV1-tk) fused with the enhanced green fluorescent protein (eGFP) under the regulation of an artificial hypoxia-responsive enhancer/promoter. In this model, tumor hypoxia would up-regulate HIF-1, and through the hypoxia-responsive promoter transactivate the HSV1-tkeGFPfusion gene. The expression of this reporter gene can be assessed with the {sup 124}I-labeled reporter substrate 2'-fluoro-2'-deoxy-1-{beta}-d-arabinofuranosyl-5-iodouracil ({sup 124}I-FIAU), which is phosphorylated by the HSV1-tk enzyme and trapped in the hypoxic cells. Animal positron emission tomography (microPET) and phosphor plate imaging (PPI) were used in this study to visualize the trapped {sup 124}I-FIAU, providing a distribution of the hypoxia-induced molecular events. The distribution of {sup 124}I-FIAU was also compared with that of an exogenous hypoxic cell marker, {sup 18}F-fluoromisonidazole (FMISO). Our results showed that {sup 124}I-FIAU microPET imaging of the hypoxia-induced reporter gene expression is feasible, and that the intratumoral distributions of {sup 124}I-FIAU and {sup 18}F-FMISO are similar. In tumor sections, detailed radioactivity distributions were obtained with PPI which also showed similarity between {sup 124}I-FIAU and {sup 18}F-FMISO. This reporter system is sufficiently sensitive to detect hypoxia-induced transcriptional activation by noninvasive imaging and might provide a valuable tool in studying tumor hypoxia and in validating existing and future

  1. Hypoxia and bicarbonate could limit the expression of iron acquisition genes in Strategy I plants by affecting ethylene synthesis and signaling in different ways.

    Science.gov (United States)

    García, María J; García-Mateo, María J; Lucena, Carlos; Romera, Francisco J; Rojas, Carmen L; Alcántara, Esteban; Pérez-Vicente, Rafael

    2014-01-01

    In a previous work, it was shown that bicarbonate (one of the most important factors causing Fe chlorosis in Strategy I plants) can limit the expression of several genes involved in Fe acquisition. Hypoxia is considered another important factor causing Fe chlorosis, mainly on calcareous soils. However, to date it is not known whether hypoxia aggravates Fe chlorosis by affecting bicarbonate concentration or by specific negative effects on Fe acquisition. Results found in this work show that hypoxia, generated by eliminating the aeration of the nutrient solution, can limit the expression of several Fe acquisition genes in Fe-deficient Arabidopsis, cucumber and pea plants, like the genes for ferric reductases AtFRO2, PsFRO1 and CsFRO1; iron transporters AtIRT1, PsRIT1 and CsIRT1; H(+) -ATPase CsHA1; and transcription factors AtFIT, AtbHLH38, and AtbHLH39. Interestingly, the limitation of the expression of Fe-acquisition genes by hypoxia did not occur in the Arabidopsis ethylene constitutive mutant ctr1, which suggests that the negative effect of hypoxia is related to ethylene, an hormone involved in the upregulation of Fe acquisition genes. As for hypoxia, results obtained by applying bicarbonate to the nutrient solution suggests that ethylene is also involved in its negative effect, since ACC (1-aminocyclopropane-1-carboxylic acid; ethylene precursor) partially reversed the negative effect of bicarbonate on the expression of Fe acquisition genes. Taken together, the results obtained show that hypoxia and bicarbonate could induce Fe chlorosis by limiting the expression of Fe acquisition genes, probably because each factor negatively affects different steps of ethylene synthesis and/or signaling. © 2013 Scandinavian Plant Physiology Society.

  2. The role of wind field induced flow velocities in destratification and hypoxia reduction at Meiling Bay of large shallow Lake Taihu, China.

    Science.gov (United States)

    Jalil, Abdul; Li, Yiping; Du, Wei; Wang, Wencai; Wang, Jianwei; Gao, Xiaomeng; Khan, Hafiz Osama Sarwar; Pan, Baozhu; Acharya, Kumud

    2018-01-01

    Wind induced flow velocity patterns and associated thermal destratification can drive to hypoxia reduction in large shallow lakes. The effects of wind induced hydrodynamic changes on destratification and hypoxia reduction were investigated at the Meiling bay (N 31° 22' 56.4″, E 120° 9' 38.3″) of Lake Taihu, China. Vertical flow velocity profile analysis showed surface flow velocities consistency with the wind field and lower flow velocity profiles were also consistent (but with delay response time) when the wind speed was higher than 6.2 m/s. Wind field and temperature found the control parameters for hypoxia reduction and for water quality conditions at the surface and bottom profiles of lake. The critical temperature for hypoxia reduction at the surface and the bottom profile was ≤24.1C° (below which hypoxic conditions were found reduced). Strong prevailing wind field (onshore wind directions ESE, SE, SSE and E, wind speed ranges of 2.4-9.1 m/s) reduced the temperature (22C° to 24.1C°) caused reduction of hypoxia at the near surface with a rise in water levels whereas, low to medium prevailing wind field did not supported destratification which increased temperature resulting in increased hypoxia. Non-prevailing wind directions (offshore) were not found supportive for the reduction of hypoxia in study area due to less variable wind field. Daytime wind field found more variable (as compared to night time) which increased the thermal destratification during daytime and found supportive for destratification and hypoxia reduction. The second order exponential correlation found between surface temperature and Chlorophyll-a (R 2 : 0.2858, Adjusted R-square: 0.2144 RMSE: 4.395), Dissolved Oxygen (R 2 : 0.596, Adjusted R-square: 0.5942, RMSE: 0.3042) concentrations. The findings of the present study reveal the driving mechanism of wind induced thermal destratification and hypoxic conditions, which may further help to evaluate the wind role in eutrophication

  3. In vivo evidence suggesting reciprocal renal hypoxia-inducible factor-1 upregulation and signal transducer and activator of transcription 3 activation in response to hypoxic and non-hypoxic stimuli.

    Science.gov (United States)

    Nechemia-Arbely, Yael; Khamaisi, Mogher; Rosenberger, Christian; Koesters, Robert; Shina, Ahuva; Geva, Carmit; Shriki, Anat; Klaus, Stephen; Rosen, Seymour; Rose-John, Stefan; Galun, Eithan; Axelrod, Jonathan H; Heyman, Samuel N

    2013-04-01

    In vitro studies suggest that combined activation of hypoxia-inducible factor (HIF) and signal transducer and activator of transcription 3 (STAT3) promotes the hypoxia response. However, their interrelationship in vivo remains poorly defined. The present study investigated the possible relationship between HIF-1 upregulation and STAT3 activation in the rodent kidney in vivo. Activation of HIF-1 and STAT3 was analysed by immunohistochemical staining and western blot analysis in: (i) models of hypoxia-associated kidney injury induced by radiocontrast media or rhabdomyolysis; (ii) following activation of STAT3 by the interleukin (IL)-6-soluble IL-6 receptor complex; or (iii) following HIF-1α stabilization using hypoxic and non-hypoxic stimuli (mimosine, FG-4497, CO, CoCl(2)) and in targeted von Hippel-Lindau-knockout mice. Western blot analysis and immunostaining revealed marked induction of both transcription factors under all conditions tested, suggesting that in vivo STAT3 can trigger HIF and vice versa. Colocalization of HIF-1α and phosphorylated STAT3 was detected in some, but not all, renal cell types, suggesting that in some cells a paracrine mechanism may be responsible for the reciprocal activation of the two transcription factors. Nevertheless, in several cell types spatial concordance was observed under the majority of conditions tested, suggesting that HIF-1 and STAT3 may act as cotranscription factors. These in vivo studies suggest that, in response to renal hypoxic-stress, upregulation of HIF-1 and activation of STAT3 may be both reciprocal and cell type dependent. © 2013 The Authors Clinical and Experimental Pharmacology and Physiology © 2013 Wiley Publishing Asia Pty Ltd.

  4. 2011 Summer Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  5. 2008 Summer Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  6. Radioprotective effect of exogenic hypoxia in fractionated irradiation

    International Nuclear Information System (INIS)

    Kazymbetov, P.; Yarmonenko, S.P.; Vajnson, A.A.

    1988-01-01

    During the experiments with mice it is established, that exogenic hypoxia protective effect (8%O 2 ), evaluated according to survival rate, decreases at the change from single to fractionated irradiation. Dose change factor (DCF) is equal to 1.55 and 1.22-1.31, respectively. Skin protection using exogenic hypoxia at the local fractionated irradiation is expressed more, than at the fractionated one. DCF is equal to 1.56 and 1.28, respectively. Exogenic hypoxia protection effect in the tumor is expressed rather weakly. DCF at single and fractionated irradiation constitutes 1.03 and 1.07-1.13, respectively. Due to skin preferential protection the therapeutic gain factor at irradiation under the exogenic hypoxia conditions constitutes 1.24 and 1.38-1.46, respectively, at single and fractionated irradiation

  7. 2013 Summer Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  8. Exercise performed at hypoxia influences mood state and anxiety symptoms

    Directory of Open Access Journals (Sweden)

    Jorge Fernando Tavares de Souza

    2015-06-01

    Full Text Available During hypoxia conditions, psychological states can be worsened. However, little information is available regarding the effect of physical exercise performed in hypoxia conditions on mood state and anxiety symptoms. The aim of the present study was to elucidate the acute effect of moderate physical exercise performed at hypoxia on mood states and anxiety symptoms in healthy young subjects. Ten volunteers were subjected to the following conditions: a normoxic condition (NC and a hypoxic condition (HC. They performed 45 min of physical exercise. Their anxiety symptoms and mood states were evaluated at the initial time point as well as immediately following and 30 and 60 min after the exercise session. Our results showed a significant increase in post-exercise anxiety symptoms and a significant decrease in mood scores immediately after and 30 min after exercise performed in the HC. Moderate physical activity performed at hypoxia condition increased post-exercise anxiety and worsened mood state.

  9. Hypoxia promotes tumor growth in linking angiogenesis to immune escape

    Directory of Open Access Journals (Sweden)

    Salem eCHOUAIB

    2012-02-01

    Full Text Available Despite the impressive progress over the past decade, in the field of tumor immunology, such as the identification of tumor antigens and antigenic peptides as potential targets, there are still many obstacles in eliciting an effective immune response to eradicate cancer. It has become increasingly clear that tumor microenvironment plays a crucial role in the control of immune protection and contains many overlapping mechanisms to evade antigen specific immunotherapy. Obviously, tumors have evolved to utilize hypoxic stress to their own advantage by activating key biochemical and cellular pathways that are important in progression, survival and metastasis. Among the hypoxia-induced genes, hypoxia-inducible factor (HIF-1 and vascular endothelial growth factor (VEGF play a determinant role in promoting tumor cell growth and survival. In this regard, hypoxia is emerging as an attractive target for cancer therapy. How the microenvironmental hypoxia poses both obstacles and opportunities for new therapeutic immune interventions will be discussed.

  10. Elevation of hypoxia resistance with the use of gutimine

    Energy Technology Data Exchange (ETDEWEB)

    Vinogradov, V.M.; Pastushenkov, L.V.; Sumina, E.N.

    Experimental data demonstrating the protection from the adverse effects of hypoxia offered by the antioxidant gutimine and its analogs are presented. The experiments included preliminary studies of hypoxia resistance and recovery under simulated altitude, studies of circulatory hypoxia in the brain and in intrauterine fetuses, studies of myocardial ischemia during acute and chronic experiments and studies where cardiac, kidney and limb circulation is cut off. The compound was also found to be effective in cases of hemorrhagic hypotension, complex hypoxia in peritonitis, meningococcal meningitis, and the weakening of uterine muscle contractility during prolonged deliveries, and in cranial-cerebral trauma. Mechanisms of the antihypoxic action of gutimine and its analogs have been found to include the reduction of oxygen utilization, the activation of aerobic and anaerobic metabolism, the acceleration of lactate utilization, the inhibition of lipolysis in fat tissue, and stabilization of cell membranes. Clinical observations also support the experimental data.

  11. Qidantongmai Protects Endothelial Cells Against Hypoxia-Induced ...

    African Journals Online (AJOL)

    induced damage. The ability of QDTM to modulate the serum VEGF-A level may play an important role in its effects on endothelial cells. Key words: Traditional Chinese Medicine, human umbilical vein endothelial cells, hypoxia, VEGF ...

  12. 2015 Summer Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  13. 2012 Summer Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  14. 2009 Summer Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  15. Short-term hypoxia/reoxygenation activates the angiogenic pathway ...

    Indian Academy of Sciences (India)

    2013-04-20

    Apr 20, 2013 ... angiogenic pathway in the rat caudate putamen as a neuroprotective mechanism to hypoxia .... (1:3 w/v) with a homogenator (Pellet Pestle Motor Cordless, ..... showing that the capillary density in the rat cerebral cortex was.

  16. 2010 Summer Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  17. Study on the effect of hypoxia on apoptosis of cultured newly born rat cardiac myocytes

    International Nuclear Information System (INIS)

    Su Weidong; Li Huiqiang; Yao Zhi

    2005-01-01

    Objective: To investigate the possible hypoxia-mediated cellular apoptosis after ischemic cardiac injury via a model of cultured newly born rat cardiac myocytes. Methods: Cardiac myocytes cultures from newly born rats (1-3d) were examined for apoptosis with HE stain and flow cytometry after cultured 96h and again examined after exposure to hypoxic environment for 16h. Results: Apoptotic changes were evident in the hypoxic culture cells. The HE stain revealed cellular shrinkage, nuclear chromosomal condensation with cytoplasmic eosinophilia. Also, distinct apoptosis peak was observed in the flow cytometry. Conclusion: This experiment proved that hypoxic model of cardiac myocyte culture showed definite apoptosis of the cells. (authors)

  18. Hypoxia and Its Acid-Base Consequences: From Mountains to Malignancy.

    Science.gov (United States)

    Swenson, Erik R

    Hypoxia, depending upon its magnitude and circumstances, evokes a spectrum of mild to severe acid-base changes ranging from alkalosis to acidosis, which can alter many responses to hypoxia at both non-genomic and genomic levels, in part via altered hypoxia-inducible factor (HIF) metabolism. Healthy people at high altitude and persons hyperventilating to non-hypoxic stimuli can become alkalotic and alkalemic with arterial pH acutely rising as high as 7.7. Hypoxia-mediated respiratory alkalosis reduces sympathetic tone, blunts hypoxic pulmonary vasoconstriction and hypoxic cerebral vasodilation, and increases hemoglobin oxygen affinity. These effects and others can be salutary or counterproductive to tissue oxygen delivery and utilization, based upon magnitude of each effect and summation. With severe hypoxia either in the setting of profound arterial hemoglobin desaturation and reduced O2 content or poor perfusion (ischemia) at the global or local level, metabolic and hypercapnic acidosis develop along with considerable lactate formation and pH falling to below 6.8. Although conventionally considered to be injurious and deleterious to cell function and survival, both acidoses may be cytoprotective by various anti-inflammatory, antioxidant, and anti-apoptotic mechanisms which limit total hypoxic or ischemic-reperfusion injury. Attempts to correct acidosis by giving bicarbonate or other alkaline agents under these circumstances ahead of or concurrent with reoxygenation efforts may be ill advised. Better understanding of this so-called "pH paradox" or permissive acidosis may offer therapeutic possibilities. Rapidly growing cancers often outstrip their vascular supply compromising both oxygen and nutrient delivery and metabolic waste disposal, thus limiting their growth and metastatic potential. However, their excessive glycolysis and lactate formation may not necessarily represent oxygen insufficiency, but rather the Warburg effect-an attempt to provide a large amount

  19. Management of renal dysfunction following term perinatal hypoxia-ischaemia.

    LENUS (Irish Health Repository)

    Sweetman, Deirdre U

    2013-03-01

    Acute kidney injury frequently develops following the term perinatal hypoxia-ischaemia. Quantifying the degree of acute kidney injury is difficult, however, as the methods currently in use are suboptimal. Acute kidney injury management is largely supportive with little evidence basis for many interventions. This review discusses management strategies and novel biomarkers that may improve diagnosis and management of renal injury following perinatal hypoxia-ischaemia.

  20. Upregulated copper transporters in hypoxia-induced pulmonary hypertension.

    Directory of Open Access Journals (Sweden)

    Adriana M Zimnicka

    Full Text Available Pulmonary vascular remodeling and increased arterial wall stiffness are two major causes for the elevated pulmonary vascular resistance and pulmonary arterial pressure in patients and animals with pulmonary hypertension. Cellular copper (Cu plays an important role in angiogenesis and extracellular matrix remodeling; increased Cu in vascular smooth muscle cells has been demonstrated to be associated with atherosclerosis and hypertension in animal experiments. In this study, we show that the Cu-uptake transporter 1, CTR1, and the Cu-efflux pump, ATP7A, were both upregulated in the lung tissues and pulmonary arteries of mice with hypoxia-induced pulmonary hypertension. Hypoxia also significantly increased expression and activity of lysyl oxidase (LOX, a Cu-dependent enzyme that causes crosslinks of collagen and elastin in the extracellular matrix. In vitro experiments show that exposure to hypoxia or treatment with cobalt (CoCl2 also increased protein expression of CTR1, ATP7A, and LOX in pulmonary arterial smooth muscle cells (PASMC. In PASMC exposed to hypoxia or treated with CoCl2, we also confirmed that the Cu transport is increased using 64Cu uptake assays. Furthermore, hypoxia increased both cell migration and proliferation in a Cu-dependent manner. Downregulation of hypoxia-inducible factor 1α (HIF-1α with siRNA significantly attenuated hypoxia-mediated upregulation of CTR1 mRNA. In summary, the data from this study indicate that increased Cu transportation due to upregulated CTR1 and ATP7A in pulmonary arteries and PASMC contributes to the development of hypoxia-induced pulmonary hypertension. The increased Cu uptake and elevated ATP7A also facilitate the increase in LOX activity and thus the increase in crosslink of extracellular matrix, and eventually leading to the increase in pulmonary arterial stiffness.

  1. Improved severe hepatopulmonary syndrome after liver transplantation in an adolescent with end-stage liver disease secondary to biliary atresia

    Directory of Open Access Journals (Sweden)

    Tae Jun Park

    2014-03-01

    Full Text Available Hepatopulmonary syndrome (HPS is a serious complication of end-stage liver disease, which is characterized by hypoxia, intrapulmonary vascular dilatation, and liver cirrhosis. Liver transplantation (LT is the only curative treatment modality for patients with HPS. However, morbidity and mortality after LT, especially in cases of severe HPS, remain high. This case report describes a patient with typical findings of an extracardiac pulmonary arteriovenous shunt on contrast-enhanced transesophageal echocardiography (TEE, and clubbing fingers, who had complete correction of HPS by deceased donor LT. The patient was a 16-year-old female who was born with biliary atresia and underwent porto-enterostomy on the 55th day after birth. She had been suffered from progressive liver failure with dyspnea, clubbing fingers, and cyanosis. Preoperative arterial blood gas analysis revealed severe hypoxia (arterial O2 tension of 54.5 mmHg and O2 saturation of 84.2%. Contrast-enhanced TEE revealed an extracardiac right-to-left shunt, which suggested an intrapulmonary arteriovenous shunt. The patient recovered successfully after LT, not only with respect to physical parameters but also for pychosocial activity, including school performance, during the 30-month follow-up period.

  2. The zebrafish miR-462/miR-731 cluster is induced under hypoxic stress via hypoxia-inducible factor 1α and functions in cellular adaptations.

    Science.gov (United States)

    Huang, Chun-Xiao; Chen, Nan; Wu, Xin-Jie; Huang, Cui-Hong; He, Yan; Tang, Rong; Wang, Wei-Min; Wang, Huan-Ling

    2015-12-01

    Hypoxia, a unique and essential environmental stress, evokes highly coordinated cellular responses, and hypoxia-inducible factor (HIF) 1 in the hypoxia signaling pathway, an evolutionarily conserved cellular signaling pathway, acts as a master regulator of the transcriptional response to hypoxic stress. MicroRNAs (miRNAs), a major class of posttranscriptional gene expression regulators, also play pivotal roles in orchestrating hypoxia-mediated cellular adaptations. Here, global miRNA expression profiling and quantitative real-time PCR indicated that the up-regulation of the miR-462/miR-731 cluster in zebrafish larvae is induced by hypoxia. It was further validated that miR-462 and miR-731 are up-regulated in a Hif-1α-mediated manner under hypoxia and specifically target ddx5 and ppm1da, respectively. Overexpression of miR-462 and miR-731 represses cell proliferation through blocking cell cycle progress of DNA replication, and induces apoptosis. In situ detection revealed that the miR-462/miR-731 cluster is highly expressed in a consistent and ubiquitous manner throughout the early developmental stages. Additionally, the transcripts become restricted to the notochord, pharyngeal arch, liver, and gut regions from postfertilization d 3 to 5. These data highlight a previously unidentified role of the miR-462/miR-731 cluster as a crucial signaling mediator for hypoxia-mediated cellular adaptations and provide some insights into the potential function of the cluster during embryonic development. © FASEB.

  3. Oroxylin A regulates glucose metabolism in response to hypoxic stress with the involvement of Hypoxia-inducible factor-1 in human hepatoma HepG2 cells.

    Science.gov (United States)

    Dai, Qinsheng; Yin, Qian; Wei, Libin; Zhou, Yuxin; Qiao, Chen; Guo, Yongjian; Wang, Xiaotang; Ma, Shiping; Lu, Na

    2016-08-01

    Metabolic alteration in cancer cells is one of the most conspicuous characteristics that distinguish cancer cells from normal cells. In this study, we investigated the influence and signaling ways of oroxylin A affecting cancer cell energy metabolism under hypoxia. The data showed that oroxylin A remarkably reduced the generation of lactate and glucose uptake under hypoxia in HepG2 cells. Moreover, oroxylin A inhibited HIF-1α expression and its stability. The downstream targets (PDK1, LDHA, and HK II), as well as their mRNA levels were also suppressed by oroxylin A under hypoxia. The silencing or the overexpression of HIF-1α assays suggested that HIF-1α is required for metabolic effect of oroxylin A in HepG2 cells during hypoxia. Furthermore, oroxylin A could reduce the expression of complex III in mitochondrial respiratory chain, and then decrease the accumulation of ROS at moderate concentrations (0-50 µM) under hypoxia, which was benefit for its inhibition on glycolytic activity by decreasing ROS-mediated HIF-1 expression. Besides, oroxylin A didn't cause the loss of MMP under hypoxia and had no obvious effects on the expression of OXPHOS complexes, suggesting that oroxylin A did not affect mitochondrial mass at the moderate stress of oroxylin A. The suppressive effect of oroxylin A on glycolysis led to a significantly repress of ATP generation, for ATP generation mostly depends on glycolysis in HepG2 cells. This study revealed a new aspect of glucose metabolism regulation of oroxylin A under hypoxia, which may contribute to its new anticancer mechanism. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

  4. Hypoxia-induced DNA hypermethylation in human pulmonary fibroblasts is associated with Thy-1 promoter methylation and the development of a pro-fibrotic phenotype

    Directory of Open Access Journals (Sweden)

    Robinson Claire M

    2012-08-01

    Full Text Available Abstract Background Pulmonary fibrosis is a debilitating and lethal disease with no effective treatment options. Understanding the pathological processes at play will direct the application of novel therapeutic avenues. Hypoxia has been implicated in the pathogenesis of pulmonary fibrosis yet the precise mechanism by which it contributes to disease progression remains to be fully elucidated. It has been shown that chronic hypoxia can alter DNA methylation patterns in tumour-derived cell lines. This epigenetic alteration can induce changes in cellular phenotype with promoter methylation being associated with gene silencing. Of particular relevance to idiopathic pulmonary fibrosis (IPF is the observation that Thy-1 promoter methylation is associated with a myofibroblast phenotype where loss of Thy-1 occurs alongside increased alpha smooth muscle actin (α-SMA expression. The initial aim of this study was to determine whether hypoxia regulates DNA methylation in normal human lung fibroblasts (CCD19Lu. As it has been reported that hypoxia suppresses Thy-1 expression during lung development we also studied the effect of hypoxia on Thy-1 promoter methylation and gene expression. Methods CCD19Lu were grown for up to 8 days in hypoxia and assessed for global changes in DNA methylation using flow cytometry. Real-time PCR was used to quantify expression of Thy-1, α-SMA, collagen I and III. Genomic DNA was bisulphite treated and methylation specific PCR (MSPCR was used to examine the methylation status of the Thy-1 promoter. Results Significant global hypermethylation was detected in hypoxic fibroblasts relative to normoxic controls and was accompanied by increased expression of myofibroblast markers. Thy-1 mRNA expression was suppressed in hypoxic cells, which was restored with the demethylating agent 5-aza-2′-deoxycytidine. MSPCR revealed that Thy-1 became methylated following fibroblast exposure to 1% O2. Conclusion These data suggest that global and

  5. Rapid dual-tracer PTSM+ATSM PET imaging of tumour blood flow and hypoxia: a simulation study

    International Nuclear Information System (INIS)

    Rust, T C; Kadrmas, D J

    2006-01-01

    Blood flow and hypoxia are interrelated aspects of physiology that affect cancer treatment and response. Cu-PTSM and Cu-ATSM are related PET tracers for blood flow and hypoxia, and the ability to rapidly image both tracers in a single scan would bring several advantages over conventional single-tracer techniqu